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Xu H, Dong P, Wang H, Sin I, Kang CS, Ren S, Sun X, Chong HS. Synthesis and evaluation of a novel bifunctional ligand 3o-C-NETA for Yttrium-90 and Lutetium-177. Bioorg Med Chem Lett 2025; 120:130136. [PMID: 39947352 DOI: 10.1016/j.bmcl.2025.130136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/23/2025] [Accepted: 02/09/2025] [Indexed: 02/28/2025]
Abstract
A bifunctional ligand is an essential component for targeted cancer therapy using cytotoxic radionuclides. We report the synthesis and evaluation of a novel bifunctional ligand, 3o-C-NETA, designed for labeling a bioactive small molecule or an antibody with β-particle emitting radionuclides 90Y and 177Lu. 3o-C-NETA is an octadentate chelating agent and contains both a macrocyclic backbone (1,4,7-triazacyclononane, TACN) and pendant donor groups. 3o-C-NETA was efficiently synthesized via the regiospecific ring opening of a functionalized aziridinium ion with tert-Butyl protected NODA (1,4,7-triazacyclononane-1,4-diacetic acid) and evaluated for radiolabeling kinetics and in vitro complex stability with 90Y and 177Lu. The new bifunctional ligand (3o-C-NETA) rapidly bound to 90Y or 177Lu, and the corresponding 90Y- or 177Lu-labeled 3o-C-NETA remained stable in human serum for two weeks.
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Affiliation(s)
- Hua Xu
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States
| | - Pengfei Dong
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States
| | - Haixing Wang
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States
| | - Inseok Sin
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States
| | - Chi Soo Kang
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States
| | - Siyuan Ren
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States
| | - Xiang Sun
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States
| | - Hyun-Soon Chong
- Department of Chemistry, Lewis College of Science and Letters, Illinois Institute of Technology, Chicago, IL, United States.
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Goto H, Shiraishi Y, Okada S. Continuing progress in radioimmunotherapy for hematologic malignancies. Blood Rev 2025; 69:101250. [PMID: 39609167 DOI: 10.1016/j.blre.2024.101250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/23/2024] [Accepted: 11/14/2024] [Indexed: 11/30/2024]
Abstract
Radioimmunotherapy (RIT) involves combining a cytotoxic radionuclide with an antibody (Ab) targeting a tumor antigen. Compared with conventional therapies, RIT improves the therapeutic efficacy of Ab and ameliorates toxicity. This comprehensive review describes the current advancements and future prospects in RIT for treating hematologic malignancies based on recent investigations. Although β-particle RITs targeting CD20 are effective with low toxicity in patients with relapsed/refractory indolent or transformed non-Hodgkin's lymphoma, these treatments have not gained popularity because of the increasing availability of new therapies. RIT using single-domain antibodies is expected to improve tumor penetrance and reduce radiation exposure to non-target organs. To enhance RIT efficacy, α-particle RIT and pretargeted radioimmunotherapy (PRIT) are currently being developed. Alpha-particle RIT demonstrates substantial antitumor activity and reduced bystander effects due to its high linear energy transfer and short particle range. PRIT may increase the tumor-to-whole body dose ratio.
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Affiliation(s)
- Hiroki Goto
- Division of Radioisotope and Tumor Pathobiology, Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
| | - Yoshioki Shiraishi
- Radioisotope Center, Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
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Edamadaka Y, Parghane RV, Sahu S, Lad S, Kamaldeep, Wanage G, Shanmukhaiah C, Kulkarni V, Basu S. Internal dosimetry and biodistribution of indigenously prepared 177 Lu-DOTA-rituximab in lymphoma and other hematological malignancies treated with rituximab. Nucl Med Commun 2024; 45:823-834. [PMID: 38975801 DOI: 10.1097/mnm.0000000000001875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/09/2024]
Abstract
OBJECTIVE The aim of this study was to evaluate the biodistribution and dosimetry of lutetium-177-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ( 177 Lu-DOTA)-rituximab in CD20 + non-Hodgkin's lymphoma and other hematological malignancies treated with rituximab. METHODS The standard dosimetry protocol was used, with cold rituximab infusion, then a diagnostic activity of 177 Lu-DOTA-rituximab. Planar images were acquired at multiple time points. Normal organs and tumor dosimetry were performed by using organ and tumor-specific regions of interest and whole-body counts were obtained serially after pixel matched, background, scatter, and attenuation correction. The mean radiation absorbed doses were obtained from OLINDA/EXM v2.1.1 and ORIGIN software. RESULTS A total of 22 patients were included in this study. Prolonged blood pool clearance of 177 Lu-DOTA-rituximab with long residence time in the blood pool and normal organs were observed. The whole body effective half-life was 104.5 ± 22 h. The mean total body radiation absorbed dose was 0.208 ± 0.03 mGy/MBq and the mean total body effective dose was 0.196 ± 0.05 mGy/MBq of 177 Lu-DOTA-rituximab. The mean radiation absorbed doses of 0.613 ± 0.21, 1.68 ± 2, 1.01 ± 0.42, and 0.136 ± 0.02mGy/MBq were seen for the liver, spleen, kidneys, and bone marrow, respectively. Tumor lesion uptake was noticed in two patients with tumor radiation absorbed doses were 0.842 mGy/MBq in one and 9.9 mGy/MBq in the other patient. A strong correlation was obtained between the cumulative activities of radiation-absorbed doses derived from ORIGIN and OLINDA software methods at a significant P value less than 0.001. CONCLUSION The results of our study demonstrated favorable biodistribution and dosimetry of indigenously produced 177 Lu-DOTA-rituximab in patients with CD20 + lymphoma. These results can be used for future studies of radioimmunotherapy employing 177 Lu-DOTA-rituximab.
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Affiliation(s)
- Yeshwanth Edamadaka
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe,
- Homi Bhabha National Institute,
| | - Rahul V Parghane
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe,
- Homi Bhabha National Institute,
| | - Sudeep Sahu
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe,
| | - Sangita Lad
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe,
| | - Kamaldeep
- Homi Bhabha National Institute,
- Health Physics Division, Bhabha Atomic Research Centre,
| | - Gaurav Wanage
- Homi Bhabha National Institute,
- Health Physics Division, Bhabha Atomic Research Centre,
| | | | - Vrinda Kulkarni
- Department of Hematology, TN Medical College and BYL Nair Hospital, Mumbai, Maharashtra, India
| | - Sandip Basu
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre Annexe,
- Homi Bhabha National Institute,
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Lee KK, Chakraborty M, Hu A, Kanagasundaram T, Thorek DLJ, Wilson JJ. Chelation of [ 111In]In 3+ with the dual-size-selective macrocycles py-macrodipa and py 2-macrodipa. Dalton Trans 2024; 53:14634-14647. [PMID: 39163366 PMCID: PMC11663299 DOI: 10.1039/d4dt02146k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
Indium-111 (111In) is a diagnostic radiometal that is important in nuclear medicine for single-photon emission computed tomography (SPECT). In order to apply this radiometal, it needs to be stably chelated and conjugated to a targeting vector that delivers it to diseased tissue. Identifying effective chelators that are capable of binding and retaining [111In]In3+in vivo is an important research area. In this study, two 18-membered macrocyclic chelators, py-macrodipa and py2-macrodipa, were investigated for their ability to form stable coordination complexes with In3+ and to be effectively radiolabeled with [111In]In3+. The In3+ complexes of these two chelators were characterized by NMR spectroscopy, X-ray crystallography, and density functional theory calculations. These studies show that both py-macrodipa and py2-macrodipa form 8-coordinate In3+ complexes and attain an asymmetric conformation, consistent with prior studies on this ligand class with small rare earth metal ions. Spectrophotometric titrations were carried out to determine the thermodynamic stability constants (log KML) of [In(py-macrodipa)]+ and [In(py2-macrodipa)]+, which were found to be 18.96(6) and 19.53(5), respectively, where the values in parentheses are the errors of the last significant figures obtained from the standard deviation from three independent replicates. Radiolabeling studies showed that py-macrodipa and py2-macrodipa can quantitatively be radiolabeled with [111In]In3+ at 25 °C within 5 min, even at ligand concentrations as low as 1 μM. The in vitro stability of the radiolabeled complexes was investigated in human serum at 37 °C, revealing that ∼90% of [111In][In(py-macrodipa)]+ and [111In][In(py2-macrodipa)]+ remained intact after 7 days. The biodistribution of these radiolabeled complexes in mice was investigated, showing lower uptake in the kidneys, liver, and blood at the 24 h mark compared to [111In]InCl3. These results demonstrate the potential of py-macrodipa and py2-macrodipa as chelators for [111In]In3+, suggesting their value for SPECT radiopharmaceuticals.
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Affiliation(s)
- Kevin K Lee
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
| | - Mou Chakraborty
- Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA
- Program in Quantitative Molecular Therapeutics, Washington University School of Medicine, St. Louis, Missouri, 63110, USA
| | - Aohan Hu
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
| | - Thines Kanagasundaram
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
| | - Daniel L J Thorek
- Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA
- Program in Quantitative Molecular Therapeutics, Washington University School of Medicine, St. Louis, Missouri, 63110, USA
- Department of Biomedical Engineering, Washington University, St. Louis, Missouri, 63110, USA
| | - Justin J Wilson
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
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Rice SL, Muñoz FG, Benjamin J, Alnablsi MW, Pillai A, Osborne JR, Beets-Tan R. Transcatheter pseudo-vascular isolation for localization and concentration of a large molecule theranostic probe into a transgenic OncoPIG kidney tumor. Nucl Med Biol 2024; 136-137:108939. [PMID: 39003976 DOI: 10.1016/j.nucmedbio.2024.108939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/09/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024]
Abstract
INTRODUCTION Great strides have been made identifying molecular and genetic changes expressed by various tumor types. These molecular and genetic changes are used as pharmacologic targets for precision treatment using large molecule (LM) proteins with high specificity. Theranostics exploits these LM biomolecules via radiochemistry, creating sensitive diagnostic and therapeutic agents. Intravenous (i.v.) LM drugs have an extended biopharmaceutical half-life thus resulting in an insufficient therapeutic index, permitting only palliative brachytherapy due to unacceptably high rates of systemic nontarget radiation doses to normal tissue. We employ tumor arteriole embolization isolating a tumor from the systemic circulation, and local intra-arterial (i.a.) infusion to improve uptake of a LM drug within a porcine renal tumor (RT). METHODS In an oncopig RT we assess the in vivo biodistribution of 99mTc-labeled macroaggregated albumin (MAA) a surrogate for a LM theranostics agent in the RT, kidney, liver, spleen, muscle, blood, and urine. Control animals underwent i.v. infusion and experimental group undergoing arteriography with pseudovascular isolation (PVI) followed by direct i.a. injection. RESULTS Injected dose per gram (%ID/g) of the LM at 1 min was 86.75 ± 3.76 and remained elevated up to 120 min (89.35 ± 5.77) with i.a. PVI, this increase was statistically significant (SS) compared to i.v. (13.38 ± 1.56 and 12.02 ± 1.05; p = 0.0003 p = 0.0006 at 1 and 120 min respectively). The circulating distribution of LM in the blood was less with i.a. vs i.v. infusion (2.28 ± 0.31 vs 25.17 ± 1.84 for i.v. p = 0.033 at 1 min). Other organs displayed a trend towards less exposure to radiation for i.a. with PVI compared to i.v. which was not SS. CONCLUSION PVI followed by i.a. infusion of a LM drug has the potential to significantly increase the first pass uptake within a tumor. This minimally invasive technique can be translated into clinical practice, potentially rendering monoclonal antibody based radioimmunotherapy a viable treatment for renal tumors.
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Affiliation(s)
- Samuel L Rice
- Netherlands Cancer Institute-Antoni van Leeuwenhoekziekenhuis, Department of Radiology, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands; UT Southwestern Medical Center, Department of Radiology, Interventional Radiology Section, 5959 Harry Hines Blvd., Dallas, TX 75390-9061, Professional Office Building I (HP6.600) Mail Code 8834, United States of America.
| | - Fernando Gómez Muñoz
- Netherlands Cancer Institute-Antoni van Leeuwenhoekziekenhuis, Department of Radiology, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands
| | - Jamaal Benjamin
- UT Southwestern Medical Center, Department of Radiology, Interventional Radiology Section, 5959 Harry Hines Blvd., Dallas, TX 75390-9061, Professional Office Building I (HP6.600) Mail Code 8834, United States of America
| | - Mhd Wisam Alnablsi
- UT Southwestern Medical Center, Department of Radiology, Interventional Radiology Section, 5959 Harry Hines Blvd., Dallas, TX 75390-9061, Professional Office Building I (HP6.600) Mail Code 8834, United States of America
| | - Anil Pillai
- UT Southwestern Medical Center, Department of Radiology, Interventional Radiology Section, 5959 Harry Hines Blvd., Dallas, TX 75390-9061, Professional Office Building I (HP6.600) Mail Code 8834, United States of America
| | - Joseph R Osborne
- New York-Presbyterian Weill Cornell Medical Center, Department of Radiology, 1305 York Avenue 3rd Floor, New York, NY 10021, United States of America
| | - Regina Beets-Tan
- Netherlands Cancer Institute-Antoni van Leeuwenhoekziekenhuis, Department of Radiology, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands
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Garaulet G, Báez BB, Medrano G, Rivas-Sánchez M, Sánchez-Alonso D, Martinez-Torrecuadrada JL, Mulero F. Radioimmunotheragnosis in Cancer Research. Cancers (Basel) 2024; 16:2896. [PMID: 39199666 PMCID: PMC11352548 DOI: 10.3390/cancers16162896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/02/2024] [Accepted: 08/13/2024] [Indexed: 09/01/2024] Open
Abstract
The combination of immunoPET-where an antibody (Ab) is labeled with an isotope for PET imaging-and radioimmunotherapy (RIT), using the same antibody with a therapeutic isotope, offers significant advantages in cancer management. ImmunoPET allows non-invasive imaging of antigen expression, which aids in patient selection for subsequent radioimmunotherapy. It also facilitates the assessment of tumor response to therapy, allowing for treatment adjustments if necessary. In addition, immunoPET provides critical pharmacokinetic data, including antibody biodistribution and clearance rates, which are essential for dosimetry calculations and treatment protocol optimization. There are still challenges to overcome. Identifying appropriate target antigens that are selectively expressed on cancer cells while minimally expressed on normal tissues remains a major hurdle to reduce off-target toxicity. In addition, it is critical to optimize the pharmacokinetics of radiolabeled antibodies to maximize tumor uptake and minimize normal tissue uptake, particularly in vital organs such as the liver and kidney. This approach offers the potential for targeted and personalized cancer therapy with reduced systemic toxicity by exploiting the specificity of monoclonal antibodies and the cytotoxic effects of radiation. However, further research is needed to address remaining challenges and to optimize these technologies for clinical use.
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Affiliation(s)
- Guillermo Garaulet
- Molecular Imaging Unit, Spanish National Cancer Center—CNIO, 28029 Madrid, Spain; (G.G.); (B.B.B.); (G.M.)
| | - Bárbara Beatriz Báez
- Molecular Imaging Unit, Spanish National Cancer Center—CNIO, 28029 Madrid, Spain; (G.G.); (B.B.B.); (G.M.)
| | - Guillermo Medrano
- Molecular Imaging Unit, Spanish National Cancer Center—CNIO, 28029 Madrid, Spain; (G.G.); (B.B.B.); (G.M.)
| | - María Rivas-Sánchez
- Protein Production Unit, Spanish National Cancer Center—CNIO, 28029 Madrid, Spain; (M.R.-S.); (D.S.-A.)
| | - David Sánchez-Alonso
- Protein Production Unit, Spanish National Cancer Center—CNIO, 28029 Madrid, Spain; (M.R.-S.); (D.S.-A.)
| | | | - Francisca Mulero
- Molecular Imaging Unit, Spanish National Cancer Center—CNIO, 28029 Madrid, Spain; (G.G.); (B.B.B.); (G.M.)
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Tonon G, Rizzolio F, Visentin F, Scattolin T. Antibody Drug Conjugates for Cancer Therapy: From Metallodrugs to Nature-Inspired Payloads. Int J Mol Sci 2024; 25:8651. [PMID: 39201338 PMCID: PMC11355040 DOI: 10.3390/ijms25168651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/02/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
This review highlights significant advancements in antibody-drug conjugates (ADCs) equipped with metal-based and nature-inspired payloads, focusing on synthetic strategies for antibody conjugation. Traditional methods such us maleimide and succinimide conjugation and classical condensation reactions are prevalent for metallodrugs and natural compounds. However, emerging non-conventional strategies such as photoconjugation are gaining traction due to their milder conditions and, in an aspect which minimizes side reactions, selective formation of ADC. The review also summarizes the therapeutic and diagnostic properties of these ADCs, highlighting their enhanced selectivity and reduced side effects in cancer treatment compared to non-conjugated payloads. ADCs combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy drugs, offering a targeted approach to the elimination of cancer cells while sparing healthy tissues. This targeted mechanism has demonstrated impressive clinical efficacy in various malignancies. Key future advancements include improved linker technology for enhanced stability and controlled release of cytotoxic agents, incorporation of novel, more potent, cytotoxic agents, and the identification of new cancer-specific antigens through genomic and proteomic technologies. ADCs are also expected to play a crucial role in combination therapies with immune checkpoint inhibitors, CAR-T cells, and small molecule inhibitors, leading to more durable and potentially curative outcomes. Ongoing research and clinical trials are expanding their capabilities, paving the way for more effective, safer, and personalized treatments, positioning ADCs as a cornerstone of modern medicine and offering new hope to patients.
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Affiliation(s)
- Giovanni Tonon
- Department of Molecular Sciences and Nanosystems, Università Ca’ Foscari Campus Scientifico, Via Torino 155, 30174 Venezia-Mestre, Italy; (G.T.); (F.R.)
| | - Flavio Rizzolio
- Department of Molecular Sciences and Nanosystems, Università Ca’ Foscari Campus Scientifico, Via Torino 155, 30174 Venezia-Mestre, Italy; (G.T.); (F.R.)
- Pathology Unit, Department of Molecular Biology and Translational Research, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano, Italy
| | - Fabiano Visentin
- Department of Molecular Sciences and Nanosystems, Università Ca’ Foscari Campus Scientifico, Via Torino 155, 30174 Venezia-Mestre, Italy; (G.T.); (F.R.)
| | - Thomas Scattolin
- Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Via Marzolo 1, 35131 Padova, Italy
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Song H, Sgouros G. Alpha and Beta Radiation for Theragnostics. PET Clin 2024; 19:307-323. [PMID: 38688775 DOI: 10.1016/j.cpet.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2024]
Abstract
Targeted radionuclide therapy (TRT) has significantly evolved from its beginnings with iodine-131 to employing carrier molecules with beta emitting isotopes like lutetium-177. With the success of Lu-177-DOTATATE for neuroendocrine tumors and Lu-177-PSMA-617 for prostate cancer, several other beta emitting radioisotopes, such as Cu-67 and Tb-161, are being explored for TRT. The field has also expanded into targeted alpha therapy (TAT) with agents like radium-223 for bone metastases in prostate cancer, and several other alpha emitter radioisotopes with carrier molecules, such as Ac-225, and Pb-212 under clinical trials. Despite these advancements, the scope of TRT in treating diverse solid tumors and integration with other therapies like immunotherapy remains under investigation. The success of antibody-drug conjugates further complements treatments with TRT, though challenges in treatment optimization continue.
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Affiliation(s)
- Hong Song
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Stanford University, Stanford, CA 94305, USA.
| | - George Sgouros
- Division of Radiological Physics, Department of Radiology and Radiological Sciences, The Johns Hopkins University, Baltimore, MD 21205, USA
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Fowler NH, Chavez JC, Riedell PA. Moving T-Cell Therapies into the Standard of Care for Patients with Relapsed or Refractory Follicular Lymphoma: A Review. Target Oncol 2024; 19:495-510. [PMID: 38896212 PMCID: PMC11271334 DOI: 10.1007/s11523-024-01070-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2024] [Indexed: 06/21/2024]
Abstract
Patients with follicular lymphoma, an indolent form of non-Hodgkin lymphoma, typically experience multiple relapses over their disease course. Periods of remission become progressively shorter with worse clinical outcomes after each subsequent line of therapy. Currently, no clear standard of care/preferred treatment approach exists for patients with relapsed or refractory follicular lymphoma. As novel agents continue to emerge for treatment in the third-line setting, guidance is needed for selecting the most appropriate therapy for each patient. Several classes of targeted therapeutic agents, including monoclonal antibodies, phosphoinositide 3-kinase inhibitors, enhancer of zeste homolog 2 inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and bispecific antibodies, have been approved by regulatory authorities based on clinical benefit in patients with relapsed or refractory follicular lymphoma. Additionally, antibody-drug conjugates and other immunocellular therapies are being evaluated in this setting. Effective integration of CAR-T cell therapy into the treatment paradigm after two or more prior therapies requires appropriate patient selection based on transformation status following a rebiopsy; a risk evaluation based on age, fitness, and remission length; and eligibility for CAR-T cell therapy. Consideration of important logistical factors (e.g., proximity to the treatment center and caregiver support during key periods of CAR-T cell therapy) is also critical. Overall, an individualized treatment plan that considers patient-related factors (e.g., age, disease status, tumor burden, comorbidities) and prior treatment types is recommended for patients with relapsed or refractory follicular lymphoma. Future analyses of real-world data and a better understanding of mechanisms of relapse are needed to further refine patient selection and identify optimal sequencing of therapies in this setting.
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Affiliation(s)
| | - Julio C Chavez
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA
| | - Peter A Riedell
- David and Etta Jonas Center for Cellular Therapy, University of Chicago, Chicago, IL, USA
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10
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Paul S, Konig MF, Pardoll DM, Bettegowda C, Papadopoulos N, Wright KM, Gabelli SB, Ho M, van Elsas A, Zhou S. Cancer therapy with antibodies. Nat Rev Cancer 2024; 24:399-426. [PMID: 38740967 PMCID: PMC11180426 DOI: 10.1038/s41568-024-00690-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/29/2024] [Indexed: 05/16/2024]
Abstract
The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.
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Affiliation(s)
- Suman Paul
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Maximilian F Konig
- Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Drew M Pardoll
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Chetan Bettegowda
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Katharine M Wright
- Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA
| | - Sandra B Gabelli
- Discovery Chemistry, Merck Research Laboratory, Merck and Co, West Point, PA, USA.
| | - Mitchell Ho
- Antibody Engineering Program, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
| | | | - Shibin Zhou
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
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11
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Lawal IO, Abubakar SO, Ndlovu H, Mokoala KMG, More SS, Sathekge MM. Advances in Radioligand Theranostics in Oncology. Mol Diagn Ther 2024; 28:265-289. [PMID: 38555542 DOI: 10.1007/s40291-024-00702-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2024] [Indexed: 04/02/2024]
Abstract
Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.
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Affiliation(s)
- Ismaheel O Lawal
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, NE, Atlanta, GA, 30322, USA.
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa.
| | - Sofiullah O Abubakar
- Department of Radiology and Nuclear Medicine, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
| | - Honest Ndlovu
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, 0001, South Africa
| | - Kgomotso M G Mokoala
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, 0001, South Africa
| | - Stuart S More
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Division of Nuclear Medicine, Department of Radiation Medicine, University of Cape Town, Cape Town, 7700, South Africa
| | - Mike M Sathekge
- Department of Nuclear Medicine, University of Pretoria, Pretoria, 0001, South Africa
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, 0001, South Africa
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12
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Dabkowska A, Domka K, Firczuk M. Advancements in cancer immunotherapies targeting CD20: from pioneering monoclonal antibodies to chimeric antigen receptor-modified T cells. Front Immunol 2024; 15:1363102. [PMID: 38638442 PMCID: PMC11024268 DOI: 10.3389/fimmu.2024.1363102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/25/2024] [Indexed: 04/20/2024] Open
Abstract
CD20 located predominantly on the B cells plays a crucial role in their development, differentiation, and activation, and serves as a key therapeutic target for the treatment of B-cell malignancies. The breakthrough of monoclonal antibodies directed against CD20, notably exemplified by rituximab, revolutionized the prognosis of B-cell malignancies. Rituximab, approved across various hematological malignancies, marked a paradigm shift in cancer treatment. In the current landscape, immunotherapies targeting CD20 continue to evolve rapidly. Beyond traditional mAbs, advancements include antibody-drug conjugates (ADCs), bispecific antibodies (BsAbs), and chimeric antigen receptor-modified (CAR) T cells. ADCs combine the precision of antibodies with the cytotoxic potential of drugs, presenting a promising avenue for enhanced therapeutic efficacy. BsAbs, particularly CD20xCD3 constructs, redirect cytotoxic T cells to eliminate cancer cells, thereby enhancing both precision and potency in their therapeutic action. CAR-T cells stand as a promising strategy for combatting hematological malignancies, representing one of the truly personalized therapeutic interventions. Many new therapies are currently being evaluated in clinical trials. This review serves as a comprehensive summary of CD20-targeted therapies, highlighting the progress and challenges that persist. Despite significant advancements, adverse events associated with these therapies and the development of resistance remain critical issues. Understanding and mitigating these challenges is paramount for the continued success of CD20-targeted immunotherapies.
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Affiliation(s)
- Agnieszka Dabkowska
- Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Domka
- Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Malgorzata Firczuk
- Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
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13
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Kumar V, Barwal A, Sharma N, Mir DS, Kumar P, Kumar V. Therapeutic proteins: developments, progress, challenges, and future perspectives. 3 Biotech 2024; 14:112. [PMID: 38510462 PMCID: PMC10948735 DOI: 10.1007/s13205-024-03958-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 02/13/2024] [Indexed: 03/22/2024] Open
Abstract
Proteins are considered magic molecules due to their enormous applications in the health sector. Over the past few decades, therapeutic proteins have emerged as a promising treatment option for various diseases, particularly cancer, cardiovascular disease, diabetes, and others. The formulation of protein-based therapies is a major area of research, however, a few factors still hinder the large-scale production of these therapeutic products, such as stability, heterogenicity, immunogenicity, high cost of production, etc. This review provides comprehensive information on various sources and production of therapeutic proteins. The review also summarizes the challenges currently faced by scientists while developing protein-based therapeutics, along with possible solutions. It can be concluded that these proteins can be used in combination with small molecular drugs to give synergistic benefits in the future.
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Affiliation(s)
- Vimal Kumar
- University Institute of Biotechnology, Chandigarh University, Gharuan, Mohali, Punjab 140413 India
| | - Arti Barwal
- Department of Microbial Biotechnology, Panjab University, South Campus, Sector-25, Chandigarh, 160014 India
| | - Nitin Sharma
- Department of Biotechnology, Chandigarh Group of Colleges, Mohali, Punjab 140307 India
| | - Danish Shafi Mir
- University Institute of Biotechnology, Chandigarh University, Gharuan, Mohali, Punjab 140413 India
| | - Pradeep Kumar
- Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, 173229 India
| | - Vikas Kumar
- University Institute of Biotechnology, Chandigarh University, Gharuan, Mohali, Punjab 140413 India
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14
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Laoruangroj C, Atherton PJ, Wiseman GA, Ansell S, Feldman AL, Schumacher P, Witzig TE. The asymptomatic follicular lymphoma (AFL) trial: single-agent rituximab immunotherapy versus 90Y-ibritumomab tiuxetan radioimmunotherapy (RIT) for patients with new, untreated follicular lymphoma. Leuk Lymphoma 2024; 65:333-338. [PMID: 38189774 DOI: 10.1080/10428194.2023.2295792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 12/12/2023] [Indexed: 01/09/2024]
Abstract
Patients with asymptomatic follicular lymphoma (AFL) are candidates for observation or immunotherapy. Given the effectiveness of radiation therapy in FL, another option is 90Yttrium-ibritumomab tiuxetan radioimmunotherapy (RIT). We conducted a trial where untreated AFL patients were randomized to rituximab 375 mg/m2 weekly × 4 or rituximab 250 mg/m2 days 1, 8, and 0.4 mCi/kg (maximum 32 mCi) of RIT day 8. Twenty patients were enrolled before the study was halted due to unavailability of RIT. The ORR for rituximab and RIT were 90% and 80%, respectively; the CR rate at 6 months was 30% and 60%, respectively. After a median follow-up of 67 months, eight patients have progressed-three in the rituximab arm and five in the RIT arm and five have required systemic therapy. All patients remain alive. Both agents are highly active for AFL. The 1-week treatment with RIT and sparing of T-cells make combination therapy with newer agents attractive.
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Affiliation(s)
| | - Pamela J Atherton
- Department of Quantitative Health Sciences, Mayo Clinic Rochester, MN, USA
| | | | - Stephen Ansell
- Division of Hematology, Department of Medicine, Mayo Clinic Rochester, MN, USA
| | - Andrew L Feldman
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA
| | - Peyton Schumacher
- Department of Quantitative Health Sciences, Mayo Clinic Rochester, MN, USA
| | - Thomas E Witzig
- Division of Hematology, Department of Medicine, Mayo Clinic Rochester, MN, USA
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15
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Wang H, Yang S, Chen L, Li Y, He P, Wang G, Dong H, Ma P, Ding G. Tumor diagnosis using carbon-based quantum dots: Detection based on the hallmarks of cancer. Bioact Mater 2024; 33:174-222. [PMID: 38034499 PMCID: PMC10684566 DOI: 10.1016/j.bioactmat.2023.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/15/2023] [Accepted: 10/05/2023] [Indexed: 12/02/2023] Open
Abstract
Carbon-based quantum dots (CQDs) have been shown to have promising application value in tumor diagnosis. Their use, however, is severely hindered by the complicated nature of the nanostructures in the CQDs. Furthermore, it seems impossible to formulate the mechanisms involved using the inadequate theoretical frameworks that are currently available for CQDs. In this review, we re-consider the structure-property relationships of CQDs and summarize the current state of development of CQDs-based tumor diagnosis based on biological theories that are fully developed. The advantages and deficiencies of recent research on CQDs-based tumor diagnosis are thus explained in terms of the manifestation of nine essential changes in cell physiology. This review makes significant progress in addressing related problems encountered with other nanomaterials.
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Affiliation(s)
- Hang Wang
- National Key Laboratory of Materials for Integrated Circuit, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
- CAS Center for Excellence in Superconducting Electronics (CENSE), Chinese Academy of Sciences, Shanghai, 200050, PR China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences (UCAS), Beijing, 100049, PR China
| | - Siwei Yang
- National Key Laboratory of Materials for Integrated Circuit, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences (UCAS), Beijing, 100049, PR China
| | - Liangfeng Chen
- National Key Laboratory of Materials for Integrated Circuit, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences (UCAS), Beijing, 100049, PR China
| | - Yongqiang Li
- National Key Laboratory of Materials for Integrated Circuit, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences (UCAS), Beijing, 100049, PR China
| | - Peng He
- National Key Laboratory of Materials for Integrated Circuit, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences (UCAS), Beijing, 100049, PR China
| | - Gang Wang
- Department of Microelectronic Science and Engineering, School of Physical Science and Technology, Ningbo University, Ningbo, 315211, PR China
| | - Hui Dong
- National Key Laboratory of Materials for Integrated Circuit, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
- CAS Center for Excellence in Superconducting Electronics (CENSE), Chinese Academy of Sciences, Shanghai, 200050, PR China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences (UCAS), Beijing, 100049, PR China
| | - Peixiang Ma
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China
| | - Guqiao Ding
- National Key Laboratory of Materials for Integrated Circuit, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai, 200050, PR China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences (UCAS), Beijing, 100049, PR China
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16
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Goto H, Shiraishi Y, Okada S. Recent preclinical and clinical advances in radioimmunotherapy for non-Hodgkin's lymphoma. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:208-224. [PMID: 38464386 PMCID: PMC10918239 DOI: 10.37349/etat.2024.00213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 12/28/2023] [Indexed: 03/12/2024] Open
Abstract
Radioimmunotherapy (RIT) is a therapy that combines a radioactive nucleotide with a monoclonal antibody (mAb). RIT enhances the therapeutic effect of mAb and reduces toxicity compared with conventional treatment. The purpose of this review is to summarize the current progress of RIT for treating non-Hodgkin's lymphoma (NHL) based on recent preclinical and clinical studies. The efficacy of RIT targeting the B-lymphocyte antigen cluster of differentiation 20 (CD20) has been demonstrated in clinical trials. Two radioimmunoconjugates targeting CD20, yttrium-90 (90Y)-ibritumomab-tiuxetan (Zevalin) and iodine-131 (131I)-tositumomab (Bexxar), have been approved in the USA Food and Drug Administration (FDA) for treating relapsed/refractory indolent or transformed NHL in 2002 and 2003, respectively. Although these two radioimmunoconjugates are effective and least toxic, they have not achieved popularity due to increasing access to novel therapies and the complexity of their delivery process. RIT is constantly evolving with the identification of novel targets and novel therapeutic strategies using newer radionuclides such as alpha-particle isotopes. Alpha-particles show very short path lengths and high linear energy transfer. These characteristics provide increased tumor cell-killing activities and reduced non-specific bystander responses on normal tissue. This review also discusses reviewed pre-targeted RIT (PRIT) and immuno-positron emission tomography (PET). PRIT potentially increases the dose of radionuclide delivered to tumors while toxicities to normal tissues are limited. Immuno-PET is a molecular imaging tracer that combines the high sensitivity of PET with the specific targeting capability of mAb. Immuno-PET strategies targeting CD20 and other antigens are currently being developed. The theragnostic approach by immuno-PET will be useful in monitoring the treatment response.
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Affiliation(s)
- Hiroki Goto
- Division of Radioisotope and Tumor Pathobiology, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
| | - Yoshioki Shiraishi
- Radioisotope Center, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
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Zhang T, Lei H, Chen X, Dou Z, Yu B, Su W, Wang W, Jin X, Katsube T, Wang B, Zhang H, Li Q, Di C. Carrier systems of radiopharmaceuticals and the application in cancer therapy. Cell Death Discov 2024; 10:16. [PMID: 38195680 PMCID: PMC10776600 DOI: 10.1038/s41420-023-01778-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 01/11/2024] Open
Abstract
Radiopharmaceuticals play a vital role in cancer therapy. The carrier of radiopharmaceuticals can precisely locate and guide radionuclides to the target, where radionuclides kill surrounding tumor cells. Effective application of radiopharmaceuticals depends on the selection of an appropriate carrier. Herein, different types of carriers of radiopharmaceuticals and the characteristics are briefly described. Subsequently, we review radiolabeled monoclonal antibodies (mAbs) and their derivatives, and novel strategies of radiolabeled mAbs and their derivatives in the treatment of lymphoma and colorectal cancer. Furthermore, this review outlines radiolabeled peptides, and novel strategies of radiolabeled peptides in the treatment of neuroendocrine neoplasms, prostate cancer, and gliomas. The emphasis is given to heterodimers, bicyclic peptides, and peptide-modified nanoparticles. Last, the latest developments and applications of radiolabeled nucleic acids and small molecules in cancer therapy are discussed. Thus, this review will contribute to a better understanding of the carrier of radiopharmaceuticals and the application in cancer therapy.
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Affiliation(s)
- Taotao Zhang
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Huiwen Lei
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Xiaohua Chen
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China
| | - Zhihui Dou
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Boyi Yu
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Wei Su
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China
| | - Wei Wang
- College of Life Science, Northwest Normal University, Lanzhou, 730000, China
| | - Xiaodong Jin
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China
| | - Takanori Katsube
- National Institute of Radiological Sciences, National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan
| | - Bing Wang
- National Institute of Radiological Sciences, National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan
| | - Hong Zhang
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China.
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China.
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China.
| | - Qiang Li
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China.
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China.
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China.
| | - Cuixia Di
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, 101408, Beijing, China.
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, 101408, Beijing, China.
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, 516029, China.
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18
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Ladetto M, Tavarozzi R, Zanni M, Evangelista A, Ferrero S, Tucci A, Botto B, Bolis S, Volpetti S, Zilioli VR, Puccini B, Arcari A, Pavone V, Gaidano G, Corradini P, Tani M, Cavallo F, Milone G, Ghiggi C, Pinto A, Pastore D, Ferreri AJM, Latte G, Patti C, Re F, Benedetti F, Luminari S, Pennese E, Bossi E, Boccomini C, Anastasia A, Bottelli C, Ciccone G, Vitolo U. Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial. Ann Oncol 2024; 35:118-129. [PMID: 37922989 DOI: 10.1016/j.annonc.2023.10.095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/11/2023] [Accepted: 10/03/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. PATIENTS AND METHODS Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). RESULTS Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189). CONCLUSIONS Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.
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Affiliation(s)
- M Ladetto
- Department of Translational Medicine, University of Eastern Piedmont, Novara; SCDU di Ematologia, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria.
| | - R Tavarozzi
- Department of Translational Medicine, University of Eastern Piedmont, Novara; SCDU di Ematologia, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria
| | - M Zanni
- SCDU di Ematologia, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria
| | - A Evangelista
- SSD of Clinical Epidemiology, Universitaria Città della Salute e della Scienza di Torino and Centre for Cancer Prevention Piemonte, Torino
| | - S Ferrero
- Department of Molecular Biotechnologies and Health Sciences, Universitaria Città della Salute e della Scienza di Torino and Centre for Cancer Prevention Piemonte, Torino
| | - A Tucci
- Department of Hematology, Spedali Civili, Brescia
| | - B Botto
- Struttura Complessa Ematologia, AOU Città della salute e della scienza di Torino, Turin
| | - S Bolis
- SC Ematologia ASST-Monza, Monza
| | - S Volpetti
- Division of Hematology, Clinica Ematologica, Centro Trapianti e Terapie Cellulari Carlo Melzi, DISM, Azienda Ospedaliero Universitaria S. M. Misericordia, Udine
| | - V R Zilioli
- Division of Haematology, ASST Grande Ospedale Metropolitano Niguarda, Milano
| | - B Puccini
- Department of Haematology, University of Florence, Firenze
| | - A Arcari
- Hematology Unit, Ospedale Guglielmo da Saliceto, Piacenza
| | - V Pavone
- A. O. C. Panico-U.O.C Ematologia e Trapianto, Tricase, Lecce
| | - G Gaidano
- SCDU di Ematologia, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria; Division of Hematology, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara
| | - P Corradini
- Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milano
| | - M Tani
- Hematology Unit, Department of Oncology and Hematology, "Santa Maria delle Croci" Hospital, Ravenna
| | - F Cavallo
- Department of Molecular Biotechnologies and Health Sciences, Universitaria Città della Salute e della Scienza di Torino and Centre for Cancer Prevention Piemonte, Torino
| | - G Milone
- Division of Hematology and Program for Hematopoietic Transplantation, Azienda Ospedaliera Policlinico Vittorio Emanuele, Catania
| | - C Ghiggi
- Hematology Division, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova
| | - A Pinto
- Department of Hematology, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico "Fondazione G Pascale", Naples
| | | | - A J M Ferreri
- Onco-Hematology Department, Fondazione Centro San Raffaele, Milano
| | - G Latte
- Unità di Ematologia e Trapianto di Midollo Osseo, San Francesco Hospital, Nuoro
| | - C Patti
- Divisione di Oncoematologia, Azienda Villa Sofia - Cervello, Palermo
| | - F Re
- Department of Hematology, A.O.U. di Parma, Parma
| | - F Benedetti
- Department of Medicine, Section of Hematology and Bone Marrow Transplant Unit, University of Verona, Verona
| | - S Luminari
- Department of Hematology, IRCCS Reggio Emilia, Reggio Emilia
| | - E Pennese
- Lymphoma Unit, Department of Hematology, Ospedale Spirito Santo, Pescara
| | - E Bossi
- SC Ematologia ASST-Monza, Monza
| | - C Boccomini
- Struttura Complessa Ematologia, AOU Città della salute e della scienza di Torino, Turin
| | - A Anastasia
- Department of Hematology, Spedali Civili, Brescia
| | - C Bottelli
- Department of Hematology, Spedali Civili, Brescia
| | - G Ciccone
- SSD of Clinical Epidemiology, Universitaria Città della Salute e della Scienza di Torino and Centre for Cancer Prevention Piemonte, Torino
| | - U Vitolo
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
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19
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Gulyak EL, Alferova VA, Korshun VA, Sapozhnikova KA. Introduction of Carbonyl Groups into Antibodies. Molecules 2023; 28:7890. [PMID: 38067618 PMCID: PMC10707781 DOI: 10.3390/molecules28237890] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 11/26/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
Antibodies and their derivatives (scFv, Fabs, etc.) represent a unique class of biomolecules that combine selectivity with the ability to target drug delivery. Currently, one of the most promising endeavors in this field is the development of molecular diagnostic tools and antibody-based therapeutic agents, including antibody-drug conjugates (ADCs). To meet this challenge, it is imperative to advance methods for modifying antibodies. A particularly promising strategy involves the introduction of carbonyl groups into the antibody that are amenable to further modification by biorthogonal reactions, namely aliphatic, aromatic, and α-oxo aldehydes, as well as aliphatic and aryl-alkyl ketones. In this review, we summarize the preparation methods and applications of site-specific antibody conjugates that are synthesized using this approach.
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Affiliation(s)
| | | | | | - Ksenia A. Sapozhnikova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia; (E.L.G.); (V.A.A.); (V.A.K.)
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20
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Strati P, Spiotto MT. Incorporating Immunotherapy with Radiotherapy for Lymphomas. LYMPHATICS 2023; 1:273-286. [PMID: 39917366 PMCID: PMC11800356 DOI: 10.3390/lymphatics1030018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
Radiotherapy and/or chemotherapy have been used for nearly 100 years to treat lymphoma. Recently, immunotherapy has been incorporated into the treatment of lymphomas. Here, we will review both the role of immunotherapy in lymphoma as well as the feasibility of incorporating immunotherapies with conventional lymphoma treatments, especially radiotherapy. Immunotherapy agents include checkpoint inhibitors that target the PD-1/PD-L1 axis, CTLA-4, or CD47. In addition, other immunotherapy agents such as bi-specific antibodies and CD19 CAR-T cell therapy are being implemented in various non-Hodgkin's lymphomas. Extrapolating from observations in other disease sites and incorporating immunotherapy with conventional treatments of lymphoma, including radiotherapy, may have opposing effects. Radiotherapy may stimulate anti-tumor immune responses that synergize with immunotherapies. In contrast, radiotherapy, as well as chemotherapy, may also induce local and systemic immune dysfunction which reduces the efficacy of immunotherapies. With newer radiation treatment techniques and limited radiation fields, it is likely that the efficacy of immunotherapy can be maintained when included with conventional treatments. Therefore, there remains an unmet need to better understand the role of immunotherapy alone and in combination with current treatments in lymphoma patients.
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Affiliation(s)
- Paolo Strati
- Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael T. Spiotto
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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21
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Pouget JP, Chan TA, Galluzzi L, Constanzo J. Radiopharmaceuticals as combinatorial partners for immune checkpoint inhibitors. Trends Cancer 2023; 9:968-981. [PMID: 37612188 PMCID: PMC11311210 DOI: 10.1016/j.trecan.2023.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/25/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple cancer types. However, only a fraction of patients with cancer responds to ICIs employed as stand-alone therapeutics, calling for the development of safe and effective combinatorial regimens to extend the benefits of ICIs to a larger patient population. In addition to exhibiting a good safety and efficacy profile, targeted radionuclide therapy (TRT) with radiopharmaceuticals that specifically accumulate in the tumor microenvironment has been associated with promising immunostimulatory effects that (at least in preclinical cancer models) provide a robust platform for the development of TRT/ICI combinations. We discuss preclinical and clinical findings suggesting that TRT stands out as a promising partner for the development of safe and efficient combinatorial regimens involving ICIs.
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Affiliation(s)
- Jean-Pierre Pouget
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.
| | - Timothy A Chan
- Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; National Center for Regenerative Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Centre, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
| | - Julie Constanzo
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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22
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Wang J, Baidoun F, Tun HW, Alhaj Moustafa M. 90Yttrium Ibritumomab Tiuxetan (Zevalin) for the Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Report of 5 Cases. Blood Lymphat Cancer 2023; 13:59-65. [PMID: 37810176 PMCID: PMC10559791 DOI: 10.2147/blctt.s398809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 09/07/2023] [Indexed: 10/10/2023]
Abstract
Radioimmunotherapy (RIT) with radio-labeled monoclonal antibodies to CD20 produces a high response rate in patients with low-grade B-cell lymphomas. The use of this modality in patients with chronic lymphocytic leukemia (CLL) has been sporadic in clinical trials and was hampered by the extensive marrow involvement seen commonly in patients with CLL, which would produce a high risk for marrow aplasia after treatment with RIT. Herein, we report our experience with RIT in 5 patients with CLL or SLL showing short-lived responses and significant myelosuppression. After 90Y-ibritumomab tiuxetan treatment, the median time to relapse was 65 days, and no cases of MDS or AML were observed during follow-up. All patients experienced grade ≥3 thrombocytopenia and neutropenia, with median durations of 39.5 days and 107 days, respectively.
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Affiliation(s)
- Jing Wang
- Department of Internal Medicine, Mayo Clinic Florida, Jacksonville, FL, 32224, USA
| | - Firas Baidoun
- Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA
| | - Han W Tun
- Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA
| | - Muhamad Alhaj Moustafa
- Division of Hematology and Medical Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USA
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23
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Matarasso S, Assouline S. Mosunetuzumab and the emerging role of T-cell-engaging therapy in follicular lymphoma. Future Oncol 2023; 19:2083-2101. [PMID: 37882361 DOI: 10.2217/fon-2023-0274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2023] Open
Abstract
Follicular lymphoma (FL) is the most common indolent lymphoma. Since the advent of rituximab, FL has seen a progressive improvement in patient prognosis. While chemotherapy combined with an anti-CD20 monoclonal antibody remains standard first-line therapy, most patients will relapse and require subsequent therapy. T-cell-redirecting therapies can be very potent and are transforming the therapeutic landscape in the relapsed and refractory (R/R) setting. T-cell-dependent bispecific antibodies, of which mosunetuzumab is the first to be approved for R/R FL, are proving to be a highly effective, 'off-the-shelf' option with manageable toxicities. This review covers approved treatments for R/R FL and focuses on preclinical and clinical data available for mosunetuzumab (Lunsumio™), with the goal of determining its role in the treatment of R/R FL.
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Affiliation(s)
- Sarah Matarasso
- Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine, E725, Montreal, QC, H3T 1E2, Canada
| | - Sarit Assouline
- Lady Davis Institute, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine, E725, Montreal, QC, H3T 1E2, Canada
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24
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Obata H, Ogawa M, Zalutsky MR. DNA Repair Inhibitors: Potential Targets and Partners for Targeted Radionuclide Therapy. Pharmaceutics 2023; 15:1926. [PMID: 37514113 PMCID: PMC10384049 DOI: 10.3390/pharmaceutics15071926] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
The present review aims to explore the potential targets/partners for future targeted radionuclide therapy (TRT) strategies, wherein cancer cells often are not killed effectively, despite receiving a high average tumor radiation dose. Here, we shall discuss the key factors in the cancer genome, especially those related to DNA damage response/repair and maintenance systems for escaping cell death in cancer cells. To overcome the current limitations of TRT effectiveness due to radiation/drug-tolerant cells and tumor heterogeneity, and to make TRT more effective, we propose that a promising strategy would be to target the DNA maintenance factors that are crucial for cancer survival. Considering their cancer-specific DNA damage response/repair ability and dysregulated transcription/epigenetic system, key factors such as PARP, ATM/ATR, amplified/overexpressed transcription factors, and DNA methyltransferases have the potential to be molecular targets for Auger electron therapy; moreover, their inhibition by non-radioactive molecules could be a partnering component for enhancing the therapeutic response of TRT.
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Affiliation(s)
- Honoka Obata
- Department of Advanced Nuclear Medicine Sciences, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
- Department of Molecular Imaging and Theranostics, National Institutes for Quantum Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
- Departments of Radiology and Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
- Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan
| | - Mikako Ogawa
- Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo 060-0812, Japan
| | - Michael R Zalutsky
- Departments of Radiology and Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA
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25
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Mdanda S, Ngema LM, Mdlophane A, Sathekge MM, Zeevaart JR. Recent Innovations and Nano-Delivery of Actinium-225: A Narrative Review. Pharmaceutics 2023; 15:1719. [PMID: 37376167 DOI: 10.3390/pharmaceutics15061719] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/13/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
The actinium-225 (225Ac) radioisotope exhibits highly attractive nuclear properties for application in radionuclide therapy. However, the 225Ac radionuclide presents multiple daughter nuclides in its decay chain, which can escape the targeted site, circulate in plasma, and cause toxicity in areas such as kidneys and renal tissues. Several ameliorative strategies have been devised to circumvent this issue, including nano-delivery. Alpha-emitting radionuclides and nanotechnology applications in nuclear medicine have culminated in major advancements that offer promising therapeutic possibilities for treating several cancers. Accordingly, the importance of nanomaterials in retaining the 225Ac daughters from recoiling into unintended organs has been established. This review expounds on the advancements of targeted radionuclide therapy (TRT) as an alternative anticancer treatment. It discusses the recent developments in the preclinical and clinical investigations on 225Ac as a prospective anticancer agent. Moreover, the rationale for using nanomaterials in improving the therapeutic efficacy of α-particles in targeted alpha therapy (TAT) with an emphasis on 225Ac is discussed. Quality control measures in the preparation of 225Ac-conjugates are also highlighted.
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Affiliation(s)
- Sipho Mdanda
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria 0028, South Africa
- Department of Nuclear Medicine, University of Pretoria, Pretoria 0001, South Africa
| | - Lindokuhle M Ngema
- Wits Advanced Drug Delivery Platform (WADDP) Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Johannesburg 2193, South Africa
- Johns Hopkins Medicine, Department of Radiation Oncology and Molecular Radiation Sciences, Baltimore, MD 21218, USA
| | - Amanda Mdlophane
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria 0028, South Africa
- Department of Nuclear Medicine, University of Pretoria, Pretoria 0001, South Africa
| | - Mike M Sathekge
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria 0028, South Africa
- Department of Nuclear Medicine, University of Pretoria, Pretoria 0001, South Africa
| | - Jan Rijn Zeevaart
- Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria 0028, South Africa
- Radiochemistry, The South African Nuclear Energy Corporation, Pelindaba, Hartbeespoort 0240, South Africa
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26
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Buck AK, Serfling SE, Kraus S, Samnick S, Dreher N, Higuchi T, Rasche L, Einsele H, Werner RA. Theranostics in Hematooncology. J Nucl Med 2023:jnumed.122.265199. [PMID: 37290799 DOI: 10.2967/jnumed.122.265199] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/08/2023] [Indexed: 06/10/2023] Open
Abstract
In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes 90Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as 131I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of 131I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.
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Affiliation(s)
- Andreas K Buck
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany;
| | | | - Sabrina Kraus
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; and
| | - Samuel Samnick
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Niklas Dreher
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Takahiro Higuchi
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
| | - Leo Rasche
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; and
| | - Hermann Einsele
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; and
| | - Rudolf A Werner
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland
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27
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Pomykala KL, Hadaschik BA, Sartor O, Gillessen S, Sweeney CJ, Maughan T, Hofman MS, Herrmann K. Next generation radiotheranostics promoting precision medicine. Ann Oncol 2023; 34:507-519. [PMID: 36924989 DOI: 10.1016/j.annonc.2023.03.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
Radiotheranostics is a field of rapid growth with some approved treatments including 131I for thyroid cancer, 223Ra for osseous metastases, 177Lu-DOTATATE for neuroendocrine tumors, and 177Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, and several more under investigation. In this review, we will cover the fundamentals of radiotheranostics, the key clinical studies that have led to current success, future developments with new targets, radionuclides and platforms, challenges with logistics and reimbursement and, lastly, forthcoming considerations regarding dosimetry, identifying the right line of therapy, artificial intelligence and more.
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Affiliation(s)
- K L Pomykala
- Institute for Artificial Intelligence in Medicine, University Hospital Essen, Essen, Germany
| | - B A Hadaschik
- Department of Urology, University Hospital Essen, Essen, Germany
| | - O Sartor
- School of Medicine, Tulane University, New Orleans, USA
| | - S Gillessen
- Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Università della Svizzera Italiana, Lugano, Switzerland; Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - C J Sweeney
- Dana-Farber Cancer Institute, Boston, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, USA
| | - T Maughan
- Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK
| | - M S Hofman
- Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - K Herrmann
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany.
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28
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Cicone F, Santo G, Bodet-Milin C, Cascini GL, Kraeber-Bodéré F, Stokke C, Kolstad A. Radioimmunotherapy of Non-Hodgkin B-cell Lymphoma: An update. Semin Nucl Med 2023; 53:413-425. [PMID: 36635112 DOI: 10.1053/j.semnuclmed.2022.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023]
Abstract
Systemic radioimmunotherapy (RIT) is arguably the most effective and least toxic anticancer treatment for non-Hodgkin lymphoma (NHL). In treatment-naïve patients with indolent NHL, the efficacy of a single injection of RIT compares with that of multiple cycles of combination chemotherapy. However, 20 years following the approval of the first CD20-targeting radioimmunoconjugates 90Y-Ibritumomab-tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), the number of patients referred for RIT in western countries has dramatically decreased. Notwithstanding this, the development of RIT has continued. Therapeutic targets other than CD20 have been identified, new vector molecules have been produced allowing for faster delivery of RIT to the target, and innovative radionuclides with favorable physical characteristics such as alpha emitters have been more widely available. In this article, we reviewed the current status of RIT in NHL, with particular focus on recent clinical and preclinical developments.
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Affiliation(s)
- Francesco Cicone
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy; Nuclear Medicine Unit, University Hospital "Mater Domini", Catanzaro, Italy.
| | - Giulia Santo
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Caroline Bodet-Milin
- Nuclear Medicine Department, Nantes Université, Univ Angers, CHU Nantes, INSERM, CNRS, CRCI2NA, F-44000 Nantes, France
| | - Giuseppe Lucio Cascini
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy; Nuclear Medicine Unit, University Hospital "Mater Domini", Catanzaro, Italy
| | - Françoise Kraeber-Bodéré
- Nuclear Medicine Department, Nantes Université, Univ Angers, CHU Nantes, INSERM, CNRS, CRCI2NA, F-44000 Nantes, France
| | - Caroline Stokke
- Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway; Department of Physics, University of Oslo, Oslo, Norway
| | - Arne Kolstad
- Department of Oncology, Innlandet Hospital Trust Division Gjøvik, Lillehammer, Norway
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29
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Facile Preparation of Samarium Carbonate-Polymethacrylate Microspheres as a Neutron-Activatable Radioembolic Agent for Hepatic Radioembolization. Pharmaceutics 2023; 15:pharmaceutics15030877. [PMID: 36986738 PMCID: PMC10051741 DOI: 10.3390/pharmaceutics15030877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 03/02/2023] [Accepted: 03/03/2023] [Indexed: 03/11/2023] Open
Abstract
Radioembolization shows great potential as a treatment for intermediate- and advanced-stage liver cancer. However, the choices of radioembolic agents are currently limited, and hence the treatment is relatively costly compared to other approaches. In this study, a facile preparation method was developed to produce samarium carbonate-polymethacrylate [152Sm2(CO3)3-PMA] microspheres as neutron activatable radioembolic microspheres for hepatic radioembolization. The developed microspheres emits both therapeutic beta and diagnostic gamma radiations for post-procedural imaging. The 152Sm2(CO3)3-PMA microspheres were produced from commercially available PMA microspheres through the in situ formation of 152Sm2(CO3)3 within the pores of the PMA microspheres. Physicochemical characterization, gamma spectrometry and radionuclide retention assay were performed to evaluate the performance and stability of the developed microspheres. The mean diameter of the developed microspheres was determined as 29.30 ± 0.18 µm. The scanning electron microscopic images show that the spherical and smooth morphology of the microspheres remained after neutron activation. The 153Sm was successful incorporated into the microspheres with no elemental and radionuclide impurities produced after neutron activation, as indicated by the energy dispersive X-ray analysis and gamma spectrometry. Fourier transform infrared spectroscopy confirmed that there was no alteration to the chemical groups of the microspheres after neutron activation. After 18 h of neutron activation, the microspheres produced an activity of 4.40 ± 0.08 GBq.g−1. The retention of 153Sm on the microspheres was greatly improved to greater than 98% over 120 h when compared to conventionally radiolabeling method at ~85%. The 153Sm2(CO3)3-PMA microspheres achieved suitable physicochemical properties as theragnostic agent for hepatic radioembolization and demonstrated high radionuclide purity and 153Sm retention efficiency in human blood plasma.
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30
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Shah HJ, Ruppell E, Bokhari R, Aland P, Lele VR, Ge C, McIntosh LJ. Current and upcoming radionuclide therapies in the direction of precision oncology: A narrative review. Eur J Radiol Open 2023; 10:100477. [PMID: 36785643 PMCID: PMC9918751 DOI: 10.1016/j.ejro.2023.100477] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 11/30/2022] [Accepted: 12/13/2022] [Indexed: 02/01/2023] Open
Abstract
As new molecular tracers are identified to target specific receptors, tissue, and tumor types, opportunities arise for the development of both diagnostic tracers and their therapeutic counterparts, termed "theranostics." While diagnostic tracers utilize positron emitters or gamma-emitting radionuclides, their theranostic counterparts are typically bound to beta and alpha emitters, which can deliver specific and localized radiation to targets with minimal collateral damage to uninvolved surrounding structures. This is an exciting time in molecular imaging and therapy and a step towards personalized and precise medicine in which patients who were either without treatment options or not candidates for other therapies now have expanded options, with tangible data showing improved outcomes. This manuscript explores the current state of theranostics, providing background, treatment specifics, and toxicities, and discusses future potential trends.
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Affiliation(s)
- Hina J. Shah
- Department of Radiology, Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA,Department of Imaging, Dana-Farber Cancer Institute, Boston, MA 02115, USA,Corresponding author at: Department of Radiology, Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.
| | - Evan Ruppell
- Department of Radiology, University of Massachusetts Chan Medical School, Memorial Health Care, Worcester, MA 01655, USA
| | - Rozan Bokhari
- Department of Radiology, Beth Israel Lahey Health, Burlington, MA 01803, USA
| | - Parag Aland
- In-charge Nuclear Medicine and PET/CT, Infinity Medical Centre, Mumbai, Maharashtra 400015, India
| | - Vikram R. Lele
- Chief, Department of Nuclear Medicine and PET/CT, Jaslok Hospital and Research Centre, Mumbai, Maharashtra 400026, India
| | - Connie Ge
- University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Lacey J. McIntosh
- Division of Oncologic and Molecular Imaging, University of Massachusetts Chan Medical School / Memorial Health Care, Worcester, MA 0165, USA
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31
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Chen S, Bas M, Happel S, Randhawa P, McNeil S, Kurakina E, Zeisler S, Maskell K, Hoehr C, Ramogida CF, Radchenko V. Determination of distribution coefficients of mercury and gold on selected extraction chromatographic resins - towards an improved separation method of mercury-197 from proton-irradiated gold targets. J Chromatogr A 2023; 1688:463717. [PMID: 36565656 DOI: 10.1016/j.chroma.2022.463717] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/11/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
Radioisotope mercury-197g (197gHg, half-life: 64.14 h) along with its metastable isomer (197mHg, half-life: 23.8 h) are potential candidates for targeted Meitner-Auger electron therapy due to their suitable decay properties. Their production can be achieved via proton irradiation of a natural gold target, but the number of studies surrounding their separation from an irradiated gold target is limited. This study focuses on the determination of distribution coefficients (Kd) of gold (III) and mercury (II) on seven extraction chromatographic resins. Mercury Kd were measured by means of radiotracers and Inductively Coupled Plasma Mass Spectrometry (ICP_MS); values obtained from the two methods were generally in good agreement. These results can provide insight on Hg and Au chemistry and aid in the design of improved separation system(s).
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Affiliation(s)
- Shaohuang Chen
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada; Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Marine Bas
- TrisKem International SAS, 3 Rue des Champs Géons ZAC de L'Éperon, Bruz, Brittany 35170, France
| | - Steffen Happel
- TrisKem International SAS, 3 Rue des Champs Géons ZAC de L'Éperon, Bruz, Brittany 35170, France
| | - Parmissa Randhawa
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada; Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Scott McNeil
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada
| | - Elena Kurakina
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada
| | - Stefan Zeisler
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada
| | - Keiran Maskell
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada; Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Cornelia Hoehr
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada; Department of Physics and Astronomy, University of Victoria, 3800 Finnerty Road, Victoria, British Columbia V8P 5C2, Canada; Department of Computer Science, Mathematics, Physics and Statistics, University of British Columbia Okanagan, 3187 University Way, Kelowna, British Columbia V1V 1V7, Canada
| | - Caterina F Ramogida
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada; Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Valery Radchenko
- Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada; Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
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Salerno KE, Roy S, Ribaudo C, Fisher T, Patel RB, Mena E, Escorcia FE. A Primer on Radiopharmaceutical Therapy. Int J Radiat Oncol Biol Phys 2023; 115:48-59. [PMID: 35970373 PMCID: PMC9772089 DOI: 10.1016/j.ijrobp.2022.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/25/2022] [Accepted: 08/03/2022] [Indexed: 12/24/2022]
Abstract
The goal of this article is to serve as a primer for the United States-based radiation oncologist who may be interested in learning more about radiopharmaceutical therapy (RPT). Specifically, we define RPT, review the data behind its current and anticipated indications, and discuss important regulatory considerations for incorporating it into clinical practice. RPT represents an opportunity for radiation oncologists to leverage 2 key areas of expertise, namely therapeutic radiation therapy and oncology, and apply them in a distinct context in collaboration with nuclear medicine and medical oncology colleagues. Although not every radiation oncologist will incorporate RPT into their day-to-day practice, it is important to understand the role for this modality and how it can be appropriately used in select patients.
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Affiliation(s)
- Kilian E Salerno
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Soumyajit Roy
- Radiation Oncology Department, Rush Medical Center, Chicago, Illinois
| | - Cathy Ribaudo
- Division of Radiation Safety, National Institutes of Health, Bethesda, Maryland
| | - Teresa Fisher
- Division of Radiation Safety, National Institutes of Health, Bethesda, Maryland
| | - Ravi B Patel
- Radiation Oncology Department, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Esther Mena
- Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Freddy E Escorcia
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Molecular Imaging Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
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Kerr CP, Grudzinski JJ, Nguyen TP, Hernandez R, Weichert JP, Morris ZS. Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment. Pharmaceutics 2022; 15:128. [PMID: 36678756 PMCID: PMC9865370 DOI: 10.3390/pharmaceutics15010128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023] Open
Abstract
Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention-a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies.
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Affiliation(s)
- Caroline P. Kerr
- Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Joseph J. Grudzinski
- Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Thanh Phuong Nguyen
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Reinier Hernandez
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Jamey P. Weichert
- Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Zachary S. Morris
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
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Takashima H, Ohnuki K, Manabe S, Koga Y, Tsumura R, Anzai T, Wang Y, Yin X, Sato N, Shigekawa Y, Nambu A, Usuda S, Haba H, Fujii H, Yasunaga M. Tumor Targeting of 211At-Labeled Antibody under Sodium Ascorbate Protection against Radiolysis. Mol Pharm 2022; 20:1156-1167. [PMID: 36573995 PMCID: PMC9906747 DOI: 10.1021/acs.molpharmaceut.2c00869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Astatine-211 (211At) is an alpha emitter applicable to radioimmunotherapy (RIT), a cancer treatment that utilizes radioactive antibodies to target tumors. In the preparation of 211At-labeled monoclonal antibodies (211At-mAbs), the possibility of radionuclide-induced antibody denaturation (radiolysis) is of concern. Our previous study showed that this 211At-induced radiochemical reaction disrupts the cellular binding activity of an astatinated mAb, resulting in attenuation of in vivo antitumor effects, whereas sodium ascorbate (SA), a free radical scavenger, prevents antibody denaturation, contributing to the maintenance of binding and antitumor activity. However, the influence of antibody denaturation on the pharmacokinetics of 211At-mAbs relating to tumor accumulation, blood circulation time, and distribution to normal organs remains unclear. In this study, we use a radioactive anti-human epidermal growth factor receptor 2 (anti-HER2) mAb to demonstrate that an 211At-induced radiochemical reaction disrupts active targeting via an antigen-antibody interaction, whereas SA helps to maintain targeting. In contrast, there was no difference in blood circulation time as well as distribution to normal organs between the stabilized and denatured immunoconjugates, indicating that antibody denaturation may not affect tumor accumulation via passive targeting based on the enhanced permeability and retention effect. In a high-HER2-expressing xenograft model treated with 1 MBq of 211At-anti-HER2 mAbs, SA-dependent maintenance of active targeting contributed to a significantly better response. In treatment with 0.5 or 0.2 MBq, the stabilized radioactive mAb significantly reduced tumor growth compared to the denatured immunoconjugate. Additionally, through a comparison between a stabilized 211At-anti-HER2 mAb and radioactive nontargeted control mAb, we demonstrate that active targeting significantly enhances tumor accumulation of radioactivity and in vivo antitumor effect. In RIT with 211At, active targeting contributes to efficient tumor accumulation of radioactivity, resulting in a potent antitumor effect. SA-dependent protection that successfully maintains tumor targeting will facilitate the clinical application of alpha-RIT.
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Affiliation(s)
- Hiroki Takashima
- Division
of Developmental Therapeutics, Exploratory
Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Kazunobu Ohnuki
- Division
of Functional Imaging, Exploratory Oncology
Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Shino Manabe
- Laboratory
of Functional Molecule Chemistry, Pharmaceutical Department and Institute
of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan,Research
Center for Pharmaceutical Development, Graduate School of Pharmaceutical
Sciences & Faculty of Pharmaceutical Sciences, Tohoku University, 6-3
Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan,Glycometabolic
Biochemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Yoshikatsu Koga
- Division
of Developmental Therapeutics, Exploratory
Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan,Department
of Strategic Programs, Exploratory Oncology
Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Ryo Tsumura
- Division
of Developmental Therapeutics, Exploratory
Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Takahiro Anzai
- Division
of Developmental Therapeutics, Exploratory
Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Yang Wang
- Nishina
Center for Accelerator-Based Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Xiaojie Yin
- Nishina
Center for Accelerator-Based Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Nozomi Sato
- Nishina
Center for Accelerator-Based Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Yudai Shigekawa
- Nishina
Center for Accelerator-Based Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Akihiro Nambu
- Nishina
Center for Accelerator-Based Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Sachiko Usuda
- Nishina
Center for Accelerator-Based Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Hiromitsu Haba
- Nishina
Center for Accelerator-Based Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Hirofumi Fujii
- Division
of Functional Imaging, Exploratory Oncology
Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan
| | - Masahiro Yasunaga
- Division
of Developmental Therapeutics, Exploratory
Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan,Tel.: +81-4-7134-6857. Fax: +81-4-7134-6866.
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Szakács Z, Lal A, Kristensen J, Farkas N, Ritter Z, Kiss S, Alizadeh H, Balikó A. 90Y-ibritumomab Tiuxetan in B-cell Non-Hodgkin Lymphomas: Real-world Data From the United Arab Emirates. Adv Radiat Oncol 2022; 7:100882. [PMID: 36148378 PMCID: PMC9486419 DOI: 10.1016/j.adro.2021.100882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 12/15/2021] [Indexed: 11/17/2022] Open
Abstract
Purpose B-cell non-Hodgkin lymphomas (NHLs) are significant contributors to cancer-related mortality. In this single-arm, retrospective cohort study, we aimed to examine the outcomes of a radioimmunotherapeutic modality, 90Y-labeled ibritumomab tiuxetan (90YIT) in B-cell NHLs. Methods and Materials We conducted this study based on data from the United Arab Emirates lymphoma registry. All patients with NHL subjected to 90YIT were eligible for inclusion. The country of research lacked a national autologous stem cell transplantation (ASCT) center, but many ASCT-eligible patients received 90YIT. We investigated overall survival (OS) and event-free survival (EFS), as well as safety outcomes. Results Between 2004 and 2008, 54 of 111 patients with B-cell NHL received radioimmunotherapy. The therapy was applied as first-line treatment in 18 cases (33.3%) and second- or later-line treatment in 36 cases (66.7%). All patients were evaluable for response. The first-line group consisted mainly of follicular lymphoma cases, and 3 of 18 patients died (16.7%) during the follow-up (range, 22-67 months). Median OS was not reached. No progression occurred after treatment (median EFS, 36.5 months [Q1-Q3 range, 30.5-44 months]). The second- or later-line group consisted mainly of diffuse large B-cell lymphoma cases, and 3 of 36 patients died (8.3%) during the follow-up (range, 4-68 months). Median OS was not reached. One case of progression was registered (median EFS: 33 months [Q1-Q3 range, 30.5-44 months]). 90YIT had acceptable short- and long-term safety profiles. Conclusions The findings suggest that patients with NHL may benefit from 90YIT as salvage treatment if ASCT is not available; however, this should be validated in randomized studies.
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Affiliation(s)
- Zsolt Szakács
- Division of Hematology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Amar Lal
- Tawam Hospital (in affiliation with Johns Hopkins Medicine), Al Ain, United Arab Emirates
| | - Jorgen Kristensen
- Sheikh Khalifa Medical City, Al Tibbiya, Abu Dhabi, United Arab Emirates
| | - Nelli Farkas
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary
| | - Zsombor Ritter
- Division of Nuclear Medicine, Department of Medical Imaging, Medical School, University of Pécs, Pécs, Hungary
| | - Szabolcs Kiss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Hussain Alizadeh
- Division of Hematology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- Corresponding author: Hussain Alizadeh, MD, PhD
| | - Anett Balikó
- Tolna County Balassa János Hospital (in affiliation with Medical School, University of Pécs), Szekszárd, Hungary
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36
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Cheal SM, Chung SK, Vaughn BA, Cheung NKV, Larson SM. Pretargeting: A Path Forward for Radioimmunotherapy. J Nucl Med 2022; 63:1302-1315. [PMID: 36215514 DOI: 10.2967/jnumed.121.262186] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/07/2022] [Indexed: 12/19/2022] Open
Abstract
Pretargeted radioimmunodiagnosis and radioimmunotherapy aim to efficiently combine antitumor antibodies and medicinal radioisotopes for high-contrast imaging and high-therapeutic-index (TI) tumor targeting, respectively. As opposed to conventional radioimmunoconjugates, pretargeted approaches separate the tumor-targeting step from the payload step, thereby amplifying tumor uptake while reducing normal-tissue exposure. Alongside contrast and TI, critical parameters include antibody immunogenicity and specificity, availability of radioisotopes, and ease of use in the clinic. Each of the steps can be optimized separately; as modular systems, they can find broad applications irrespective of tumor target, tumor type, or radioisotopes. Although this versatility presents enormous opportunity, pretargeting is complex and presents unique challenges for clinical translation and optimal use in patients. The purpose of this article is to provide a brief historical perspective on the origins and development of pretargeting strategies in nuclear medicine, emphasizing 2 protein delivery systems that have been extensively evaluated (i.e., biotin-streptavidin and hapten-bispecific monoclonal antibodies), as well as radiohaptens and radioisotopes. We also highlight recent innovations, including pretargeting with bioorthogonal chemistry and novel protein vectors (such as self-assembling and disassembling proteins and Affibody molecules). We caution the reader that this is by no means a comprehensive review of the past 3 decades of pretargeted radioimmunodiagnosis and pretargeted radioimmunotherapy. But we do aim to highlight major developmental milestones and to identify benchmarks for success with regard to TI and toxicity in preclinical models and clinically. We believe this approach will lead to the identification of key obstacles to clinical success, revive interest in the utility of radiotheranostics applications, and guide development of the next generation of pretargeted theranostics.
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Affiliation(s)
- Sarah M Cheal
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York;
| | - Sebastian K Chung
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Brett A Vaughn
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nai-Kong V Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; and
| | - Steven M Larson
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
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Stokke C, Kvassheim M, Blakkisrud J. Radionuclides for Targeted Therapy: Physical Properties. Molecules 2022; 27:5429. [PMID: 36080198 PMCID: PMC9457625 DOI: 10.3390/molecules27175429] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/19/2022] [Accepted: 08/21/2022] [Indexed: 11/16/2022] Open
Abstract
A search in PubMed revealed that 72 radionuclides have been considered for molecular or functional targeted radionuclide therapy. As radionuclide therapies increase in number and variations, it is important to understand the role of the radionuclide and the various characteristics that can render it either useful or useless. This review focuses on the physical characteristics of radionuclides that are relevant for radionuclide therapy, such as linear energy transfer, relative biological effectiveness, range, half-life, imaging properties, and radiation protection considerations. All these properties vary considerably between radionuclides and can be optimised for specific targets. Properties that are advantageous for some applications can sometimes be drawbacks for others; for instance, radionuclides that enable easy imaging can introduce more radiation protection concerns than others. Similarly, a long radiation range is beneficial in targets with heterogeneous uptake, but it also increases the radiation dose to tissues surrounding the target, and, hence, a shorter range is likely more beneficial with homogeneous uptake. While one cannot select a collection of characteristics as each radionuclide comes with an unchangeable set, all the 72 radionuclides investigated for therapy-and many more that have not yet been investigated-provide numerous sets to choose between.
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Affiliation(s)
- Caroline Stokke
- Department of Physics and Computational Radiology, Division of Radiology and Nuclear Medicine, Oslo University Hospital, P.O. Box 4959 Nydalen, 0424 Oslo, Norway
- Department of Physics, University of Oslo, Problemveien 7, 0315 Oslo, Norway
| | - Monika Kvassheim
- Department of Physics and Computational Radiology, Division of Radiology and Nuclear Medicine, Oslo University Hospital, P.O. Box 4959 Nydalen, 0424 Oslo, Norway
- Division of Clinical Medicine, University of Oslo, Problemveien 7, 0315 Oslo, Norway
| | - Johan Blakkisrud
- Department of Physics and Computational Radiology, Division of Radiology and Nuclear Medicine, Oslo University Hospital, P.O. Box 4959 Nydalen, 0424 Oslo, Norway
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38
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Bodei L, Herrmann K, Schöder H, Scott AM, Lewis JS. Radiotheranostics in oncology: current challenges and emerging opportunities. Nat Rev Clin Oncol 2022; 19:534-550. [PMID: 35725926 PMCID: PMC10585450 DOI: 10.1038/s41571-022-00652-y] [Citation(s) in RCA: 160] [Impact Index Per Article: 53.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2022] [Indexed: 12/20/2022]
Abstract
Structural imaging remains an essential component of diagnosis, staging and response assessment in patients with cancer; however, as clinicians increasingly seek to noninvasively investigate tumour phenotypes and evaluate functional and molecular responses to therapy, theranostics - the combination of diagnostic imaging with targeted therapy - is becoming more widely implemented. The field of radiotheranostics, which is the focus of this Review, combines molecular imaging (primarily PET and SPECT) with targeted radionuclide therapy, which involves the use of small molecules, peptides and/or antibodies as carriers for therapeutic radionuclides, typically those emitting α-, β- or auger-radiation. The exponential, global expansion of radiotheranostics in oncology stems from its potential to target and eliminate tumour cells with minimal adverse effects, owing to a mechanism of action that differs distinctly from that of most other systemic therapies. Currently, an enormous opportunity exists to expand the number of patients who can benefit from this technology, to address the urgent needs of many thousands of patients across the world. In this Review, we describe the clinical experience with established radiotheranostics as well as novel areas of research and various barriers to progress.
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Affiliation(s)
- Lisa Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Radiology, Weill Cornell Medical School, New York, NY, USA
| | - Ken Herrmann
- German Cancer Consortium, University Hospital Essen, Essen, Germany
- Department of Nuclear Medicine, University of Duisburg-Essen, University Hospital Essen, Essen, Germany
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Radiology, Weill Cornell Medical School, New York, NY, USA
| | - Andrew M Scott
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Jason S Lewis
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Radiology, Weill Cornell Medical School, New York, NY, USA.
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Pharmacology, Weill Cornell Medical School, New York, NY, USA.
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Alhaj Moustafa M, Peterson J, Hoppe BS, Jiang J, Wiseman GA, Witzig TE, Tun HW. Real World Long-term Follow-up Experience with Yttrium-90 ibritumomab tiuxetan in Previously Untreated Patients with Low-Grade Follicular Lymphoma and Marginal Zone Lymphoma. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:618-625. [PMID: 35400611 DOI: 10.1016/j.clml.2022.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/11/2022] [Accepted: 03/13/2022] [Indexed: 06/14/2023]
Abstract
INTRODUCTION Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immuno conjugate. Clinical trials of (90)Y-IT as a first-line stand-alone treatment in follicular lymphoma (FL) and/or marginal zone lymphoma (MZL) showed high efficacy. However, long-term survival outcomes and toxicities are not well-defined. METHODS We report a retrospective single-institution, multi-center study of (90)Y-IT in previously untreated low grade (LG)-FL and MZL at Mayo Clinic Cancer Center between January 2000 and October 2019. We selected patients with LG-FL and MZL who received standard-dose (90)Y-IT as a single agent in the first line setting. RESULTS The cohort (n = 51) consists of previously untreated LG-FL (n = 41) or MZL (n = 10). Median follow-up was 5.3 years (95% CI; 4.2, 6.2). Overall response rate (ORR) was 100% with complete response rate (CR) of 94%. Continuous CR was observed in 59% patients who had more than 2 years of follow-up. Long-term CR (>7 years) was seen in 25% of patients. Median progression free survival (mPFS) for the whole cohort was not reached (NR) (95% CI; 4.9, NR). Bulky disease was associated with shorter median PFS of 3.5 years (CI 95%; 0.8, 4.9) compared to non-bulky disease NR (CI 95%; 5.8, NR), P = .02. The incidence of grade 3 or higher thrombocytopenia, neutropenia and anemia were 47%, 37%, and 4% respectively. No therapy-related myelodysplasia or acute myeloid leukemia were observed. CONCLUSION Long real-life follow-up showed that single-agent (90)Y-IT is highly efficacious with durable long-term survival in previously untreated LG-FL and MZL without significant risk for secondary malignancies.
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Affiliation(s)
| | | | | | | | | | | | - Han W Tun
- Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
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40
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Caers J, Duray E, Vrancken L, Marcion G, Bocuzzi V, De Veirman K, Krasniqi A, Lejeune M, Withofs N, Devoogdt N, Dumoulin M, Karlström AE, D’Huyvetter M. Radiotheranostic Agents in Hematological Malignancies. Front Immunol 2022; 13:911080. [PMID: 35865548 PMCID: PMC9294596 DOI: 10.3389/fimmu.2022.911080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/06/2022] [Indexed: 12/23/2022] Open
Abstract
Radioimmunotherapy (RIT) is a cancer treatment that combines radiation therapy with tumor-directed monoclonal antibodies (Abs). Although RIT had been introduced for the treatment of CD20 positive non-Hodgkin lymphoma decades ago, it never found a broad clinical application. In recent years, researchers have developed theranostic agents based on Ab fragments or small Ab mimetics such as peptides, affibodies or single-chain Abs with improved tumor-targeting capacities. Theranostics combine diagnostic and therapeutic capabilities into a single pharmaceutical agent; this dual application can be easily achieved after conjugation to radionuclides. The past decade has seen a trend to increased specificity, fastened pharmacokinetics, and personalized medicine. In this review, we discuss the different strategies introduced for the noninvasive detection and treatment of hematological malignancies by radiopharmaceuticals. We also discuss the future applications of these radiotheranostic agents.
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Affiliation(s)
- Jo Caers
- Laboratory of Hematology, GIGA I³, University of Liège, Liège, Belgium
- Department of Hematology, CHU de Liège, Liège, Belgium
- *Correspondence: Jo Caers,
| | - Elodie Duray
- Laboratory of Hematology, GIGA I³, University of Liège, Liège, Belgium
- Centre for Protein Engineering, Inbios, University of Liège, Liège, Belgium
| | - Louise Vrancken
- Laboratory of Hematology, GIGA I³, University of Liège, Liège, Belgium
- Department of Hematology, CHU de Liège, Liège, Belgium
| | - Guillaume Marcion
- Laboratory of Hematology, GIGA I³, University of Liège, Liège, Belgium
| | - Valentina Bocuzzi
- Laboratory of Hematology, GIGA I³, University of Liège, Liège, Belgium
| | - Kim De Veirman
- Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ahmet Krasniqi
- Laboratory of In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium
| | - Margaux Lejeune
- Laboratory of Hematology, GIGA I³, University of Liège, Liège, Belgium
| | - Nadia Withofs
- Department of Nuclear Medicine, CHU de Liège, Liège, Belgium
| | - Nick Devoogdt
- Laboratory of In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium
| | - Mireille Dumoulin
- Centre for Protein Engineering, Inbios, University of Liège, Liège, Belgium
| | - Amelie Eriksson Karlström
- Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Matthias D’Huyvetter
- Laboratory of In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium
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Ning WJ, Liu X, Zeng HY, An ZQ, Luo WX, Xia NS. Recent progress in antibody-based therapeutics for triple-negative breast cancer. Expert Opin Drug Deliv 2022; 19:815-832. [PMID: 35738312 DOI: 10.1080/17425247.2022.2093853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is a subtype of severely aggressive breast cancer that lacks the expression of oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2) and is highly metastatic and related to a poor prognosis. Current standard treatments are still limited to systemic chemotherapy, radiotherapy, and surgical resection. More effective treatments are urgently needed. AREAS COVERED The immunogenicity of TNBC has provided opportunities for the development of targeted immunotherapy. In this review, we focus on the recent development in antibody-based drug modalities, including angiogenesis inhibitors, immune checkpoint inhibitors, antibody-drug conjugates, immunoconjugates, T cell-redirecting bispecific antibodies and CAR-T cells, and their mechanisms of action in TNBC. EXPERT OPINION At present, the treatment of TNBC is still a major challenge that needs to be addressed. Novel immunotherapies are promising opportunities for improving the management of this aggressive disease.
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Affiliation(s)
- Wen-Jing Ning
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Hong-Ye Zeng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Zhi-Qiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wen-Xin Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Ning-Shao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
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Jeong SH. Treatment of indolent lymphoma. Blood Res 2022; 57:120-129. [PMID: 35483936 PMCID: PMC9057664 DOI: 10.5045/br.2022.2022054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/08/2022] [Accepted: 04/21/2022] [Indexed: 11/18/2022] Open
Abstract
Treatment of indolent lymphoma has improved significantly in recent decades since the advent of rituximab (anti-CD20 monoclonal antibody). Although, some patients with limited disease can be cured with radiation therapy alone, most patients experience disease progression and recurrence during follow-up despite early initiation of treatment. Thus, watch-and-wait is still regarded the standard for asymptomatic patients. Patients with indolent lymphoma have a significant heterogeneity in terms of tumor burden, symptoms (according to anatomical sites) and the need for instant therapy. Therefore, the initiation of treatment and treatment option should be decided with a clear goal in each patient according to the need for therapy and clinical benefits with the chosen treatment. In this review, we cover the current treatment of follicular lymphoma and marginal zone lymphoma.
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Affiliation(s)
- Seong Hyun Jeong
- Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea
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43
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Kind F, Michalski K, Yousefzadeh-Nowshahr E, Meyer PT, Mix M, Ruf J. Bone marrow impairment during early [ 177Lu]PSMA-617 radioligand therapy: Haematotoxicity or tumour progression? EJNMMI Res 2022; 12:20. [PMID: 35403915 PMCID: PMC9001754 DOI: 10.1186/s13550-022-00891-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/27/2022] [Indexed: 11/23/2022] Open
Abstract
Background The recent phase III VISION-trial confirms the treatment efficacy of radioligand therapy with [177Lu]PSMA-617 (PSMA-RLT) in metastatic castration-resistant prostate cancer (mCRPC). In PSMA-RLT, the relatively low absorbed bone marrow dose allows for multiple therapy cycles with relatively low risk of haematological adverse events (hAE). However, as disease progression itself may be a cause of bone marrow impairment, the aim of this study was to assess potential relations between impairment of haematological status and response to PSMA-RLT. Methods In this retrospective analysis, haematological parameters (HP) of 64 patients with mCRPC were systematically acquired over two cycles (12–16 weeks) of PSMA-RLT from baseline to restaging. Changes in HP were analysed qualitatively (CTCAE 5.0) and quantitatively. The HP changes from baseline were compared to quantitative and qualitative biochemical and imaging response, using PCWG3 and PROMISE criteria. Results All grade 3/4 hAE observed were associated with disseminated or diffuse bone involvement as well as biochemical non-response at restaging. Quantitatively, at baseline, HP inversely correlated with biochemical and volumetric (on PET) tumour burden as well as bone involvement pattern (p ≤ 0.043). Among patients with disseminated or diffuse bone involvement, percentage changes in HP (%HP) at restaging inversely correlated with serological and imaging tumour burden (p ≤ 0.017). Biochemical non-responders showed a significant decrease in %HP (p ≤ 0.001) while HP in biochemical responders remained stable (p ≥ 0.079). Conclusion During early cycles of PSMA-RLT, qualitative and quantitative bone marrow impairment appears to be closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events, showing a significant decline of haematological parameters. This implies that in patients with advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles. German Clinical Trial Register DRKS00013665. Registered 28 December 2017, retrospectively registered (www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013665)
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Affiliation(s)
- Felix Kind
- Department of Nuclear Medicine, Faculty of Medicine, Medical Centre - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.
| | - Kerstin Michalski
- Department of Nuclear Medicine, Faculty of Medicine, Medical Centre - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Elham Yousefzadeh-Nowshahr
- Department of Nuclear Medicine, Faculty of Medicine, Medical Centre - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany
| | - Philipp T Meyer
- Department of Nuclear Medicine, Faculty of Medicine, Medical Centre - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Michael Mix
- Department of Nuclear Medicine, Faculty of Medicine, Medical Centre - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Juri Ruf
- Department of Nuclear Medicine, Faculty of Medicine, Medical Centre - University of Freiburg, Hugstetter Str. 55, 79106, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair. Expert Rev Mol Med 2022; 24:e15. [PMID: 35357290 DOI: 10.1017/erm.2022.6] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α-particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose.
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45
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90-yttrium-ibritumomab tiuxetan as first-line treatment for follicular lymphoma: updated efficacy and safety results at an extended median follow-up of 9.6 years. Ann Hematol 2022; 101:781-788. [PMID: 35150296 PMCID: PMC8913448 DOI: 10.1007/s00277-022-04781-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/27/2022] [Indexed: 11/29/2022]
Abstract
Radioimmunotherapy with 90-yttrium-ibritumomab tiuxetan (90Y-IT) as first-line treatment in patients with follicular lymphoma (FL) demonstrated promising results with a complete remission (CR) rate of 56% and a median progression-free survival (PFS) of 26 months, when initially analyzed after a median follow-up of 30.6 months. The aim of this long-term follow-up was to investigate whether clinical benefits were maintained and new safety signals appeared. Fifty-nine patients, aged ≥ 50 years, with FL grade 1 to 3A in stages II to IV were treated with 90Y-IT as first-line therapy. If CR without evidence of minimal residual disease (MRD), partial response or stable disease was achieved 6 months after treatment, patients were observed without further treatment. Patients with CR but persisting MRD received consolidation therapy with rituximab. The primary endpoint was the clinical response rate. Secondary endpoints were time to progression, safety, and tolerability. After a median follow-up of 9.6 years, median PFS was 3.6 years, and 8-year PFS was 38.3%. Median overall survival (OS) was not reached during the extended follow-up, and 8-year OS amounted to 69.2%. Age 65 years and above or disease progression within 24 months of treatment were significantly associated with shorter OS. An important finding was the lack of new safety signals. In particular, no increase in secondary malignancies or transformation into aggressive lymphoma was observed compared to trials with a similar follow-up. In summary, 90Y-IT as first-line treatment demonstrates a favorable safety profile and long-term clinical activity in a substantial fraction of FL patients in need of therapy. ClinicalTrials.gov Identifier: NCT00772655.
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Cicone F, Sarnelli A, Guidi C, Belli ML, Ferrari ME, Wahl R, Cremonesi M, Paganelli G. Dosimetric Approaches for Radioimmunotherapy of Non-Hodgkin Lymphoma in Myeloablative Setting. Semin Nucl Med 2022; 52:191-214. [PMID: 34996594 DOI: 10.1053/j.semnuclmed.2021.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Radioimmunotherapy (RIT) is a safe and active treatment available for non-Hodgkin lymphomas (NHLs). In particular, two monoclonal antibodies raised against CD20, that is Zevalin (90Y-ibritumomab-tiuxetan) and Bexxar (131I-tositumomab) received FDA approval for the treatment of relapsing/refractory indolent or transformed NHLs. RIT is likely the most effective and least toxic anticancer agent in NHLs. However, its use in the clinical setting is still debated and, in case of relapse after optimized rituximab-containing regimens, the efficacy of RIT at standard dosage is suboptimal. Thus, clinical trials were based on the hypothesis that the inclusion of RIT in myeloablative conditioning would allow to obtain improved efficacy and toxicity profiles when compared to myeloablative total-body irradiation and/or high-dose chemotherapy regimens. Standard-activity RIT has a safe toxicity profile, and the utility of pretherapeutic dosimetry in this setting can be disputed. In contrast, dose-escalation clinical protocols require the assessment of radiopharmaceutical biodistribution and dosimetry before the therapeutic injection, as dose constrains for critical organs may be exceeded when RIT is administered at high activities. The aim of the present study was to review and discuss the internal dosimetry protocols that were adopted for non-standard RIT administration in the myeloablative setting before hematopoietic stem cell transplantation in patients with NHLs.
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Affiliation(s)
- Francesco Cicone
- Department of Experimental and Clinical Medicine, and Neuroscience Research Centre, PET/RM Unit, "Magna Graecia" University of Catanzaro, Catanzaro, Italy; Nuclear Medicine Unit, University Hospital "Mater Domini", Catanzaro, Italy
| | - Anna Sarnelli
- Medical Physics Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
| | - Claretta Guidi
- Medical Physics Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Maria Luisa Belli
- Medical Physics Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | | | - Richard Wahl
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Marta Cremonesi
- Radiation Research Unit, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Giovanni Paganelli
- Nuclear Medicine Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
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47
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Coltoff AR, Jurcic JG. Targeted radionuclide therapy of hematologic malignancies. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00117-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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48
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Duan H, Iagaru A, Aparici CM. Radiotheranostics - Precision Medicine in Nuclear Medicine and Molecular Imaging. Nanotheranostics 2022; 6:103-117. [PMID: 34976584 PMCID: PMC8671964 DOI: 10.7150/ntno.64141] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/09/2021] [Indexed: 02/07/2023] Open
Abstract
'See what you treat and treat what you see, at a molecular level', could be the motto of theranostics. The concept implies diagnosis (imaging) and treatment of cells (usually cancer) using the same molecule, thus guaranteeing a targeted cytotoxic approach of the imaged tumor cells while sparing healthy tissues. As the brilliant late Sam Gambhir would say, the imaging agent acts like a 'molecular spy' and reveals where the tumoral cells are located and the extent of disease burden (diagnosis). For treatment, the same 'molecular spy' docks to the same tumor cells, this time delivering cytotoxic doses of radiation (treatment). This duality represents the concept of a 'theranostic pair', which follows the scope and fundamental principles of targeted precision and personalized medicine. Although the term theranostic was noted in medical literature in the early 2000s, the principle is not at all new to nuclear medicine. The first example of theranostic dates back to 1941 when Dr. Saul Hertz first applied radioiodine for radionuclide treatment of thyroid cells in patients with hyperthyroidism. Ever since, theranostics has been an integral element of nuclear medicine and molecular imaging. The more we understand tumor biology and molecular pathology of carcinogenesis, including specific mutations and receptor expression profiles, the more specific these 'molecular spies' can be developed for diagnostic molecular imaging and subsequent radionuclide targeted therapy (radiotheranostics). The appropriate selection of the diagnostic and therapeutic radionuclide for the 'theranostic pair' is critical and takes into account not only the type of cytotoxic radiation emission, but also the linear energy transfer (LET), and the physical half-lives. Advances in radiochemistry and radiopharmacy with new radiolabeling techniques and chelators are revolutionizing the field. The landscape of cytotoxic systemic radionuclide treatments has dramatically expanded through the past decades thanks to all these advancements. This article discusses present and promising future theranostic applications for various types of diseases such as thyroid disorders, neuroendocrine tumors (NET), pediatric malignancies, and prostate cancer (PC), and provides an outlook for future perspectives.
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Affiliation(s)
| | | | - Carina Mari Aparici
- Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Stanford University, Stanford, CA, USA
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49
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De Veirman K, Puttemans J, Krasniqi A, Ertveldt T, Hanssens H, Romao E, Hose D, Goyvaert C, Vlummens P, Muyldermans S, Breckpot K, Bruchertseifer F, Morgenstern A, D'Huyvetter M, Devoogdt N. CS1-specific single-domain antibodies labeled with Actinium-225 prolong survival and increase CD8+ T cells and PD-L1 expression in Multiple Myeloma. Oncoimmunology 2021; 10:2000699. [PMID: 34777918 PMCID: PMC8583167 DOI: 10.1080/2162402x.2021.2000699] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment option to eradicate residual cancer cells. In this study, we developed and characterized single-domain antibodies (sdAbs) against the MM-antigen CS1 and evaluated its therapeutic potential in MM using TRNT. We first validated CS1 as potential target for TRNT. CS1 is expressed in normal and malignant plasma cells in different disease stages including progression and relapse. It is expressed in dormant as well as proliferating MM cells, while low expression could be observed in environmental cells. Biodistribution studies demonstrated the specific uptake of anti-CS1 sdAbs in tissues of 5TMM cell infiltration including bone, spleen and liver. TRNT using anti-CS1 sdAbs labeled with actinium-225 significantly prolonged survival of syngeneic, immunocompetent 5T33MM mice. In addition, we observed an increase in CD8+ T-cells and more overall PD-L1 expression on immune and non-immune cells, implying an interferon gamma signature using actinium-225 labeled CS1-directed sdAbs. In this proof-of-principle study, we highlight, for the first time, the therapeutic potential and immunomodulating effects of anti-CS1 radionuclide therapy to target residual MM cells.
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Affiliation(s)
- Kim De Veirman
- Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Janik Puttemans
- Department of Medical Imaging, Laboratory for in Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ahmet Krasniqi
- Department of Medical Imaging, Laboratory for in Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Brussels, Belgium
| | - Thomas Ertveldt
- Laboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Heleen Hanssens
- Department of Medical Imaging, Laboratory for in Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ema Romao
- Department of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Dirk Hose
- Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Cleo Goyvaert
- Laboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Philip Vlummens
- Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.,Department of Clinical Hematology, Ghent University Hospital, Ghent, Belgium
| | - Serge Muyldermans
- Department of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Karine Breckpot
- Laboratory for Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | | | | | - Matthias D'Huyvetter
- Department of Medical Imaging, Laboratory for in Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Brussels, Belgium
| | - Nick Devoogdt
- Department of Medical Imaging, Laboratory for in Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel, Brussels, Belgium
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50
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Calais J, Czernin J, Thin P, Gartmann J, Nguyen K, Armstrong WR, Allen-Auerbach M, Quon A, Bahri S, Gupta P, Gardner L, Dahlbom M, He B, Esfandiari R, Ranganathan D, Herrmann K, Eiber M, Fendler WP, Delpassand E. Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312). J Nucl Med 2021; 62:1447-1456. [PMID: 34272322 PMCID: PMC8724902 DOI: 10.2967/jnumed.121.262543] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/07/2021] [Indexed: 11/16/2022] Open
Abstract
The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.
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Affiliation(s)
| | | | - Pan Thin
- Ahmanson Translational Theranostics Division, Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Jeannine Gartmann
- Ahmanson Translational Theranostics Division, Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Kathleen Nguyen
- Ahmanson Translational Theranostics Division, Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Wesley R. Armstrong
- Ahmanson Translational Theranostics Division, Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | | | | | | | - Pawan Gupta
- Ahmanson Translational Theranostics Division, Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Linda Gardner
- Ahmanson Translational Theranostics Division, Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Magnus Dahlbom
- Ahmanson Translational Theranostics Division, Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, California
| | - Beilei He
- Advanced Accelerator Applications, a Novartis Company, Geneva, Switzerland
| | | | | | - Ken Herrmann
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; and
| | - Matthias Eiber
- Department of Nuclear Medicine, Technical University Munich, Klinikum rechts der Isar, Munich, Germany
| | - Wolfgang P. Fendler
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; and
| | - Ebrahim Delpassand
- Excel Diagnostics and Nuclear Oncology Center, Houston, Texas
- RadioMedix, Inc., Houston, Texas
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