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1
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Liang G, Ma Y, Deng P, Li S, He C, He H, Liu H, Fan Y, Li Z. Role of cell-based therapies in digestive disorders: Obstacles and opportunities. Regen Ther 2025; 29:1-18. [PMID: 40124469 PMCID: PMC11925584 DOI: 10.1016/j.reth.2025.02.009] [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: 12/22/2024] [Revised: 02/01/2025] [Accepted: 02/20/2025] [Indexed: 03/25/2025] Open
Abstract
Stem cell-based therapies have emerged as a promising frontier in the treatment of gastrointestinal disorders, offering potential solutions for challenges posed by conventional treatments. This review comprehensively examines recent advancements in cell-based therapeutic strategies, particularly focusing on stem cell applications, immunotherapy, and cellular therapies for digestive diseases. It highlights the successful differentiation of enteric neural progenitors from pluripotent stem cells and their application in animal models, such as Hirschsprung disease. Furthermore, the review evaluates clinical trials and experimental studies demonstrating the potential of stem cells in regenerating damaged tissues, modulating immune responses, and promoting healing in conditions like Crohn's disease and liver failure. By addressing challenges, such as scalability, immunogenicity, and ethical considerations, the review underscores the translational opportunities and obstacles in realizing the clinical potential of these therapies. Concluding with an emphasis on future directions, the study provides insights into optimizing therapeutic efficacy and fostering innovations in personalized medicine for digestive disorders.
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Affiliation(s)
- Guodong Liang
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yuehan Ma
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ping Deng
- Medical Department, Jilin Cancer Hospital, Changchun 130012, China
| | - Shufeng Li
- First Department of Gynecological Tumor, Jilin Cancer Hospital, Changchun 130012, China
| | - Chunyan He
- Department of Anaesthesia, Jilin Cancer Hospital, Changchun 130012, China
| | - Haihang He
- Department of Otorhinolaryngology, Oral Maxillofacial, Head and Neck, Jilin Cancer Hospital, Changchun 130012, China
| | - Hairui Liu
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Yunda Fan
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
| | - Ze Li
- First Surgery Department of Colorectal, Gastric and Abdominal Tumors, Jilin Cancer Hospital, Changchun 130012, China
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Alb M, Reiche K, Rade M, Sewald K, Loskill P, Cipriano M, Maulana TI, van der Meer AD, Weener HJ, Clerbaux LA, Fogal B, Patel N, Adkins K, Lund E, Perkins E, Cooper C, van den Brulle J, Morgan H, Rubic-Schneider T, Ling H, DiPetrillo K, Moggs J, Köhl U, Hudecek M. Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept. J Immunotoxicol 2024; 21:S13-S28. [PMID: 39655500 DOI: 10.1080/1547691x.2024.2345158] [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: 07/10/2023] [Revised: 02/21/2024] [Accepted: 04/15/2024] [Indexed: 12/18/2024] Open
Abstract
The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable in vitro and in vivo models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy. The IMI2/EU project imSAVAR (immune safety avatar: non-clinical mimicking of the immune system effects of immunomodulatory therapies) aims at creating a platform for novel tools and models for enhanced non-clinical prediction of possible adverse events associated with immunomodulatory therapies. This platform shall in the future guide early non-clinical safety assessment of novel immune therapeutics thereby also reducing the costs of their development. Therefore, we review current opportunities and challenges associated with non-clinical in vitro and in vivo models for the safety assessment of CAR T cell therapy ranging from organ-on-chip models up to advanced biomarker screening.
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MESH Headings
- Humans
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Cytokine Release Syndrome/immunology
- Cytokine Release Syndrome/therapy
- Cytokine Release Syndrome/diagnosis
- Animals
- T-Lymphocytes/immunology
- Neoplasms/therapy
- Neoplasms/immunology
- Cytokines/metabolism
- Cytokines/immunology
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/genetics
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Affiliation(s)
- Miriam Alb
- Medizinische Klinik und Poliklinik II, Lehrstuhl für Zelluläre Immuntherapie, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Kristin Reiche
- Fraunhofer-Institut für Zelltherapie und Immunologie IZI, Leipzig, Germany
| | - Michael Rade
- Fraunhofer-Institut für Zelltherapie und Immunologie IZI, Leipzig, Germany
| | - Katherina Sewald
- Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM, Hannover, Germany
| | - Peter Loskill
- Institute for Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany
- 3R-Center for In vitro Models and Alternatives to Animal Testing, Eberhard Karls University Tübingen, Tübingen
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Madalena Cipriano
- Institute for Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany
- 3R-Center for In vitro Models and Alternatives to Animal Testing, Eberhard Karls University Tübingen, Tübingen
| | - Tengku Ibrahim Maulana
- Institute for Biomedical Engineering, Eberhard Karls University Tübingen, Tübingen, Germany
- 3R-Center for In vitro Models and Alternatives to Animal Testing, Eberhard Karls University Tübingen, Tübingen
| | | | - Huub J Weener
- Applied Stem Cell Technologies, University of Twente, Enschede, the Netherlands
| | | | - Birgit Fogal
- Department on Nonclinical Drug Safety, Boehringer Ingelheim Pharmaceutical, Inc, Ridgefield, CT, USA
| | - Nirav Patel
- Preclinical Safety, Research and Development, Sanofi-Aventis US, LLC, Cambridge, MA, USA
| | - Karissa Adkins
- Preclinical Safety, Research and Development, Sanofi-Aventis US, LLC, Cambridge, MA, USA
| | - Emma Lund
- Labcorp Drug Development Inc, Derbyshire, UK
| | | | | | | | - Hannah Morgan
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | | | - Hui Ling
- Novartis Biomedical Research, Cambridge, MA, USA
| | | | - Jonathan Moggs
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Ulrike Köhl
- Fraunhofer-Institut für Zelltherapie und Immunologie IZI, Leipzig, Germany
| | - Michael Hudecek
- Medizinische Klinik und Poliklinik II, Lehrstuhl für Zelluläre Immuntherapie, Universitätsklinikum Würzburg, Würzburg, Germany
- Fraunhofer-Institut für Zelltherapie und Immunologie IZI, Leipzig, Germany
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3
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Yoshimoto S, Kudo A, Rotolo A, Foos K, Olenick L, Takagi S, Mason NJ. Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma. iScience 2024; 27:110863. [PMID: 39314237 PMCID: PMC11418608 DOI: 10.1016/j.isci.2024.110863] [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: 01/10/2024] [Revised: 07/07/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical outcomes in patients with relapsed/refractory B cell leukemias; however, response rates in patients with large B cell lymphoma (LBCL) are less impressive. Expression of PD-1 on activated T cells and PD-L1 on malignant, stromal, and immune cells within the tumor microenvironment (TME) contribute to CAR-T exhaustion, hypofunction, and treatment failures. Here, a comparative approach is taken to develop a chimeric switch receptor (CSR) with potential to augment CAR-T persistence, function, and clinical efficacy in immune competent, pet dogs with spontaneous B cell lymphoma (BCL). We show that similar to human CAR-T cells, expression of a PD-1/CD28 CSR in canine CAR-T cells results in enhanced function against PD-L1+ targets and preserves central memory phenotype. We also demonstrate that these effects depend upon active CSR signaling. This work paves the way for in vivo studies in canine BCL patients to inform human trial design.
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Affiliation(s)
- Sho Yoshimoto
- Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, Japan
| | - Ayano Kudo
- Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, Japan
| | - Antonia Rotolo
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kay Foos
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lauren Olenick
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Satoshi Takagi
- Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, Japan
| | - Nicola J. Mason
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Srivastava S, Singh S, Singh A. Augmenting the landscape of chimeric antigen receptor T-cell therapy. Expert Rev Anticancer Ther 2024; 24:755-773. [PMID: 38912754 DOI: 10.1080/14737140.2024.2372330] [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: 02/01/2024] [Accepted: 06/21/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION The inception of recombinant DNA technology and live cell genomic alteration have paved the path for the excellence of cell and gene therapies and often provided the first curative treatment for many indications. The approval of the first Chimeric Antigen Receptor (CAR) T-cell therapy was one of the breakthrough innovations that became the headline in 2017. Currently, the therapy is primarily restricted to a few nations, and the market is growing at a CAGR (current annual growth rate) of 11.6% (2022-2032), as opposed to the established bio-therapeutic market at a CAGR of 15.9% (2023-2030). The limited technology democratization is attributed to its autologous nature, lack of awareness, therapy inclusion criteria, high infrastructure cost, trained personnel, complex manufacturing processes, regulatory challenges, recurrence of the disease, and long-term follow-ups. AREAS COVERED This review discusses the vision and strategies focusing on the CAR T-cell therapy democratization with mitigation plans. Further, it also covers the strategies to leverage the mRNA-based CAR T platform for building an ecosystem to ensure availability, accessibility, and affordability to the community. EXPERT OPINION mRNA-guided CAR T cell therapy is a rapidly growing area wherein a collaborative approach among the stakeholders is needed for its success.
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Affiliation(s)
| | - Sanjay Singh
- mRNA Department, Gennova Biopharmaceuticals Ltd. ITBT Park, Pune, India
| | - Ajay Singh
- mRNA Department, Gennova Biopharmaceuticals Ltd. ITBT Park, Pune, India
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Rotolo A, Atherton MJ. Applications and Opportunities for Immune Cell CAR Engineering in Comparative Oncology. Clin Cancer Res 2024; 30:2359-2369. [PMID: 38573683 PMCID: PMC11147717 DOI: 10.1158/1078-0432.ccr-23-3690] [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] [Received: 12/07/2023] [Revised: 01/31/2024] [Accepted: 04/02/2024] [Indexed: 04/05/2024]
Abstract
Chimeric antigen receptor (CAR) T-adoptive cell therapy has transformed the treatment of human hematologic malignancies. However, its application for the treatment of solid tumors remains challenging. An exciting avenue for advancing this field lies in the use of pet dogs, in which cancers that recapitulate the biology, immunological features, and clinical course of human malignancies arise spontaneously. Moreover, their large size, outbred genetic background, shared environment with humans, and immunocompetency make dogs ideal for investigating and optimizing CAR therapies before human trials. Here, we will outline how challenges in early clinical trials in patients with canine lymphoma, including issues related to autologous CAR T-cell manufacturing, limited CAR T-cell persistence, and tumor antigen escape, mirrored challenges observed in human CAR T trials. We will then highlight emerging adoptive cell therapy strategies currently under investigation in dogs with hematological and solid cancers, which will provide crucial safety and efficacy data on novel CAR T regimens that can be used to support clinical trials. By drawing from ongoing studies, we will illustrate how canine patients with spontaneous cancer may serve as compelling screening platforms to establish innovative CAR therapy approaches and identify predictive biomarkers of response, with a specific emphasis on solid tumors. With increased funding for canine immunotherapy studies, multi-institutional investigations are poised to generate highly impactful clinical data that should translate into more effective human trials, ultimately benefiting both human and canine cancer patients.
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MESH Headings
- Animals
- Dogs
- Humans
- Dog Diseases/therapy
- Dog Diseases/immunology
- Immunotherapy, Adoptive/methods
- Neoplasms/therapy
- Neoplasms/immunology
- Neoplasms/genetics
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Clinical Trials, Veterinary as Topic
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Affiliation(s)
- Antonia Rotolo
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Matthew J. Atherton
- Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
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6
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Bergman PJ. Cancer Immunotherapy. Vet Clin North Am Small Anim Pract 2024; 54:441-468. [PMID: 38158304 DOI: 10.1016/j.cvsm.2023.12.002] [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: 01/03/2024]
Abstract
The enhanced understanding of immunology experienced over the last 5 decades afforded through the tools of molecular biology has recently translated into cancer immunotherapy becoming one of the most exciting and rapidly expanding fields. Human cancer immunotherapy is now recognized as one of the pillars of treatment alongside surgery, radiation, and chemotherapy. The field of veterinary cancer immunotherapy has also rapidly advanced in the last decade with a handful of commercially available products and a plethora of investigational cancer immunotherapies, which will hopefully expand our veterinary oncology treatment toolkit over time.
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Affiliation(s)
- Philip J Bergman
- Clinical Studies, VCA; Katonah Bedford Veterinary Center, Bedford Hills, NY, USA; Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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7
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Berdecka D, De Smedt SC, De Vos WH, Braeckmans K. Non-viral delivery of RNA for therapeutic T cell engineering. Adv Drug Deliv Rev 2024; 208:115215. [PMID: 38401848 DOI: 10.1016/j.addr.2024.115215] [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: 11/21/2023] [Revised: 02/07/2024] [Accepted: 02/14/2024] [Indexed: 02/26/2024]
Abstract
Adoptive T cell transfer has shown great success in treating blood cancers, resulting in a growing number of FDA-approved therapies using chimeric antigen receptor (CAR)-engineered T cells. However, the effectiveness of this treatment for solid tumors is still not satisfactory, emphasizing the need for improved T cell engineering strategies and combination approaches. Currently, CAR T cells are mainly manufactured using gammaretroviral and lentiviral vectors due to their high transduction efficiency. However, there are concerns about their safety, the high cost of producing them in compliance with current Good Manufacturing Practices (cGMP), regulatory obstacles, and limited cargo capacity, which limit the broader use of engineered T cell therapies. To overcome these limitations, researchers have explored non-viral approaches, such as membrane permeabilization and carrier-mediated methods, as more versatile and sustainable alternatives for next-generation T cell engineering. Non-viral delivery methods can be designed to transport a wide range of molecules, including RNA, which allows for more controlled and safe modulation of T cell phenotype and function. In this review, we provide an overview of non-viral RNA delivery in adoptive T cell therapy. We first define the different types of RNA therapeutics, highlighting recent advancements in manufacturing for their therapeutic use. We then discuss the challenges associated with achieving effective RNA delivery in T cells. Next, we provide an overview of current and emerging technologies for delivering RNA into T cells. Finally, we discuss ongoing preclinical and clinical studies involving RNA-modified T cells.
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Affiliation(s)
- Dominika Berdecka
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
| | - Stefaan C De Smedt
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Winnok H De Vos
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
| | - Kevin Braeckmans
- Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
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Stucchi A, Maspes F, Montee-Rodrigues E, Fousteri G. Engineered Treg cells: The heir to the throne of immunotherapy. J Autoimmun 2024; 144:102986. [PMID: 36639301 DOI: 10.1016/j.jaut.2022.102986] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/15/2022] [Indexed: 01/13/2023]
Abstract
Recently, increased interest in the use of Tregs as adoptive cell therapy for the treatment of autoimmune diseases and transplant rejection had led to several advances in the field. However, Treg cell therapies, while constantly advancing, indiscriminately suppress the immune system without the permanent stabilization of certain diseases. Genetically modified Tregs hold great promise towards solving these problems, but, challenges in identifying the most potent Treg subtype, accompanied by the ambiguity involved in identifying the optimal Treg source, along with its expansion and engineering in a clinical-grade setting remain paramount. This review highlights the recent advances in methodologies for the development of genetically engineered Treg cell-based treatments for autoimmune, inflammatory diseases, and organ rejection. Additionally, it provides a systematized guide to all the recent progress in the field and informs the readers of the feasibility and safety of engineered adoptive Treg cell therapy, with the aim to provide a framework for researchers involved in the development of engineered Tregs.
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Affiliation(s)
- Adriana Stucchi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Federica Maspes
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Ely Montee-Rodrigues
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Cambridge Epigenetix, Cambridge, Cambridgeshire, United Kingdom
| | - Georgia Fousteri
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
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Cao JW, Lake J, Impastato R, Chow L, Perez L, Chubb L, Kurihara J, Verneris MR, Dow S. Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity. Cancer Immunol Immunother 2024; 73:77. [PMID: 38554158 PMCID: PMC10981605 DOI: 10.1007/s00262-024-03642-4] [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: 11/09/2023] [Accepted: 01/25/2024] [Indexed: 04/01/2024]
Abstract
The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. The goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed B7-H3; whereas, levels were undetectable on normal dog tissues. Both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little anti-tumor activity was generated by B7-H3 CAR T cells; whereas, B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.
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Affiliation(s)
- Jennifer W Cao
- Department of Microbiology, Immunology, and Pathology, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Campus Delivery 1678, Fort Collins, CO, USA
| | - Jessica Lake
- Department of Pediatrics, Center for Cancer and Blood Disorders, University of Colorado and Children's Hospital of Colorado, Research Complex 1, North Tower 12800 E. 19th Ave. Mail Stop 8302, Room P18-4108, Aurora, CO, 80045, USA
| | - Renata Impastato
- Department of Clinical Sciences, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Lyndah Chow
- Department of Clinical Sciences, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Luisanny Perez
- Department of Clinical Sciences, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Laura Chubb
- Department of Clinical Sciences, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Jade Kurihara
- Department of Clinical Sciences, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
| | - Michael R Verneris
- Department of Pediatrics, Center for Cancer and Blood Disorders, University of Colorado and Children's Hospital of Colorado, Research Complex 1, North Tower 12800 E. 19th Ave. Mail Stop 8302, Room P18-4108, Aurora, CO, 80045, USA.
| | - Steven Dow
- Department of Microbiology, Immunology, and Pathology, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Campus Delivery 1678, Fort Collins, CO, USA.
- Department of Clinical Sciences, Flint Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
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10
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Xia YY, Chi KH, Liao AT, Lee JJ. Limited Clinical Efficacy with Potential Adverse Events in a Pilot Study of Autologous Adoptive Cell Therapy in Canine Oral Malignant Melanoma. Vet Sci 2024; 11:150. [PMID: 38668417 PMCID: PMC11053650 DOI: 10.3390/vetsci11040150] [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: 02/28/2024] [Revised: 03/21/2024] [Accepted: 03/24/2024] [Indexed: 04/29/2024] Open
Abstract
Adoptive cell therapy (ACT) has been studied in several human and canine cancers with some promising clinical outcomes but not in canine oral malignant melanoma (OMM). Our manuscript aimed to explore one kind of ACT, the ex vivo-expanded autologous immune cell infusion in canine OMM, as this tumor remains a treatment dilemma. The study recruited dogs with histopathological diagnoses of oral malignant melanoma, generated their peripheral blood mononuclear cells, expanded them into predominantly non-B non-T cells via stimulations of IL-15, IL-2, and IL-21, and then re-infused the cells into tumor-bearing dogs. Ten dogs were enrolled; three dogs did not report any adverse events; three had a mildly altered appetite; one had a mildly increased liver index, while the other three developed suspected anaphylaxis at different levels. The median progression-free interval was 49 days. Dogs with progressive disease during treatment had a shorter survival. This pilot study indicates limited efficacy with potential adverse events of this ACT. Most recruited patients were in a later stage and had macroscopic disease, which might affect the treatment efficacy. Further exploration of this cell therapy in an adjuvant setting, with adequate protocol modification and standardization, could still be considered.
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Affiliation(s)
- Yuan-Yuan Xia
- Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipe 10617, Taiwan; (Y.-Y.X.); (A.T.L.)
- National Taiwan University Veterinary Hospital, College of Bioresources and Agriculture, National Taiwan University, Taipei 10672, Taiwan
| | - Kwan-Hwa Chi
- Graduate Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan;
- Department of Radiation Therapy & Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan
| | - Albert Taiching Liao
- Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipe 10617, Taiwan; (Y.-Y.X.); (A.T.L.)
| | - Jih-Jong Lee
- National Taiwan University Veterinary Hospital, College of Bioresources and Agriculture, National Taiwan University, Taipei 10672, Taiwan
- Graduate Institute of Veterinary Clinical Science, School of Veterinary Medicine, National Taiwan University, Taipei 10617, Taiwan;
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11
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Dey S, Devender M, Rani S, Pandey RK. Recent advances in CAR T-cell engineering using synthetic biology: Paving the way for next-generation cancer treatment. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 140:91-156. [PMID: 38762281 DOI: 10.1016/bs.apcsb.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2024]
Abstract
This book chapter highlights a comprehensive exploration of the transformative innovations in the field of cancer immunotherapy. CAR (Chimeric Antigen Receptor) T-cell therapy represents a groundbreaking approach to treat cancer by reprogramming a patient immune cells to recognize and destroy cancer cells. This chapter underscores the critical role of synthetic biology in enhancing the safety and effectiveness of CAR T-cell therapies. It begins by emphasizing the growing importance of personalized medicine in cancer treatment, emphasizing the shift from one-size-fits-all approaches to patient-specific solutions. Synthetic biology, a multidisciplinary field, has been instrumental in customizing CAR T-cell therapies, allowing for fine-tuned precision and minimizing unwanted side effects. The chapter highlights recent advances in gene editing, synthetic gene circuits, and molecular engineering, showcasing how these technologies are optimizing CAR T-cell function. In summary, this book chapter sheds light on the remarkable progress made in the development of CAR T-cell therapies using synthetic biology, providing hope for cancer patients and hinting at a future where highly personalized and effective cancer treatments are the norm.
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Affiliation(s)
- Sangita Dey
- CSO Department, Cellworks Research India Pvt Ltd, Bengaluru, Karnataka, India
| | - Moodu Devender
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Swati Rani
- ICAR, National Institute of Veterinary Epidemiology and Disease Informatics, Bengaluru, Karnataka, India
| | - Rajan Kumar Pandey
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden.
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12
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Stock S, Klüver AK, Fertig L, Menkhoff VD, Subklewe M, Endres S, Kobold S. Mechanisms and strategies for safe chimeric antigen receptor T-cell activity control. Int J Cancer 2023; 153:1706-1725. [PMID: 37350095 DOI: 10.1002/ijc.34635] [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: 02/26/2023] [Revised: 05/07/2023] [Accepted: 06/02/2023] [Indexed: 06/24/2023]
Abstract
The clinical application of chimeric antigen receptor (CAR) T-cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood-borne cancer types. However, CAR T-cell therapy can lead to severe therapy-associated toxicities including CAR-related hematotoxicity, ON-target OFF-tumor toxicity, cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Just as CAR T-cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T-cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T-cell activity. These approaches can mediate a reversible resting state or irreversible T-cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T-cells with T-cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T-cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T-cell activity can be regulated intracellularly through a self-regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T-cells reversibly or irreversibly for preventing and for managing therapy-associated toxicities.
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Affiliation(s)
- Sophia Stock
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- Department of Medicine III, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Anna-Kristina Klüver
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Luisa Fertig
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Vivien D Menkhoff
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Marion Subklewe
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany
| | - Stefan Endres
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany
| | - Sebastian Kobold
- Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany
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13
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Mashima R, Takada S, Miyamoto Y. RNA-Based Therapeutic Technology. Int J Mol Sci 2023; 24:15230. [PMID: 37894911 PMCID: PMC10607345 DOI: 10.3390/ijms242015230] [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: 09/11/2023] [Revised: 10/09/2023] [Accepted: 10/15/2023] [Indexed: 10/29/2023] Open
Abstract
RNA-based therapy has been an expanding area of clinical research since the COVID-19 outbreak. Often, its comparison has been made to DNA-based gene therapy, such as adeno-associated virus- and lentivirus-mediated therapy. These DNA-based therapies show persistent expression, with maximized therapeutic efficacy. However, accumulating data indicate that proper control of gene expression is occasionally required. For example, in cancer immunotherapy, cytokine response syndrome is detrimental for host animals, while excess activation of the immune system induces supraphysiological cytokines. RNA-based therapy seems to be a rather mild therapy, and it has room to fit unmet medical needs, whereas current DNA-based therapy has unclear issues. This review focused on RNA-based therapy for cancer immunotherapy, hematopoietic disorders, and inherited disorders, which have received attention for possible clinical applications.
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Affiliation(s)
- Ryuichi Mashima
- Department of Clinical Laboratory Medicine, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
| | - Shuji Takada
- Department of Systems BioMedicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
| | - Yoshitaka Miyamoto
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan
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14
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Yamauchi A, Yoshimoto S, Kudo A, Takagi S. Negative Influence of Aging on Differentiation and Proliferation of CD8 + T-Cells in Dogs. Vet Sci 2023; 10:541. [PMID: 37756063 PMCID: PMC10534501 DOI: 10.3390/vetsci10090541] [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: 06/06/2023] [Revised: 07/24/2023] [Accepted: 08/22/2023] [Indexed: 09/28/2023] Open
Abstract
Immunosenescence is an age-related change in the immune system characterized by a reduction in naïve T-cells and an impaired proliferative capacity of CD8+ T-cells in older individuals. Recent research revealed the crucial impact of immunosenescence on the development and control of cancer, and aging is one of the causes that diminish the therapeutic efficacy of cancer immunotherapies targeting CD8+ T-cell activation. Despite dog cancer being defined as an age-related disease, there are few fundamental understandings regarding the relationship between aging and the canine immune system. Therefore, we aimed to elucidate the characteristics of immunosenescence in dogs and analyzed the effects of aging on the differentiation status and proliferation of canine CD8+ T cells using T-cell specific stimulation with anti-canine CD3/CD28 antibody-coated beads and interleukin-2. As a result, we found that older dogs have a lower proliferative capacity of CD8+ T-cells and a reduction in the naïve subset in their peripheral blood. Further analysis showed that older dogs had attenuated proliferation of the effector and central memory subsets. These results indicate the importance of maintaining less differentiated subsets to expand CD8+ T-cells in dogs and provide helpful insight into the development of dog immune therapies that require T-cell expansion ex vivo.
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Affiliation(s)
- Akinori Yamauchi
- Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara 252-5201, Kanagawa, Japan
| | - Sho Yoshimoto
- Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara 252-5201, Kanagawa, Japan
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ayano Kudo
- Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara 252-5201, Kanagawa, Japan
| | - Satoshi Takagi
- Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara 252-5201, Kanagawa, Japan
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15
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Wang H, Tang L, Kong Y, Liu W, Zhu X, You Y. Strategies for Reducing Toxicity and Enhancing Efficacy of Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies. Int J Mol Sci 2023; 24:ijms24119115. [PMID: 37298069 DOI: 10.3390/ijms24119115] [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: 04/16/2023] [Revised: 05/08/2023] [Accepted: 05/16/2023] [Indexed: 06/12/2023] Open
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies has made great progress, but there are still some problems. First, T cells from tumor patients show an exhaustion phenotype; thus, the persistence and function of the CAR-Ts are poor, and achieving a satisfactory curative effect is difficult. Second, some patients initially respond well but quickly develop antigen-negative tumor recurrence. Thirdly, CAR-T treatment is not effective in some patients and is accompanied by severe side effects, such as cytokine release syndrome (CRS) and neurotoxicity. The solution to these problems is to reduce the toxicity and enhance the efficacy of CAR-T therapy. In this paper, we describe various strategies for reducing the toxicity and enhancing the efficacy of CAR-T therapy in hematological malignancies. In the first section, strategies for modifying CAR-Ts using gene-editing technologies or combining them with other anti-tumor drugs to enhance the efficacy of CAR-T therapy are introduced. The second section describes some methods in which the design and construction of CAR-Ts differ from the conventional process. The aim of these methods is to enhance the anti-tumor activity of CAR-Ts and prevent tumor recurrence. The third section describes modifying the CAR structure or installing safety switches to radically reduce CAR-T toxicity or regulating inflammatory cytokines to control the symptoms of CAR-T-associated toxicity. Together, the knowledge summarized herein will aid in designing better-suited and safer CAR-T treatment strategies.
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Affiliation(s)
- Haobing Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ling Tang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yingjie Kong
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wen Liu
- Department of Pain Treatment, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaojian Zhu
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yong You
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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16
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Oh W, Kim AMJ, Dhawan D, Kirkham PM, Ostafe R, Franco J, Aryal UK, Carnahan RH, Patsekin V, Robinson JP, Knapp DW, Lim SO. Development of an Anti-canine PD-L1 Antibody and Caninized PD-L1 Mouse Model as Translational Research Tools for the Study of Immunotherapy in Humans. CANCER RESEARCH COMMUNICATIONS 2023; 3:860-873. [PMID: 37377896 PMCID: PMC10184575 DOI: 10.1158/2767-9764.crc-22-0468] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 06/29/2023]
Abstract
Immune checkpoint blockade therapy, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types. Despite the recent success of immune checkpoint blockade therapy, however, the response rates in patients with cancer are limited (∼20%-40%). To improve the success of immune checkpoint blockade therapy, relevant preclinical animal models are essential for the development and testing of multiple combination approaches and strategies. Companion dogs naturally develop several types of cancer that in many respects resemble clinical cancer in human patients. Therefore, the canine studies of immuno-oncology drugs can generate knowledge that informs and prioritizes new immuno-oncology therapy in humans. The challenge has been, however, that immunotherapeutic antibodies targeting canine immune checkpoint molecules such as canine PD-L1 (cPD-L1) have not been commercially available. Here, we developed a new cPD-L1 antibody as an immuno-oncology drug and characterized its functional and biological properties in multiple assays. We also evaluated the therapeutic efficacy of cPD-L1 antibodies in our unique caninized PD-L1 mice. Together, these in vitro and in vivo data, which include an initial safety profile in laboratory dogs, support development of this cPD-L1 antibody as an immune checkpoint inhibitor for studies in dogs with naturally occurring cancer for translational research. Our new therapeutic antibody and caninized PD-L1 mouse model will be essential translational research tools in raising the success rate of immunotherapy in both dogs and humans. Significance Our cPD-L1 antibody and unique caninized mouse model will be critical research tools to improve the efficacy of immune checkpoint blockade therapy in both dogs and humans. Furthermore, these tools will open new perspectives for immunotherapy applications in cancer as well as other autoimmune diseases that could benefit a diverse and broader patient population.
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Affiliation(s)
- Wonkyung Oh
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana
| | - Alyssa Min Jung Kim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana
| | - Deepika Dhawan
- Department of Veterinary Clinical Science, Purdue University, West Lafayette, Indiana
| | - Perry M. Kirkham
- Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana
| | - Raluca Ostafe
- Molecular Evolution, Protein Engineering and Production, Purdue Institute for Inflammation Immunology and Infection Diseases, Purdue University, West Lafayette, Indiana
| | - Jackeline Franco
- Purdue Proteomics Facility, Bindley Bioscience Center, Purdue University, West Lafayette, Indiana
| | - Uma K. Aryal
- Purdue Proteomics Facility, Bindley Bioscience Center, Purdue University, West Lafayette, Indiana
- Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana
| | - Robert H. Carnahan
- Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Valery Patsekin
- Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana
| | - J. Paul Robinson
- Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana
| | - Deborah W. Knapp
- Department of Veterinary Clinical Science, Purdue University, West Lafayette, Indiana
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana
| | - Seung-Oe Lim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana
- Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana
- Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana
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17
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Cockey JR, Leifer CA. Racing CARs to veterinary immuno-oncology. Front Vet Sci 2023; 10:1130182. [PMID: 36876006 PMCID: PMC9982037 DOI: 10.3389/fvets.2023.1130182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 01/31/2023] [Indexed: 02/19/2023] Open
Abstract
Chimeric antigen receptors (CARs) have demonstrated remarkable promise in human oncology over the past two decades, yet similar strategies in veterinary medicine are still in development. CARs are synthetically engineered proteins comprised of a specific antigen-binding single chain variable fragment (ScFv) fused to the signaling domain of a T cell receptor and co-receptors. Patient T cells engineered to express a CAR are directed to recognize and kill target cells, most commonly hematological malignancies. The U.S Food and Drug Administration (FDA) has approved multiple human CAR T therapies, but translation of these therapies into veterinary medicine faces many challenges. In this review, we discuss considerations for veterinary use including CAR design and cell carrier choice, and discuss the future promise of translating CAR therapy into veterinary oncology.
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Affiliation(s)
| | - Cynthia A. Leifer
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
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18
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Stevenson VB, Klahn S, LeRoith T, Huckle WR. Canine melanoma: A review of diagnostics and comparative mechanisms of disease and immunotolerance in the era of the immunotherapies. Front Vet Sci 2023; 9:1046636. [PMID: 36686160 PMCID: PMC9853198 DOI: 10.3389/fvets.2022.1046636] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/12/2022] [Indexed: 01/09/2023] Open
Abstract
Melanomas in humans and dogs are highly malignant and resistant to therapy. Since the first development of immunotherapies, interest in how the immune system interacts within the tumor microenvironment and plays a role in tumor development, progression, or remission has increased. Of major importance are tumor-infiltrating lymphocytes (TILs) where distribution and cell frequencies correlate with survival and therapeutic outcomes. Additionally, efforts have been made to identify subsets of TILs populations that can contribute to a tumor-promoting or tumor-inhibiting environment, such as the case with T regulatory cells versus CD8 T cells. Furthermore, cancerous cells have the capacity to express certain inhibitory checkpoint molecules, including CTLA-4, PD-L1, PD-L2, that can suppress the immune system, a property associated with poor prognosis, a high rate of recurrence, and metastasis. Comparative oncology brings insights to comprehend the mechanisms of tumorigenesis and immunotolerance in humans and dogs, contributing to the development of new therapeutic agents that can modulate the immune response against the tumor. Therapies that target signaling pathways such as mTOR and MEK/ERK that are upregulated in cancer, or immunotherapies with different approaches such as CAR-T cells engineered for specific tumor-associated antigens, DNA vaccines using human tyrosinase or CGSP-4 antigen, anti-PD-1 or -PD-L1 monoclonal antibodies that intercept their binding inhibiting the suppression of the T cells, and lymphokine-activated killer cells are already in development for treating canine tumors. This review provides concise and recent information about diagnosis, comparative mechanisms of tumor development and progression, and the current status of immunotherapies directed toward canine melanoma.
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Affiliation(s)
- Valentina B. Stevenson
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
| | - Shawna Klahn
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
- Small Animal Clinical Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
| | - Tanya LeRoith
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
| | - William R. Huckle
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States
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19
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Yoshimoto S, Chester N, Xiong A, Radaelli E, Wang H, Brillantes M, Gulendran G, Glassman P, Siegel DL, Mason NJ. Development and pharmacokinetic assessment of a fully canine anti-PD-1 monoclonal antibody for comparative translational research in dogs with spontaneous tumors. MAbs 2023; 15:2287250. [PMID: 38047502 PMCID: PMC10793675 DOI: 10.1080/19420862.2023.2287250] [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: 07/11/2023] [Accepted: 11/20/2023] [Indexed: 12/05/2023] Open
Abstract
PD-1 checkpoint inhibitors have revolutionized the treatment of patients with different cancer histologies including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. However, only a subset of patients show a dramatic clinical response to treatment. Despite intense biomarker discovery efforts, no single robust, prognostic correlation has emerged as a valid outcome predictor. Immune competent, pet dogs develop spontaneous tumors that share similar features to human cancers including chromosome aberrations, molecular subtypes, immune signatures, tumor heterogeneity, metastatic behavior, and chemotherapeutic response. As such, they represent a valuable parallel patient population in which to investigate predictive biomarkers of checkpoint inhibition. However, the lack of a validated, non-immunogenic, canine anti-PD-1 antibody for pre-clinical use hinders this comparative approach and prevents potential clinical benefits of PD-1 blockade being realized in the veterinary clinic. To address this, fully canine single-chain variable fragments (scFvs) that bind canine (c)PD-1 were isolated from a comprehensive canine scFv phage display library. Lead candidates were identified that bound with high affinity to cPD-1 and inhibited its interaction with canine PD-L1 (cPD-L1). The lead scFv candidate re-formatted into a fully canine IgGD reversed the inhibitory effects of cPD-1:cPD-L1 interaction on canine chimeric antigen receptor (CAR) T cell function. In vivo administration showed no toxicity and revealed favorable pharmacokinetics for a reasonable dosing schedule. These results pave the way for clinical trials with anti-cPD-1 in canine cancer patients to investigate predictive biomarkers and combination regimens to inform human clinical trials and bring a promising checkpoint inhibitor into the veterinary armamentarium.
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Affiliation(s)
- Sho Yoshimoto
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Ailian Xiong
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Enrico Radaelli
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hong Wang
- Vetigenics LLC, B-Labs, Cira Center, Philadelphia, PA, USA
| | | | - Gayathri Gulendran
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Patrick Glassman
- Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA
| | - Don L. Siegel
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicola J. Mason
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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20
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Smole A, Benton A, Poussin MA, Eiva MA, Mezzanotte C, Camisa B, Greco B, Sharma P, Minutolo NG, Gray F, Bear AS, Baroja ML, Cummins C, Xu C, Sanvito F, Goldgewicht AL, Blanchard T, Rodriguez-Garcia A, Klichinsky M, Bonini C, June CH, Posey AD, Linette GP, Carreno BM, Casucci M, Powell DJ. Expression of inducible factors reprograms CAR-T cells for enhanced function and safety. Cancer Cell 2022; 40:1470-1487.e7. [PMID: 36513049 PMCID: PMC10367115 DOI: 10.1016/j.ccell.2022.11.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 08/04/2022] [Accepted: 11/10/2022] [Indexed: 12/14/2022]
Abstract
Despite the success of CAR-T cell cancer immunotherapy, challenges in efficacy and safety remain. Investigators have begun to enhance CAR-T cells with the expression of accessory molecules to address these challenges. Current systems rely on constitutive transgene expression or multiple viral vectors, resulting in unregulated response and product heterogeneity. Here, we develop a genetic platform that combines autonomous antigen-induced production of an accessory molecule with constitutive CAR expression in a single lentiviral vector called Uni-Vect. The broad therapeutic application of Uni-Vect is demonstrated in vivo by activation-dependent expression of (1) an immunostimulatory cytokine that improves efficacy, (2) an antibody that ameliorates cytokine-release syndrome, and (3) transcription factors that modulate T cell biology. Uni-Vect is also implemented as a platform to characterize immune receptors. Overall, we demonstrate that Uni-Vect provides a foundation for a more clinically actionable next-generation cellular immunotherapy.
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Affiliation(s)
- Anže Smole
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
| | - Alexander Benton
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Mathilde A Poussin
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Monika A Eiva
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Claudia Mezzanotte
- Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Barbara Camisa
- Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Beatrice Greco
- Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Prannda Sharma
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Nicholas G Minutolo
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Falon Gray
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Adham S Bear
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Miren L Baroja
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Casey Cummins
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Chong Xu
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Francesca Sanvito
- Pathology Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Andrea Lang Goldgewicht
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Tatiana Blanchard
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Alba Rodriguez-Garcia
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Michael Klichinsky
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Chiara Bonini
- Experimental Hematology Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute and University Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Carl H June
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Avery D Posey
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Gerald P Linette
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Beatriz M Carreno
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Monica Casucci
- Innovative Immunotherapies Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Daniel J Powell
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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21
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Pinard CJ, Lagree A, Lu FI, Klein J, Oblak ML, Salgado R, Cardenas JCP, Brunetti B, Muscatello LV, Sarli G, Foschini MP, Hardas A, Castillo SP, AbdulJabbar K, Yuan Y, Moore DA, Tran WT. Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy. Cancers (Basel) 2022; 14:5008. [PMID: 36291791 PMCID: PMC9599753 DOI: 10.3390/cancers14205008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/04/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Despite the important role of preclinical experiments to characterize tumor biology and molecular pathways, there are ongoing challenges to model the tumor microenvironment, specifically the dynamic interactions between tumor cells and immune infiltrates. Comprehensive models of host-tumor immune interactions will enhance the development of emerging treatment strategies, such as immunotherapies. Although in vitro and murine models are important for the early modelling of cancer and treatment-response mechanisms, comparative research studies involving veterinary oncology may bridge the translational pathway to human studies. The natural progression of several malignancies in animals exhibits similar pathogenesis to human cancers, and previous studies have shown a relevant and evaluable immune system. Veterinary oncologists working alongside oncologists and cancer researchers have the potential to advance discovery. Understanding the host-tumor-immune interactions can accelerate drug and biomarker discovery in a clinically relevant setting. This review presents discoveries in comparative immuno-oncology and implications to cancer therapy.
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Affiliation(s)
- Christopher J. Pinard
- Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
- Odette Cancer Program, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Radiogenomics Laboratory, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
| | - Andrew Lagree
- Odette Cancer Program, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Radiogenomics Laboratory, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
| | - Fang-I Lu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jonathan Klein
- Department of Radiation Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA
| | - Michelle L. Oblak
- Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Roberto Salgado
- Division of Research, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
- Department of Pathology, GZA-ZNA Hospitals, 2610 Antwerp, Belgium
| | | | - Barbara Brunetti
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano dell’Emilia, Italy
| | - Luisa Vera Muscatello
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano dell’Emilia, Italy
| | - Giuseppe Sarli
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano dell’Emilia, Italy
| | - Maria Pia Foschini
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40127 Bologna, Italy
| | - Alexandros Hardas
- Department of Pathobiology & Population Sciences, The Royal Veterinary College, Hertfordshire AL9 7TA, UK
| | - Simon P. Castillo
- Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Khalid AbdulJabbar
- Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK
| | - Yinyin Yuan
- Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
- Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK
| | - David A. Moore
- Department of Pathology, UCL Cancer Institute, London WC1E 6DD, UK
- University College Hospitals NHS Trust, London NW1 2PG, UK
| | - William T. Tran
- Odette Cancer Program, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Radiogenomics Laboratory, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Temerty Centre for AI Research and Education in Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
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22
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Duncan BB, Dunbar CE, Ishii K. Applying a Clinical Lens to Animal Models of CAR-T Cell Therapies. Mol Ther Methods Clin Dev 2022; 27:17-31. [PMID: 36156878 PMCID: PMC9478925 DOI: 10.1016/j.omtm.2022.08.008] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Chimeric antigen receptor (CAR)-T cells have emerged as a promising treatment modality for various hematologic and solid malignancies over the past decade. Animal models remain the cornerstone of pre-clinical evaluation of human CAR-T cell products and are generally required by regulatory agencies prior to clinical translation. However, pharmacokinetics and pharmacodynamics of adoptively transferred T cells are dependent on various recipient factors, posing challenges for accurately predicting human engineered T cell behavior in non-human animal models. For example, murine xenograft models did not forecast now well-established cytokine-driven systemic toxicities of CAR-T cells seen in humans, highlighting the limitations of animal models that do not perfectly recapitulate complex human immune systems. Understanding the concordance as well as discrepancies between existing pre-clinical animal data and human clinical experiences, along with established advantages and limitations of each model, will facilitate investigators’ ability to appropriately select and design animal models for optimal evaluation of future CAR-T cell products. We summarize the current state of animal models in this field, and the advantages and disadvantages of each approach depending on the pre-clinical questions being asked.
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23
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Ramos‑Cardona X, Luo W, Mohammed S. Advances and challenges of CAR T therapy and suitability of animal models (Review). Mol Clin Oncol 2022; 17:134. [PMID: 35949897 PMCID: PMC9353808 DOI: 10.3892/mco.2022.2567] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 06/06/2022] [Indexed: 11/06/2022] Open
Abstract
Chimeric antigen receptors (CARs) recently gained momentum in cancer treatment due to their ability to promote T-cell mediated responses to a specific tumor-associated antigen. CARs are part of the adoptive cell transfer (ACT) strategies that utilize patients' T lymphocytes, genetically engineered to kill cancer cells. However, despite the therapy's success against blood-related malignancies, treating solid tumors has not reached its fullest potential yet. The reasons include the complex suppressive tumor microenvironment, mutations on cancer cells' target receptors, lethal side-effects, restricted trafficking into the tumor, suboptimal persistence in vivo and the lack of animal models that faithfully resemble human tumor's immunological responses. Currently, rodent models are used to investigate the safety and efficacy of CAR therapies. However, these models are limited in representing the human disease faithfully, fail to predict the adverse treatment events and overestimate the efficacy of the therapy. On the other hand, spontaneously developed tumors in dogs are more suited in CAR research and their efficacy has been demonstrated in a number of diseases, including lymphoma, osteosarcoma and mammary tumors. The present review discusses the design and evolution of CARs, challenges of CAR in solid tumors, human and canine clinical trials and advantages of the canine model.
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Affiliation(s)
- Xavier Ramos‑Cardona
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN 47907, USA
| | - Weichuan Luo
- Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
| | - Sulma Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN 47907, USA
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24
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Atherton MJ, Rotolo A, Haran KP, Mason NJ. Case Report: Clinical and Serological Hallmarks of Cytokine Release Syndrome in a Canine B Cell Lymphoma Patient Treated With Autologous CAR-T Cells. Front Vet Sci 2022; 9:824982. [PMID: 35898541 PMCID: PMC9310037 DOI: 10.3389/fvets.2022.824982] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background Chimeric antigen receptor-T (CAR-T) cells have transformed the treatment of human B cell malignancies. With the advent of CAR-T therapy, specific and in some cases severe toxicities have been documented with cytokine release syndrome (CRS) being the most frequently reported. As dogs develop tumors spontaneously and in an immunocompetent setting, they provide a unique translational opportunity to further investigate the activity and toxicities associated with CAR-T therapy. Although various adoptive cellular therapy (ACT) trials have been documented and several more are ongoing in canine oncology, CRS has not been comprehensively described in canine cancer patients. Case Presentation Here we present the clinical and serologic changes in a dog treated with autologous CAR-T for relapsed B cell lymphoma that presented with lethargy and fever 3 days following CAR-T. Multiplexed serum cytokine profiling revealed increases in key cytokines implicated in human CRS including IL-6, MCP-1, IFNγ and IL-10 at or shortly after peak CAR-T levels in vivo. Conclusion The observations noted in this case report are consistent with CRS development following CAR-T therapy in a canine patient. The dog represents a compelling model to study the pathophysiology of CRS and pre-clinically screen novel therapeutics to prevent and treat this life-threatening condition in the setting of a complex and naturally evolved immune system.
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Affiliation(s)
- Matthew J. Atherton
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
- *Correspondence: Matthew J. Atherton
| | - Antonia Rotolo
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Kumudhini P. Haran
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Nicola J. Mason
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, United States
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
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25
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Tanaka T, Ohishi T, Saito M, Suzuki H, Kaneko MK, Kawada M, Kato Y. Defucosylated Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Exerted Antitumor Activities in Mouse Xenograft Models of Canine Mammary Gland Tumor. Monoclon Antib Immunodiagn Immunother 2022; 41:142-149. [PMID: 35666554 DOI: 10.1089/mab.2022.0009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) contributes to tumor malignancy through gene amplification and/or protein overexpression. In our previous study, we developed an anti-human EGFR (hEGFR) monoclonal antibody, clone EMab-134 (mouse IgG1, kappa), which specifically detects both hEGFR and dog EGFR (dEGFR). The defucosylated mouse IgG2a version of EMab-134 (134-mG2a-f) exhibits antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in dEGFR-overexpressed Chinese hamster ovary-K1 (CHO/dEGFR) cells and antitumor activities in mouse xenografts of CHO/dEGFR cells. In this study, the reactivity of 134-mG2a-f against a canine mammary gland tumor cell line (SNP) was examined by flow cytometry and immunocytochemistry. Furthermore, 134-mG2a-f highly exerted ADCC and CDC for SNP. The administration of 134-mG2a-f significantly suppressed the SNP xenograft growth. These results suggest that 134-mG2a-f exerts antitumor effects against dEGFR-expressing canine mammary gland tumors, and could be valuable as part of an antibody treatment regimen for them.
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Affiliation(s)
- Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Japan
| | - Masaki Saito
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
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26
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Qureischi M, Mohr J, Arellano-Viera E, Knudsen SE, Vohidov F, Garitano-Trojaola A. mRNA-based therapies: Preclinical and clinical applications. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 372:1-54. [PMID: 36064262 DOI: 10.1016/bs.ircmb.2022.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
At the fundamental level, messenger RNA (mRNA)-based therapeutics involves the delivery of in vitro-transcribed (IVT) mRNA into the cytoplasm of a target cell, where it is translated into the desired protein. IVT mRNA presents various advantages compared to DNA and recombinant protein-based approaches that make it ideal for a broad range of therapeutic applications. IVT mRNA, which is translated in the cytoplasm after transfection into cells, can encode virtually any target protein. Notably, it does not enter the nucleus, which avoids its integration into the genome and the risk of insertional mutagenesis. The large-scale production of IVT mRNA is less complex than production of recombinant proteins, and Good Manufacturing Practice-compliant mRNA production is easily scalable, ideally poising mRNA for not only off-the-shelf, but more personalized treatment approaches. IVT mRNA's safety profile, pharmacokinetics, and pharmacodynamics, including its inherent immunostimulatory capacity, can be optimized for different therapeutic applications by harnessing a wide array of optimized sequence elements, chemical modifications, purification techniques, and delivery methods. The value of IVT mRNA was recently proved during the COVID-19 pandemic when mRNA-based vaccines outperformed the efficacy of established technologies, and millions of doses were rapidly deployed. In this review, we will discuss chemical modifications of IVT mRNA and highlight numerous preclinical and clinical applications including vaccines for cancer and infectious diseases, cancer immunotherapy, protein replacement, gene editing, and cell reprogramming.
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27
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Zhang S, Black RG, Kohli K, Hayes BJ, Miller C, Koehne A, Schroeder BA, Abrams K, Schulte BC, Alexiev BA, Heimberger AB, Zhang A, Jing W, Ng JCK, Shinglot H, Seguin B, Salter AI, Riddell SR, Jensen MC, Gottschalk S, Moore PF, Torok-Storb B, Pollack SM. B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model. Mol Cancer Ther 2022; 21:999-1009. [PMID: 35405743 PMCID: PMC9381119 DOI: 10.1158/1535-7163.mct-21-0726] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 01/31/2022] [Accepted: 03/31/2022] [Indexed: 01/07/2023]
Abstract
One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.
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Affiliation(s)
- Shihong Zhang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - R. Graeme Black
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Karan Kohli
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Brian J. Hayes
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Cassandra Miller
- Comparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amanda Koehne
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Brett A. Schroeder
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,NCI, NIH, Bethesda, Maryland
| | - Kraig Abrams
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Brian C. Schulte
- Department of Medicine, University of California San Francisco, San Francisco, California
| | | | - Amy B. Heimberger
- Department of Neurologic Surgery, Northwestern University, Chicago, Illinois
| | - Ali Zhang
- Department of Medicine, Northwestern University, Chicago, Illinois
| | - Weiqing Jing
- Department of Medicine, Northwestern University, Chicago, Illinois
| | | | - Himaly Shinglot
- Department of Medicine, Northwestern University, Chicago, Illinois
| | - Bernard Seguin
- Colorado State University, Flint Animal Cancer Center, Fort Collins, Colorado
| | - Alexander I. Salter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Stanley R. Riddell
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Lyell Immunopharma, Seattle, Washington
| | - Michael C. Jensen
- Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Peter F. Moore
- Department of Veterinary Medicine, University of California Davis, Davis, California
| | - Beverly Torok-Storb
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Seth M. Pollack
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Medicine, Northwestern University, Chicago, Illinois.,Corresponding Author: Seth M. Pollack, Oncology, Northwestern University, 303 E. Superior St. #3-115, Chicago, IL 60611. E-mail:
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28
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Goto N, Suzuki H, Ohishi T, Harakawa A, Li G, Saito M, Takei J, Tanaka T, Asano T, Sano M, Kawada M, Kaneko MK, Kato Y. Antitumor Activities in Mouse Xenograft Models of Canine Fibroblastic Tumor by Defucosylated Anti-Epidermal Growth Factor Receptor Monoclonal Antibody. Monoclon Antib Immunodiagn Immunother 2022; 41:67-73. [PMID: 35377239 DOI: 10.1089/mab.2021.0059] [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: 11/12/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is involved in tumor malignancy through gene amplification and/or protein overexpression. An anti-human EGFR (hEGFR) monoclonal antibody (clone EMab-134), which explicitly detects hEGFR and dog EGFR (dEGFR), was previously developed. The defucosylated mouse IgG2a version of EMab-134 (134-mG2a-f) exhibits antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in dEGFR-overexpressed CHO-K1 (CHO/dEGFR) cells and antitumor activities in mouse xenografts of CHO/dEGFR cells. In this study, it was shown that 134-mG2a-f reacts with a canine fibroblastic tumor cell line (A-72) using flow cytometry and immunocytochemistry. Furthermore, 134-mG2a-f exerted ADCC and CDC on A-72 cell line. The administration of 134-mG2a-f significantly inhibited the A-72 xenograft growth. These results suggest that 134-mG2a-f exerts antitumor effects on dEGFR-expressing canine fibroblastic tumors.
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Affiliation(s)
- Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan
| | - Akiko Harakawa
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan
| | - Guanjie Li
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masaki Saito
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Junko Takei
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Masato Sano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Shizuoka, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.,Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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29
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A bitesize introduction to canine hematologic malignancies. Blood Adv 2022; 6:4073-4084. [PMID: 35316831 PMCID: PMC9278293 DOI: 10.1182/bloodadvances.2021005045] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/09/2022] [Indexed: 11/20/2022] Open
Abstract
Hematologic malignancies are frequently diagnosed in dogs and result in a spectrum of clinical signs associated with specific disease types. The most frequently encountered hematologic tumors in dogs include lymphoma, lymphoid and myeloid leukemias, and mast cell, plasma cell, and histiocytic neoplasias. Coupled with the heterogeneous presentations of the different categories and subtypes of canine hematologic malignancies, outcomes for these tumors are also variable. Considering this, appropriate treatment options range from active surveillance to curative intent approaches harnessing surgical, chemotherapeutic, and radiation-based modalities. The underlying pathology of many of these diseases bears remarkable resemblance to that of the corresponding diagnosis made in human patients. We introduce some of the pathogenic drivers of canine hematologic cancers alongside their clinical presentations. An overview of standard-of-care therapies for each of these diseases is also provided. As comparative oncology gains recognition as a valuable setting in which to investigate the pathogenesis of neoplasia and provide powerful, clinically relevant, immunocompetent models for the evaluation of novel therapies, the number of clinicians and scientists participating in cancer research involving dogs is expected to increase. This review aims at providing an introductory overview of canine hematologic malignancies.
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30
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Huang L, Zhang L, Li W, Li S, Wen J, Li H, Liu Z. Advances in Development of mRNA-Based Therapeutics. Curr Top Microbiol Immunol 2022; 440:147-166. [PMID: 32683507 DOI: 10.1007/82_2020_222] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Recently, mRNA-based therapeutics have been greatly boosted since the development of novel technologies of both mRNA synthesis and delivery system. Promising results were showed in both preclinical and clinical studies in the field of cancer vaccine, tumor immunotherapy, infectious disease prevention and protein replacement therapy. Recent advancements in clinical trials also encouraged scientists to attempt new applications of mRNA therapy such as gene editing and cell programming. These studies bring mRNA therapeutics closer to real-world application. Herein, we provide an overview of recent advances in mRNA-based therapeutics.
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Affiliation(s)
- Lei Huang
- Stemirna Therapeutics Inc, Shanghai, 201206, China
| | - Luyao Zhang
- Stemirna Therapeutics Inc, Shanghai, 201206, China
| | - Weiwei Li
- Stemirna Therapeutics Inc, Shanghai, 201206, China
| | - Shiqiang Li
- Stemirna Therapeutics Inc, Shanghai, 201206, China
| | - Jianguo Wen
- Stemirna Therapeutics Inc, Shanghai, 201206, China
| | - Hangwen Li
- Stemirna Therapeutics Inc, Shanghai, 201206, China.
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31
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Von Rueden SK, Fan TM. Cancer-Immunity Cycle and Therapeutic Interventions- Opportunities for Including Pet Dogs With Cancer. Front Oncol 2021; 11:773420. [PMID: 34869014 PMCID: PMC8639699 DOI: 10.3389/fonc.2021.773420] [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] [Received: 09/10/2021] [Accepted: 11/01/2021] [Indexed: 12/22/2022] Open
Abstract
The tumor-immune interplay represents a dynamic series of events executed by cellular and soluble participants that either promote or inhibit successful tumor formation and growth. Throughout a tumor’s development and progression, the host organism’s immune system reacts by generating anti-cancer defenses through various incremental and combinatorial mechanisms, and this reactive orchestration is termed the cancer-immunity cycle. Success or failure of the cancer-immunity cycle dictates the fate of both host and tumor as winner or loser. Insights into how the tumor and host immune system continuously adapt to each other throughout the lifecycle of the tumor is necessary to rationally develop new effective immunotherapies. Additionally, the evolving nature of the cancer-immunity cycle necessitates therapeutic agility, requiring real-time serial assessment of immunobiologic markers that permits tailoring of therapies to the everchanging tumor immune microenvironment. In order to accelerate advances in the field of immuno-oncology, this review summarizes the steps comprising the cancer-immunity cycle, and underscores key breakpoints in the cycle that either favor cancer regression or progression, as well as shaping of the tumor microenvironment and associated immune phenotypes. Furthermore, specific large animal models of spontaneous cancers that are deemed immunogenic will be reviewed and proposed as unique resources for validating investigational immunotherapeutic protocols that are informed by the cancer-immunity cycle. Collectively, this review will provide a progressive look into the dynamic interplay between tumor and host immune responses and raise awareness for how large animal models can be included for developing combinatorial and sequenced immunotherapies to maximizing favorable treatment outcomes.
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Affiliation(s)
- Samantha K Von Rueden
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, United States
| | - Timothy M Fan
- Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Champaign, IL, United States.,Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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32
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Irving M, Lanitis E, Migliorini D, Ivics Z, Guedan S. Choosing the Right Tool for Genetic Engineering: Clinical Lessons from Chimeric Antigen Receptor-T Cells. Hum Gene Ther 2021; 32:1044-1058. [PMID: 34662233 PMCID: PMC8697565 DOI: 10.1089/hum.2021.173] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
T cell modification with genes that encode chimeric antigen receptors (CAR-T cells) has shown tremendous promise for the treatment of B cell malignancies. The successful translation of CAR-T cell therapy to other tumor types, including solid tumors, is the next big challenge. As the field advances from second- to next-generation CAR-T cells comprising multiple genetic modifications, more sophisticated methods and tools to engineer T cells are being developed. Viral vectors, especially γ-retroviruses and lentiviruses, are traditionally used for CAR-T cell engineering due to their high transduction efficiency. However, limited genetic cargo, high costs of production under good manufacturing practice (GMP) conditions, and the high regulatory demands are obstacles for widespread clinical translation. To overcome these limitations, different nonviral approaches are being explored at a preclinical or clinical level, including transposon/transposase systems and mRNA electroporation and nonintegrating DNA nanovectors. Genome editing tools that allow efficient knockout of particular genes and/or site-directed integration of the CAR and/or other transgenes into the genome are also being evaluated for CAR-T cell engineering. In this review, we discuss the development of viral and nonviral vectors used to generate CAR-T cells, focusing on their advantages and limitations. We also discuss the lessons learned from clinical trials using the different genetic engineering tools, with special focus on safety and efficacy.
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Affiliation(s)
- Melita Irving
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Evripidis Lanitis
- Department of Oncology, Ludwig Institute for Cancer Research Lausanne, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Denis Migliorini
- Department of Oncology, Geneva University Hospitals, Geneva, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland.,Swiss Cancer Center Léman, Geneva and Lausanne, Switzerland
| | - Zoltán Ivics
- Transposition and Genome Engineering, Division of Medical Biotechnology, Paul Ehrlich Institute, Langen, Germany
| | - Sonia Guedan
- Department of Hematology and Oncology, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
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Abstract
PURPOSE Laboratory and clinical research are essential for advancing radiation research; however, there is a growing awareness that conventional laboratory animal models and early-phase clinical studies in patients have not improved the low success rates and late-stage failures in new cancer therapy efforts. There are considerable costs and inefficiencies in moving preclinical research into effective cancer therapies for patients. Canine translational models of radiation research can fill an important niche between rodent and human studies, ultimately providing valuable, predictive, translational biological and clinical results for human cancer patients. Companion dogs naturally and spontaneously develop cancers over the course of their lifetime. Many canine tumor types share important similarities to human disease, molecularly and biologically, with a comparable clinical course. Dogs receive state-of-the-art medical care, which can include radiotherapy, experimental therapeutics, and novel technologies, offering an important opportunity for radiobiology and radiation oncology research. Notably, the National Cancer Institute has developed the Comparative Oncology Program to promote this area of increased research interest. CONCLUSION In this review, the benefits and limitations of performing translational radiation research in companion dogs will be presented, and current research utilizing the canine model will be highlighted, including studies across research areas focusing on common canine tumor types treated with radiotherapy, comparative normal tissue effects, radiation and immunology research, and alternative radiation therapy approaches involving canine cancer patients.
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Affiliation(s)
- Mary-Keara Boss
- Flint Animal Cancer Center, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
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34
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Sakai O, Ogino S, Tsukui T, Igase M, Mizuno T. Development of a monoclonal antibody for the detection of anti-canine CD20 chimeric antigen receptor expression on canine CD20 chimeric antigen receptor-transduced T cells. J Vet Med Sci 2021; 83:1495-1499. [PMID: 34408098 PMCID: PMC8569873 DOI: 10.1292/jvms.21-0326] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chimeric antigen receptor (CAR) CAR-T cell therapy targeting CD20 can be a novel adoptive cell therapy for canine patients with B-cell malignancy. After injection of the CAR-T cells in vivo, monitoring circulating CAR-T cells is essential to prove in vivo persistence of CAR-T cells. In this study, we developed a novel monoclonal antibody against canine CD20 CAR, whose single-chain variable fragment was derived from the our previously reported anti-canine CD20 therapeutic antibody. Furthermore, we proved that this monoclonal antibody can detect therapeutic anti-canine CD20 chimeric antibody in the serum from healthy beagle dogs injected with the therapeutic antibody for safety study. This monoclonal antibody is a useful tool for monitoring both canine CD20-CAR-T cells and anti-canine CD20 therapeutic antibody for canine lymphoma.
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Affiliation(s)
- Osamu Sakai
- Laboratory of Molecular Diagnostics and Therapeutics, Joint Graduate School of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
| | - Shoji Ogino
- Nippon Zenyaku Kogyo Co., Ltd., Koriyama, Fukushima 963-0196, Japan
| | - Toshihiro Tsukui
- Nippon Zenyaku Kogyo Co., Ltd., Koriyama, Fukushima 963-0196, Japan
| | - Masaya Igase
- Laboratory of Molecular Diagnostics and Therapeutics, Joint Graduate School of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
| | - Takuya Mizuno
- Laboratory of Molecular Diagnostics and Therapeutics, Joint Graduate School of Veterinary Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
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35
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Di Trani CA, Fernandez-Sendin M, Cirella A, Segués A, Olivera I, Bolaños E, Melero I, Berraondo P. Advances in mRNA-based drug discovery in cancer immunotherapy. Expert Opin Drug Discov 2021; 17:41-53. [PMID: 34496689 DOI: 10.1080/17460441.2021.1978972] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors and adoptive T-cell therapy based on chimeric antigen receptors are the spearhead strategies to exploit the immune system to fight cancer. To take advantage of the full potential of the immune system, cancer immunotherapy must incorporate new biotechnologies such as mRNA technology that may synergize with already approved immunotherapies and act more effectively on immune targets. AREAS COVERED This review describes the basics of mRNA biotechnology and provides insight into the recent advances in the use of mRNA for the local and systemic delivery of immunostimulatory antibodies, proinflammatory cytokines or for optimizing adoptive T-cell therapy. EXPERT OPINION mRNA-based nanomedicines have great potential to expand the arsenal of immunotherapy tools due to their ability to simplify and accelerate drug development and their suitability for transient and local expression of immunostimulatory molecules, whose systemic and sustained expression would be toxic. The success of mRNA-based COVID-19 vaccines has highlighted the feasibility of this approach. Continuous advances in the delivery and construction of RNA-based vectors hold promise for improvements in clinical efficacy.
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Affiliation(s)
- Claudia Augusta Di Trani
- Program of Immunology and Immunotherapy, Cima Universidad De Navarra, Pamplona, Spain.,Navarra Institute for Health Research (Idisna), Pamplona, Spain
| | - Myriam Fernandez-Sendin
- Program of Immunology and Immunotherapy, Cima Universidad De Navarra, Pamplona, Spain.,Navarra Institute for Health Research (Idisna), Pamplona, Spain
| | - Assunta Cirella
- Program of Immunology and Immunotherapy, Cima Universidad De Navarra, Pamplona, Spain.,Navarra Institute for Health Research (Idisna), Pamplona, Spain
| | - Aina Segués
- Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands.,Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh UK
| | - Irene Olivera
- Program of Immunology and Immunotherapy, Cima Universidad De Navarra, Pamplona, Spain.,Navarra Institute for Health Research (Idisna), Pamplona, Spain
| | - Elixabet Bolaños
- Program of Immunology and Immunotherapy, Cima Universidad De Navarra, Pamplona, Spain.,Navarra Institute for Health Research (Idisna), Pamplona, Spain
| | - Ignacio Melero
- Program of Immunology and Immunotherapy, Cima Universidad De Navarra, Pamplona, Spain.,Navarra Institute for Health Research (Idisna), Pamplona, Spain.,Centro De Investigación Biomédica En Red De Cáncer (Ciberonc), Spain.,Departments of Oncology and Immunology, Clínica Universidad De Navarra, Pamplona, Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Cima Universidad De Navarra, Pamplona, Spain.,Navarra Institute for Health Research (Idisna), Pamplona, Spain.,Centro De Investigación Biomédica En Red De Cáncer (Ciberonc), Spain
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36
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Dias JNR, André AS, Aguiar SI, Gil S, Tavares L, Aires-da-Silva F. Immunotherapeutic Strategies for Canine Lymphoma: Changing the Odds Against Non-Hodgkin Lymphoma. Front Vet Sci 2021; 8:621758. [PMID: 34513964 PMCID: PMC8427286 DOI: 10.3389/fvets.2021.621758] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 07/27/2021] [Indexed: 12/13/2022] Open
Abstract
The new era of immune-oncology has brought complexities and challenges that emphasize the need to identify new strategies and models to develop successful and cost-effective therapies. The inclusion of a canine model in the drug development of cancer immunotherapies is being widely recognized as a valid solution to overcome several hurdles associated with conventional preclinical models. Driven by the success of immunotherapies in the treatment of human non-Hodgkin lymphoma (NHL) and by the remarkable similarities of canine NHL to its human counterpart, canine NHL has been one of the main focus of comparative research. Under the present review, we summarize a general overview of the challenges and prospects of today's cancer immunotherapies and the role that comparative medicine might play in solving the limitations brought by this rapidly expanding field. The state of art of both human and canine NHL and the rationale behind the use of the canine model to bridge the translational gap between murine preclinical studies and human clinical trials are addressed. Finally, a review of currently available immunotherapies for canine NHL is described, highlighting the potential of these therapeutic options.
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Affiliation(s)
| | | | | | | | | | - Frederico Aires-da-Silva
- Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, Avenida da Universidade Técnica, Lisbon, Portugal
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37
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Klingemann H. Immunotherapy for Dogs: Still Running Behind Humans. Front Immunol 2021; 12:665784. [PMID: 34421888 PMCID: PMC8374065 DOI: 10.3389/fimmu.2021.665784] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 07/16/2021] [Indexed: 11/13/2022] Open
Abstract
Despite all good intentions, dogs are still running behind humans in effective cancer immunotherapies. The more effective treatments in humans, like infusions of CAR-T and NK-cells are not broadly pursued for canines due to significant costs, the rather complicated logistics and the lack of targetable surface antigens. Monoclonal antibodies are challenging to develop considering the limited knowledge about canine target antigens and about their mode of action. Although immunogenic vaccines could be less costly, this approach is hampered by the fact that cancer by itself is immuno-suppressive and any preceding chemotherapy may suppress any clinically meaningful immune response. This review - rather than providing a comprehensive listing of all available immunotherapies for dogs, aims at pointing out the issues that are holding back this field but which hopefully can be addressed so that dogs can "catch up" with what is available to humans.
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38
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Maharshi V, Diksha D, Gupta P. Quality Assessment of Pre-Clinical Studies of Chimeric Antigen Receptor T-Cell Therapy Products: A Point of Focus On Safety. Curr Drug Saf 2021; 17:129-135. [PMID: 34323195 DOI: 10.2174/1574886316666210728101333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 05/20/2021] [Accepted: 06/01/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Serious adverse reactions have been reported with the use of chimeric antigen receptor (CAR) T-cell therapy in clinical setting despite the success of these products in pre-clinical stages of development. OBJECTIVE We evaluated the quality of available pre-clinical safety data of CAR T-cell therapy products. METHODS A 21 items safety-checklist was designed specifically for CAR T-cell. Literature was searched using search/MeSH terms in PubMed (October 2019 - February 2020). Studies were screened from title and abstract. Original pre-clinical researches related to CAR T-cell anti-cancer therapy were included. RESULTS Of the search results, 152 studies (3 in vivo, 39 in vitro, and 110 combined) were included. Only 7.9% studies were specifically designed to evaluate/ improve product safety. Eleven studies included target antigen(s) and no study included co-stimulatory molecule(s) expressed exclusively by tumor tissue and/or CAR T-cells. One study used CRISPR-Cas9 for CAR gene insertion. The use of switch-off mechanism and purity assessment of CAR T-cell products were reported in 13.2% and 8.6% studies respectively. Of the 149 studies with in vivo component, immuno-competent animal models were used in 24.8%. Measurement of blood pressure, temperature, body weight and serum cytokines were reported in 0, 2.7, 29.2 and 27.4% studies respectively. The tissue distribution and CAR T-cells persistence were reported in 26.5% studies. CONCLUSION Majority of the checklist parameters were not reported in the pre-clinical publications to be adequately predictive of the safety of CAR T-cells in a clinical setting.
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Affiliation(s)
- Vikas Maharshi
- Department of Pharmacology, All India Institute of Medical Sciences, Deoghar, Jharkhand , India
| | - Diksha Diksha
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
| | - Pooja Gupta
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
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39
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Brill SA, Thamm DH. There and back again: Translating adoptive cell therapy to canine cancer and improving human treatment. Vet Comp Oncol 2021; 19:420-427. [PMID: 34169631 PMCID: PMC9310446 DOI: 10.1111/vco.12744] [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: 01/19/2021] [Revised: 05/29/2021] [Accepted: 05/31/2021] [Indexed: 11/26/2022]
Abstract
Adoptive cell transfer (ACT) is a burgeoning therapeutic modality within human immuno-oncology. Novel approaches towards ACT are being developed in the pre-clinical setting faster than they can be evaluated in human clinical trials. Many of the therapeutic approaches used in human medicine have already been evaluated to some degree in canine patients. While this form of immunotherapy in veterinary medicine is still in its infancy, as these approaches develop, canine ACT will become a tool for both the veterinary oncologist and the translational researcher. This review details canine ACT trials to date, with attention given to the precedents provided by human oncology.
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Affiliation(s)
- Samuel A Brill
- Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado, USA.,Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, Colorado, USA
| | - Douglas H Thamm
- Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado, USA.,Cell and Molecular Biology Graduate Program, Colorado State University, Fort Collins, Colorado, USA.,Developmental Therapeutics Program, University of Colorado Comprehensive Cancer Center, Fort Collins, Colorado, USA
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40
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Preclinical models and technologies to advance nanovaccine development. Adv Drug Deliv Rev 2021; 172:148-182. [PMID: 33711401 DOI: 10.1016/j.addr.2021.03.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022]
Abstract
The remarkable success of targeted immunotherapies is revolutionizing cancer treatment. However, tumor heterogeneity and low immunogenicity, in addition to several tumor-associated immunosuppression mechanisms are among the major factors that have precluded the success of cancer vaccines as targeted cancer immunotherapies. The exciting outcomes obtained in patients upon the injection of tumor-specific antigens and adjuvants intratumorally, reinvigorated interest in the use of nanotechnology to foster the delivery of vaccines to address cancer unmet needs. Thus, bridging nano-based vaccine platform development and predicted clinical outcomes the selection of the proper preclinical model will be fundamental. Preclinical models have revealed promising outcomes for cancer vaccines. However, only few cases were associated with clinical responses. This review addresses the major challenges related to the translation of cancer nano-based vaccines to the clinic, discussing the requirements for ex vivo and in vivo models of cancer to ensure the translation of preclinical success to patients.
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41
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Mestrinho LA, Santos RR. Translational oncotargets for immunotherapy: From pet dogs to humans. Adv Drug Deliv Rev 2021; 172:296-313. [PMID: 33705879 DOI: 10.1016/j.addr.2021.02.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 02/10/2021] [Accepted: 02/27/2021] [Indexed: 12/21/2022]
Abstract
Preclinical studies in rodent models have been a pivotal role in human clinical research, but many of them fail in the translational process. Spontaneous tumors in pet dogs have the potential to bridge the gap between preclinical models and human clinical trials. Their natural occurrence in an immunocompetent system overcome the limitations of preclinical rodent models. Due to its reasonable cellular, molecular, and genetic homology to humans, the pet dog represents a valuable model to accelerate the translation of preclinical studies to clinical trials in humans, actually with benefits for both species. Moreover, their unique genetic features of breeding and breed-related mutations have contributed to assess and optimize therapeutics in individuals with different genetic backgrounds. This review aims to outline four main immunotherapy approaches - cancer vaccines, adaptive T-cell transfer, antibodies, and cytokines -, under research in veterinary medicine and how they can serve the clinical application crosstalk with humans.
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42
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Raes L, De Smedt SC, Raemdonck K, Braeckmans K. Non-viral transfection technologies for next-generation therapeutic T cell engineering. Biotechnol Adv 2021; 49:107760. [PMID: 33932532 DOI: 10.1016/j.biotechadv.2021.107760] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/24/2021] [Accepted: 04/24/2021] [Indexed: 12/24/2022]
Abstract
Genetically engineered T cells have sparked interest in advanced cancer treatment, reaching a milestone in 2017 with two FDA-approvals for CD19-directed chimeric antigen receptor (CAR) T cell therapeutics. It is becoming clear that the next generation of CAR T cell therapies will demand more complex engineering strategies and combinations thereof, including the use of revolutionary gene editing approaches. To date, manufacturing of CAR T cells mostly relies on γ-retroviral or lentiviral vectors, but their use is associated with several drawbacks, including safety issues, high manufacturing cost and vector capacity constraints. Non-viral approaches, including membrane permeabilization and carrier-based techniques, have therefore gained a lot of interest to replace viral transductions in the manufacturing of T cell therapeutics. This review provides an in-depth discussion on the avid search for alternatives to viral vectors, discusses key considerations for T cell engineering technologies, and provides an overview of the emerging spectrum of non-viral transfection technologies for T cells. Strengths and weaknesses of each technology will be discussed in relation to T cell engineering. Altogether, this work emphasizes the potential of non-viral transfection approaches to advance the next-generation of genetically engineered T cells.
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Affiliation(s)
- Laurens Raes
- Laboratory of General Biochemistry & Physical Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Stefaan C De Smedt
- Laboratory of General Biochemistry & Physical Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Koen Raemdonck
- Laboratory of General Biochemistry & Physical Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
| | - Kevin Braeckmans
- Laboratory of General Biochemistry & Physical Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
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43
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Szopa IM, Granica M, Bujak JK, Łabędź A, Błaszczyk M, Paulos CM, Majchrzak-Kuligowska K. Effective Activation and Expansion of Canine Lymphocytes Using a Novel Nano-Sized Magnetic Beads Approach. Front Immunol 2021; 12:604066. [PMID: 33679741 PMCID: PMC7933476 DOI: 10.3389/fimmu.2021.604066] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 01/04/2021] [Indexed: 12/18/2022] Open
Abstract
Expansion protocols for human T lymphocytes using magnetic beads, which serve as artificial antigen presenting cells (aAPCs), is well-studied. Yet, the efficacy of magnetic beads for propagation and functionality of peripheral blood lymphocytes (PBLs) isolated from companion dogs still remains limited. Domestic dog models are important in immuno-oncology field. Thus, we built the platform for induction of canine PBLs function, proliferation and biological activity using nano-sized magnetic beads (termed as MicroBeads) coated with anti-canine CD3 and CD28 antibodies. Herein we reveal that activation of canine PBLs via MicroBeads induces a range of genes involved in immediate-early response to T cell activation in dogs. Furthermore, canine T lymphocytes are effectively activated by MicroBeads, as measured by cluster formation and induction of activation marker CD25 on canine T cells as quickly as 24 h post stimulation. Similar to human T cells, canine PBLs require lower activation signal strength for efficient proliferation and expansion, as revealed by titration studies using a range of MicroBeads in the culture. Additionally, the impact of temperature was assessed in multiple stimulation settings, showing that both 37°C and 38.5°C are optimal for the expansion of canine T cells. In contrast to stimulation using plant mitogen Concanavalin A (ConA), MicroBead-based activation did not increase activation-induced cell death. In turn, MicroBeads supported the propagation of T cells with an effector memory phenotype that secreted substantial IL-2 and IFN-γ. Thus, MicroBeads represent an accessible and affordable tool for conducting immunological studies on domestic dog models. Similarities in inducing intracellular signaling pathways further underscore the importance of this model in comparative medicine. Presented herein MicroBead-based expansion platforms for canine PBLs may benefit adoptive immunotherapy in dogs and facilitate the design of next-generation clinical trials in humans.
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Affiliation(s)
- Iwona Monika Szopa
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Monika Granica
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Joanna Katarzyna Bujak
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
- Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences, Warsaw, Poland
| | - Agata Łabędź
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Maciej Błaszczyk
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
| | - Chrystal Mary Paulos
- Department of Surgery, Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, United States
| | - Kinga Majchrzak-Kuligowska
- Department of Physiological Sciences, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland
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44
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Nemec PS, Holmes JC, Hess PR. Dog leukocyte antigen-88*034:01 presents nonamer peptides from canine distemper virus hemagglutinin, large polymerase, and matrix proteins. HLA 2021; 97:428-434. [PMID: 33527745 DOI: 10.1111/tan.14197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/30/2022]
Abstract
Canine spontaneous cancers may offer greater fidelity than rodent models in advancing clinical immunotherapies. Boxers in particular are distinguished as study subjects by their popularity, and high incidence of human-relevant cancers. Further, the MHC class I allele DLA-88*034:01, with a known motif, dominates the breed, facilitating discovery of shared CTL responses against mutation-origin neoepitopes by standard prediction methods. We experimentally confirmed the allomorph's binding motif by developing an MHC surface stabilization assay. The assay validated four DLA-88*034:01-presented peptides from canine distemper virus, ubiquitously administered in routine vaccines, for positive controls in future CTL studies. In turn, these viral peptides substantiated motif-based prediction for DLA-88*034:01. The study adds new tools for studying neoepitope-specific CTL in Boxers to foster canine comparative oncology.
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Affiliation(s)
- Paige S Nemec
- Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA.,Precision Biosciences, Durham, North Carolina, USA
| | - Jennifer C Holmes
- Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA
| | - Paul R Hess
- Department of Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA
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45
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Mason NJ. Comparative Immunology and Immunotherapy of Canine Osteosarcoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1258:199-221. [PMID: 32767244 DOI: 10.1007/978-3-030-43085-6_14] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Approximately 800 people are diagnosed with osteosarcoma (OSA) per year in the USA. Although 70% of patients with localized OSA are cured with multiagent chemotherapy and surgical resection, the prognosis for patients with metastatic or relapsed disease is guarded. The small number of patients diagnosed annually contributes to an incomplete understanding of disease pathogenesis, and challenges in performing appropriately powered clinical trials and detecting correlative biomarkers of response. While mouse models of OSA are becoming increasingly sophisticated, they generally fail to accurately recapitulate tumor heterogeneity, tumor microenvironment (TME), systemic immune dysfunction, and the clinical features of tumor recurrence, metastases, and chemoresistance, which influence outcome. Pet dogs spontaneously develop OSA with an incidence that is 30-50 times higher than humans. Canine OSA parallels the human disease in its clinical presentation, biological behavior, genetic complexity, and therapeutic management. However, despite therapy, most dogs die from metastatic disease within 1 year of diagnosis. Since OSA occurs in immune-competent dogs, immune factors that sculpt tumor immunogenicity and influence responses to immune modulation are in effect. In both species, immune modulation has shown beneficial effects on patient outcome and work is now underway to identify the most effective immunotherapies, combination of immunotherapies, and correlative biomarkers that will further improve clinical response. In this chapter, the immune landscape of canine OSA and the immunotherapeutic strategies used to modulate antitumor immunity in dogs with the disease will be reviewed. From this immunological viewpoint, the value of employing dogs with spontaneous OSA to accelerate and inform the translation of immunotherapies into the human clinic will be underscored.
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Affiliation(s)
- Nicola J Mason
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. .,Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. .,Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA.
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Abstract
Comparative oncology clinical trials play an important and growing role in cancer research and drug development efforts. These trials, typically conducted in companion (pet) dogs, allow assessment of novel anticancer agents and combination therapies in a veterinary clinical setting that supports serial biologic sample collections and exploration of dose, schedule and corresponding pharmacokinetic/pharmacodynamic relationships. Further, an intact immune system and natural co-evolution of tumour and microenvironment support exploration of novel immunotherapeutic strategies. Substantial improvements in our collective understanding of the molecular landscape of canine cancers have occurred in the past 10 years, facilitating translational research and supporting the inclusion of comparative studies in drug development. The value of the approach is demonstrated in various clinical trial settings, including single-agent or combination response rates, inhibition of metastatic progression and randomized comparison of multiple agents in a head-to-head fashion. Such comparative oncology studies have been purposefully included in the developmental plan for several US FDA-approved and up-and-coming anticancer drugs. Challenges for this field include keeping pace with technology and data dissemination/harmonization, improving annotation of the canine genome and immune system, and generation of canine-specific validated reagents to support integration of correlative biology within clinical trial efforts.
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Affiliation(s)
- Amy K LeBlanc
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Christina N Mazcko
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Harman RM, Das SP, Bartlett AP, Rauner G, Donahue LR, Van de Walle GR. Beyond tradition and convention: benefits of non-traditional model organisms in cancer research. Cancer Metastasis Rev 2020; 40:47-69. [PMID: 33111160 DOI: 10.1007/s10555-020-09930-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/01/2020] [Indexed: 02/07/2023]
Abstract
Traditional laboratory model organisms are indispensable for cancer research and have provided insight into numerous mechanisms that contribute to cancer development and progression in humans. However, these models do have some limitations, most notably related to successful drug translation, because traditional model organisms are often short-lived, small-bodied, genetically homogeneous, often immunocompromised, are not exposed to natural environments shared with humans, and usually do not develop cancer spontaneously. We propose that assimilating information from a variety of long-lived, large, genetically diverse, and immunocompetent species that live in natural environments and do develop cancer spontaneously (or do not develop cancer at all) will lead to a more comprehensive understanding of human cancers. These non-traditional model organisms can also serve as sentinels for environmental risk factors that contribute to human cancers. Ultimately, expanding the range of animal models that can be used to study cancer will lead to improved insights into cancer development, progression and metastasis, tumor microenvironment, as well as improved therapies and diagnostics, and will consequently reduce the negative impacts of the wide variety of cancers afflicting humans overall.
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Affiliation(s)
- Rebecca M Harman
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Sanjna P Das
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Arianna P Bartlett
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Gat Rauner
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Leanne R Donahue
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Gerlinde R Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
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Abstract
Adoptive T cell therapy has proven effective against hematologic malignancies and demonstrated efficacy against a variety of solid tumors in preclinical studies and clinical trials. Nonetheless, antitumor responses against solid tumors remain modest, highlighting the need to enhance the effectiveness of this therapy. Genetic modification of T cells with RNA has been explored to enhance T-cell antigen specificity, effector function, and migration to tumor sites, thereby potentiating antitumor immunity. This review describes the rationale for RNA-electroporated T cell modifications and provides an overview of their applications in preclinical and clinical investigations for the treatment of hematologic malignancies and solid tumors.
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Affiliation(s)
- Fernanda Pohl-Guimarães
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Lan B Hoang-Minh
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Duane A Mitchell
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
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Matar AJ, Crepeau RL, Duran-Struuck R. Cellular Immunotherapies in Preclinical Large Animal Models of Transplantation. Transplant Cell Ther 2020; 27:36-44. [PMID: 33017660 DOI: 10.1016/j.bbmt.2020.09.032] [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: 07/16/2020] [Revised: 08/29/2020] [Accepted: 09/28/2020] [Indexed: 10/23/2022]
Abstract
Hematopoietic stem cell (HSC) transplantation and solid organ transplantation remain the only curative options for many hematologic malignancies and end-stage organ diseases. Unfortunately, the sequelae of long-term immunosuppression, as well as acute and chronic rejection, carry significant morbidities, including infection, malignancy, and graft loss. Numerous murine models have demonstrated the efficacy of adjunctive cellular therapies using HSCs, regulatory T cells, mesenchymal stem cells, and regulatory dendritic cells in modulating the alloimmune response in favor of graft tolerance; however, translation of such murine approaches to other preclinical models and in the clinic has yielded mixed results. Large animals, including nonhuman primates, swine, and canines, provide a more immunologically rigorous model in which to test the clinical translatability of these cellular therapies. Here, we highlight the contributions of large animal models to the development and optimization of HSCs and additional cellular therapies to improve organ transplantation outcomes.
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Affiliation(s)
- Abraham J Matar
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia
| | - Rebecca L Crepeau
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia
| | - Raimon Duran-Struuck
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
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In Vitro-Transcribed mRNA Chimeric Antigen Receptor T Cell (IVT mRNA CAR T) Therapy in Hematologic and Solid Tumor Management: A Preclinical Update. Int J Mol Sci 2020; 21:ijms21186514. [PMID: 32899932 PMCID: PMC7556036 DOI: 10.3390/ijms21186514] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 02/07/2023] Open
Abstract
Adoptive T cell immunotherapy has received considerable interest in the treatment of cancer. In recent years, chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising therapy in cancer treatment. In CAR T therapy, T cells from the patients are collected, reprogrammed genetically against tumor antigens, and reintroduced into the patients to trigger an immense immune response against cancer cells. CAR T therapy is successful in hematologic malignancies; however, in solid tumors, CAR T therapy faces multiple challenges, including the on-target off-tumor phenomenon, as most of the tumor-associated antigens are expressed in normal cells as well. Consequently, a transient in vitro-transcribed anti-mRNA-based CAR T cell (IVT mRNA CAR T) approach has been investigated to produce controlled cytotoxicity for a limited duration to avoid any undesirable effects in patients. In vitro and in vivo studies demonstrated the therapeutic ability of mRNA-engineered T cells in solid tumors, including melanoma, neuroblastoma and ovarian cancer; however, very few clinical trials are registered. In the present review, we discuss the effect of IVT mRNA CAR T therapy in preclinical studies related to hematologic malignancies and solid tumor management. In addition, we discuss the clinical trial studies based on IVT mRNA CAR T therapy in cancer.
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