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Zhong G, Zhang X, Guo Z, Gao Y, Zhao B, Liu X, Chen L, Qiao J, Yu C, Wang L, Li Y, Yu L. Complete remission of advanced pancreatic cancer induced by claudin18.2-targeted CAR-T cell therapy: a case report. Front Immunol 2024; 15:1325860. [PMID: 38487523 PMCID: PMC10937427 DOI: 10.3389/fimmu.2024.1325860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 02/13/2024] [Indexed: 03/17/2024] Open
Abstract
Pancreatic cancer (PC) is one of the most malignant tumors in digestive system due to its highly invasive and metastatic properties. At present, conventional treatment strategies for PC show the limited clinical efficacy. Therefore, novel effective therapeutic strategies are urgently needed. Here, we report a case of complete remission of advanced PC induced by claudin18.2-targeted CAR-T cell therapy. The patient was a 72-year-old man who was diagnosed with pancreatic ductal adenocarcinoma 2 years ago, and he experienced tumor recurrence and multiple metastases after pancreaticoduodenectomy and multi-line chemotherapies, including liver, peritoneum, and cervical lymph node metastases. Then, the patient was referred to our department for further treatment of metastatic PC, and he was enrolled in a clinical trial of claudin18.2-targeted CAR-T cell therapy. After lymphodepleting chemotherapy, the patient received claudin18.2-targeted CAR-T cell infusion at a dose of 1.2 × 106 cells/kg on November 21, 2022. During CAR-T cell therapy, the patient experienced grade 2 cytokine release syndrome (CRS) and gastric mucosa injury, which were controlled by tocilizumab and conventional symptomatic and supportive treatment. The patient achieved a complete response (CR) 1 month after claudin18.2-targeted CAR-T cell therapy, and remained in clinical remission for 8 months. Unfortunately, the patient experienced claudin18.2-negative relapse in July, 2023. Despite antigen-negative relapse after claudin18.2-targeted CAR-T cell infusion, the patient achieved sustained remission for 8 months, which indicates that claudin18.2-targeted CAR-T cell therapy is an extremely effective therapeutic strategy for the treatment of advanced PC.
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Affiliation(s)
- Guocheng Zhong
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Xiaomin Zhang
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
| | - Zheng Guo
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Yujie Gao
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Bochen Zhao
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Xianhao Liu
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Lei Chen
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Jingqiao Qiao
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Chuan Yu
- R&D Department, Shenzhen Haoshi Biotechnology Co., Ltd, Shenzhen, China
- Biomedical Laboratory, Shenzhen University-Haoshi Cell Therapy Institute, Shenzhen, China
| | - Lixin Wang
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Yisheng Li
- R&D Department, Shenzhen Haoshi Biotechnology Co., Ltd, Shenzhen, China
- Biomedical Laboratory, Shenzhen University-Haoshi Cell Therapy Institute, Shenzhen, China
| | - Li Yu
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
- Biomedical Laboratory, Shenzhen University-Haoshi Cell Therapy Institute, Shenzhen, China
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Herpels M, Ishihara J, Sadanandam A. The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities. J Pathol 2023; 260:533-550. [PMID: 37550956 DOI: 10.1002/path.6171] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/20/2023] [Accepted: 06/22/2023] [Indexed: 08/09/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer and has abysmal survival rates. In the past two decades, immunotherapeutic agents with success in other cancer types have gradually been trialled against PDACs at different stages of cancer progression, either as a monotherapy or in combination with chemotherapy. Unfortunately, to this day, chemotherapy still prolongs the survival rates the most and is prescribed in clinics despite the severe side effects in other cancer types. The low success rates of immunotherapy against PDAC have been attributed most frequently to its complex and multi-faceted tumour microenvironment (TME) and low mutational burden. In this review, we give a comprehensive overview of the immunotherapies tested in PDAC clinical trials thus far, their limitations, and potential explanations for their failure. We also discuss the existing classification of heterogenous PDACs into cancer, cancer-associated fibroblast, and immune subtypes and their potential opportunity in patient selection as a form of personalisation of PDAC immunotherapy. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Melanie Herpels
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Department of Bioengineering, Imperial College London, London, UK
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, UK
| | - Anguraj Sadanandam
- Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Global Oncology, Division of Molecular Pathology, Institute of Cancer Research, London, UK
- Centre for Translational Immunotherapy, Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
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Backlund CM, Holden RL, Moynihan KD, Garafola D, Farquhar C, Mehta NK, Maiorino L, Pham S, Iorgulescu JB, Reardon DA, Wu CJ, Pentelute BL, Irvine DJ. Cell-penetrating peptides enhance peptide vaccine accumulation and persistence in lymph nodes to drive immunogenicity. Proc Natl Acad Sci U S A 2022; 119:e2204078119. [PMID: 35914154 PMCID: PMC9371699 DOI: 10.1073/pnas.2204078119] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/29/2022] [Indexed: 12/30/2022] Open
Abstract
Peptide-based cancer vaccines are widely investigated in the clinic but exhibit modest immunogenicity. One approach that has been explored to enhance peptide vaccine potency is covalent conjugation of antigens with cell-penetrating peptides (CPPs), linear cationic and amphiphilic peptide sequences designed to promote intracellular delivery of associated cargos. Antigen-CPPs have been reported to exhibit enhanced immunogenicity compared to free peptides, but their mechanisms of action in vivo are poorly understood. We tested eight previously described CPPs conjugated to antigens from multiple syngeneic murine tumor models and found that linkage to CPPs enhanced peptide vaccine potency in vivo by as much as 25-fold. Linkage of antigens to CPPs did not impact dendritic cell activation but did promote uptake of linked antigens by dendritic cells both in vitro and in vivo. However, T cell priming in vivo required Batf3-dependent dendritic cells, suggesting that antigens delivered by CPP peptides were predominantly presented via the process of cross-presentation and not through CPP-mediated cytosolic delivery of peptide to the classical MHC class I antigen processing pathway. Unexpectedly, we observed that many CPPs significantly enhanced antigen accumulation in draining lymph nodes. This effect was associated with the ability of CPPs to bind to lymph-trafficking lipoproteins and protection of CPP-antigens from proteolytic degradation in serum. These two effects resulted in prolonged presentation of CPP-peptides in draining lymph nodes, leading to robust T cell priming and expansion. Thus, CPPs can act through multiple unappreciated mechanisms to enhance T cell priming that can be exploited for cancer vaccines with enhanced potency.
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Affiliation(s)
- Coralie M. Backlund
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
| | - Rebecca L. Holden
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Kelly D. Moynihan
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Daniel Garafola
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
| | - Charlotte Farquhar
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Naveen K. Mehta
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Laura Maiorino
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
| | - Sydney Pham
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
| | - J. Bryan Iorgulescu
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - David A. Reardon
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard University School of Medicine, Boston, MA 02215
| | - Catherine J. Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
- Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Bradley L. Pentelute
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139
- Broad Institute of MIT and Harvard, Cambridge, MA 02142
- Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139
| | - Darrell J. Irvine
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
- Broad Institute of MIT and Harvard, Cambridge, MA 02142
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
- Howard Hughes Medical Institute, Chevy Chase, MD 20815
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Yin C, Alqahtani A, Noel MS. The Next Frontier in Pancreatic Cancer: Targeting the Tumor Immune Milieu and Molecular Pathways. Cancers (Basel) 2022; 14:2619. [PMID: 35681599 PMCID: PMC9179513 DOI: 10.3390/cancers14112619] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/13/2022] [Accepted: 05/19/2022] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with abysmal prognosis. It is currently the third most common cause of cancer-related mortality, despite being the 11th most common cancer. Chemotherapy is standard of care in all stages of pancreatic cancer, yet survival, particularly in the advanced stages, often remains under one year. We are turning to immunotherapies and targeted therapies in PDAC in order to directly attack the core features that make PDAC notoriously resistant to chemotherapy. While the initial studies of these agents in PDAC have generally been disappointing, we find optimism in recent preclinical and early clinical research. We find that despite the immunosuppressive effects of the PDAC tumor microenvironment, new strategies, such as combining immune checkpoint inhibitors with vaccine therapy or chemokine receptor antagonists, help elicit strong immune responses. We also expand on principles of DNA homologous recombination repair and highlight opportunities to use agents, such as PARP inhibitors, that exploit deficiencies in DNA repair pathways. Lastly, we describe advances in direct targeting of driver mutations and metabolic pathways and highlight some technological achievements such as novel KRAS inhibitors.
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Affiliation(s)
| | | | - Marcus S. Noel
- Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, USA; (C.Y.); (A.A.)
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Pancreatic Cancer and Immunotherapy: A Clinical Overview. Cancers (Basel) 2021; 13:cancers13164138. [PMID: 34439292 PMCID: PMC8393975 DOI: 10.3390/cancers13164138] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC's immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.
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Zhu Y, Zhu X, Tang C, Guan X, Zhang W. Progress and challenges of immunotherapy in triple-negative breast cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188593. [PMID: 34280474 DOI: 10.1016/j.bbcan.2021.188593] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/26/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022]
Abstract
Triple-negative breast cancer (TNBC), a subtype of breast cancer, is defined as lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) expression. Compared with other subtypes in breast cancer, TNBC is more likely to recur and metastasize, with a lower survival rate. Due to the absence of definitive targets, there was limited novel therapeutic interventions and chemotherapy remained the primary treatment in the past decades. Following the development of immune checkpoint inhibition (ICI) in solid tumors and validation of the immunogenicity in TNBC, immunotherapy has attracted more and more attentions. On basis of accumulating clinical studies, we reviewed the current progress targeting different immune checkpoints in several-lines treatment for TNBC, including programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) inhibitor, and other novel immunotherapeutic approaches (e.g., individualized peptide vaccine, cancer-testis antigen (CTA), new antigen vaccine, RNA vaccine and chimeric antigen receptor modified T cells (CAR-T)). In order to improve the survival outcome of TNBC populations, we further discussed potential predictive biomarkers for immunotherapy (e.g., PD-L1 expression, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), microsatellite instability (MSI)/mismatch repair (MMR) deficiency) and challenges in the future treatment of TNBC.
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Affiliation(s)
- Yinxing Zhu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Xuedan Zhu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
| | - Xiaoxiang Guan
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.
| | - Wenwen Zhang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
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Michiyuki S, Tomita N, Mori Y, Kanda H, Tashiro K, Notomi T. Discrimination of a single nucleotide polymorphism in the haptoglobin promoter region, rs5472, using a competitive fluorophore-labeled probe hybridization assay following loop-mediated isothermal amplification. Biosci Biotechnol Biochem 2021; 85:359-368. [PMID: 33604636 DOI: 10.1093/bbb/zbaa012] [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: 08/17/2020] [Accepted: 09/15/2020] [Indexed: 12/22/2022]
Abstract
Personalized peptide vaccination, which involves activation of the host immune system against cancer cells using personalized peptide vaccines (PPVs), can improve overall survival in multiple cancer types. However, the clinical efficacies of PPVs vary for unknown reasons. Recently, a single nucleotide polymorphism (NG_012651.1:g.4461_5460[4960A>G]) in the haptoglobin promoter region, rs5472, was significantly associated with clinical response of PPV. Therefore, rs5472 is expected to be a predictive biomarker for PPV therapy. Here, we described a single nucleotide discrimination method for rs5472 analysis by combining the loop-mediated isothermal amplification and quenching probe methods. In evaluation of saliva samples, this method showed high concordance with the results of Sanger sequencing (100%, n = 36). Importantly, this method did not require calculation of melting temperature for single nucleotide discrimination and could therefore be carried out on a simple instrument. Accordingly, this method may be more robust and applicable to near-patient testing.
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Affiliation(s)
- Satoru Michiyuki
- Biochemical Research Laboratory, Eiken Chemical Co., Ltd., Otawara, Tochigi, Japan
| | - Norihiro Tomita
- Biochemical Research Laboratory, Eiken Chemical Co., Ltd., Otawara, Tochigi, Japan
| | - Yasuyoshi Mori
- Biochemical Research Laboratory, Eiken Chemical Co., Ltd., Otawara, Tochigi, Japan
| | - Hidetoshi Kanda
- Biochemical Research Laboratory, Eiken Chemical Co., Ltd., Otawara, Tochigi, Japan
| | - Kosuke Tashiro
- Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Nishi-Ku, Fukuoka, Japan
| | - Tsugunori Notomi
- Biochemical Research Laboratory, Eiken Chemical Co., Ltd., Otawara, Tochigi, Japan
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Waki K, Yokomizo K, Yoshiyama K, Takamori S, Komatsu N, Yamada A. Integrity of circulating cell-free DNA as a prognostic biomarker for vaccine therapy in patients with nonsmall cell lung cancer. Immunopharmacol Immunotoxicol 2021; 43:176-182. [PMID: 33541161 DOI: 10.1080/08923973.2021.1872619] [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: 12/25/2022]
Abstract
BACKGROUND Many clinical trials of immune checkpoint blockade-based combination therapies are under way. Vaccine therapy is a promising partner of combination therapies. We have developed a personalized peptide vaccination and conducted clinical trials of it in patients with various cancers. At the present time, we have only a limited number of biomarkers related to the prognosis of vaccine-treated patients. Thus, new biomarkers are urgently needed. METHODS In this study, we investigated the plasma cell-free DNA (cfDNA) integrity-a ratio of the necrotic tumor cell-derived long cfDNA fragments to the total dead cell-derived short cfDNA fragments from genomic Alu elements-in patients with advanced nonsmall cell lung cancer during treatment with the personalized peptide vaccination. RESULTS We found that (1) the cfDNA integrity was decreased after the first cycle of vaccination, and (2) the patients with high prevaccination cfDNA integrity survived longer than those with low prevaccination integrity (median survival time (MST): 17.9 versus 9.0 months, respectively; hazard ratio (HR): 0.58, p = .0049). A similar tendency was observed in postvaccination cfDNA integrity (MST: 16.4 vs 9.4 months; HR: 0.65, p = .024). CONCLUSIONS These results suggest that cfDNA integrity is a possible prognostic biomarker in patients treated with the personalized peptide vaccine.
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Affiliation(s)
- Kayoko Waki
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Kanako Yokomizo
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Koichi Yoshiyama
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Shinzo Takamori
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Nobukazu Komatsu
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan
| | - Akira Yamada
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
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Waki K, Yokomizo K, Kawano K, Tsuda N, Komatsu N, Yamada A. Integrity of plasma cell-free DNA as a prognostic factor for vaccine therapy in patients with endometrial cancer. Mol Clin Oncol 2021; 14:29. [PMID: 33414910 PMCID: PMC7783719 DOI: 10.3892/mco.2020.2191] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 11/18/2020] [Indexed: 12/09/2022] Open
Abstract
Endometrial cancer is the most prevalent gynecological cancer in developed countries. Although the prognosis of endometrial cancer is better than that of other gynecological cancers, the prognosis of advanced endometrial cancer is still poor and thus new therapeutic modalities, such as immune therapies, are urgently required. For the further development of new modalities, exploration of new biomarkers is important. The present study investigated the circulating cell-free DNA (cfDNA) integrity as a ratio of the necrotic tumor cell-derived long cfDNA fragments to the total dead cell-derived short cfDNA fragments from genomic Alu elements in patients with advanced endometrial cancer during peptide vaccination treatment. The results demonstrated that: i) The plasma cfDNA integrity was decreased during the first cycle of vaccination in patients with endometrial cancer treated with the personalized peptide vaccination, and ii) the post-vaccination cfDNA integrity levels were correlated with good prognosis. Some of these findings have been confirmed in other cancers, and thus cfDNA integrity might be an important marker for future cancer vaccine therapies in general, and might also be applicable for other immune therapies.
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Affiliation(s)
- Kayoko Waki
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka 830-0011, Japan
| | - Kanako Yokomizo
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka 830-0011, Japan
| | - Kouichiro Kawano
- Departments of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Naotake Tsuda
- Departments of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Nobukazu Komatsu
- Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Akira Yamada
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka 830-0011, Japan
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Uchino Y, Muroya D, Yoshitomi M, Shichijo S, Yamada A, Sasada T, Yamada T, Okuda K, Itoh K, Yutani S. Investigation of factors associated with reduced clinical benefits of personalized peptide vaccination for pancreatic cancer. Mol Clin Oncol 2020; 14:39. [PMID: 33437477 PMCID: PMC7788558 DOI: 10.3892/mco.2020.2201] [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: 02/20/2020] [Accepted: 12/12/2020] [Indexed: 11/29/2022] Open
Abstract
The aim of the present study was to determine the factors associated with reduced clinical benefits of personalized peptide vaccination (PPV) for pancreatic cancer. Phase II PPV clinical trials comprising 309 (8 non-advanced and 301 advanced-stage) patients with pancreatic cancer were conducted. Two to four peptides were selected among a set of 31 different peptides as vaccine candidates for personalized peptide vaccination based on human leukocyte antigen types and preexisting peptide-specific IgG levels, and subcutaneously injected. The selected peptides were subcutaneously injected. Of the 309 patients, 81 failed to complete the 1st PPV cycle due to rapid disease progression, and their median overall survival [2.1 months; 95% confidence interval (CI), 1.8-2.7] was significantly shorter than that of the remaining 228 patients (8.4 months; 95% CI, 8.4-9.9; P<0.01). ‘Immune boosting’ was defined when IgG levels before vaccination increased more than 2-fold after vaccination. Immune boosting was observed in the majority of patients with PPV irrespective of whether or not they received concomitant chemotherapy. Additionally, patients demonstrating immune boosting exhibited longer survival rates. Although the positive-response rates and peptide-specific IgG levels in pre- and post-vaccination samples differed among the 31 peptides, patients exhibiting immune boosting in response to each of the vaccinated peptides demonstrated longer survival times. Pre-vaccination factors associated with reduced clinical benefits were high c-reactive protein (CRP) levels, high neutrophil counts, lower lymphocyte and red blood cell counts, advanced disease stage and the greater number of chemotherapy courses prior to the PPV treatment. The post-vaccination factors associated with lower clinical benefits were PPV monotherapy and lower levels of immune boosting. In conclusion, pre-vaccination inflammatory signatures, rather than pre- or post-vaccination immunological signatures, were associated with reduced clinical benefits of personalized peptide vaccination (PPV) for pancreatic cancer.
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Affiliation(s)
- Yoshihiro Uchino
- Cancer Vaccine Center, Kurume University, Kurume, Fukuoka 839-0823, Japan.,Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Daisuke Muroya
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Munehiro Yoshitomi
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Shigeki Shichijo
- Cancer Vaccine Center, Kurume University, Kurume, Fukuoka 839-0823, Japan
| | - Akira Yamada
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka 830-0011, Japan
| | - Tetsuro Sasada
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Kanagawa, Yokohama 241-8515, Japan
| | - Teppei Yamada
- Department of Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan
| | - Koji Okuda
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Kyogo Itoh
- Cancer Vaccine Center, Kurume University, Kurume, Fukuoka 839-0823, Japan
| | - Shigeru Yutani
- Cancer Vaccine Center, Kurume University, Kurume, Fukuoka 839-0823, Japan
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Waki K, Yokomizo K, Kawano K, Tsuda N, Komatsu N, Yamada A. Integrity of plasma DNA is inversely correlated with vaccine-induced antitumor immunity in ovarian cancer patients. Cancer Immunol Immunother 2020; 69:2001-2007. [PMID: 32393999 PMCID: PMC7222063 DOI: 10.1007/s00262-020-02599-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/28/2020] [Indexed: 12/25/2022]
Abstract
Cancer immunotherapy including vaccine therapy is a promising modality for cancer treatment, but few patients show its clinical benefits currently. The identification of biomarkers that can identify patients who will benefit from cancer immunotherapy is thus important. Here, we investigated the potential utility of the circulating cell-free DNA (cfDNA) integrity—a ratio of necrotic cell-derived, longer DNA fragments versus apoptotic cell-derived shorter fragments of Alu gene—as a biomarker of vaccine therapy for patients with ovarian cancer. We analyzed plasma samples from 39 patients with advanced or recurrent ovarian cancer enrolled in clinical trials for personalized peptide vaccinations. We observed that (1) the cfDNA integrity was decreased after the first cycle of vaccination, and (2) the decreased levels of cfDNA integrity were correlated with vaccine-induced immune responses; i.e., decreased cfDNA integrity was observed in 91.7% and 59.3% of the IgG-positive and negative patients, respectively (p = 0.0445). Similarly, decreased cfDNA integrity was observed in 92.9% and 56.0% of CTL response-positive and negative patients, respectively (p = 0.0283). These results suggest that the circulating cfDNA integrity is a possible biomarker for cancer vaccine therapy.
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Affiliation(s)
- Kayoko Waki
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 830-0011, Japan
| | - Kanako Yokomizo
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 830-0011, Japan
| | - Kouichiro Kawano
- Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Naotake Tsuda
- Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Nobukazu Komatsu
- Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Akira Yamada
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 830-0011, Japan.
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12
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Ma M, Liu J, Jin S, Wang L. Development of tumour peptide vaccines: From universalization to personalization. Scand J Immunol 2020; 91:e12875. [PMID: 32090366 DOI: 10.1111/sji.12875] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 02/08/2020] [Accepted: 02/20/2020] [Indexed: 12/19/2022]
Abstract
In recent years, relying on the human immune system to kill tumour cells has become an effective means of cancer treatment. The development of peptide vaccines, which not only break the immune tolerance of a tumour but also attack malignant cells via specific antitumour immunity, has received increased attention in tumour immunization therapy due to their safety and easy preparation. The use of large-scale sequencing technology enables the continuous discovery of new tumour antigens. With improved accuracy of epitope prediction by computer simulation and the usage of a tetramer assay, cytotoxic lymphocyte epitopes can be screened and identified more easily. Transmembrane peptide and nanoparticle technologies promote more effective intake and delivery of antigens. Consequently, considerable evolution from universal to personalized peptide vaccines has taken place, and such vaccines induce an efficient and specific immune response targeting tumour neoantigens. Recently, genomic analysis and bioinformatics approaches have greatly facilitated the breakthrough of personalized peptide vaccines targeting neoantigens, resulting in a renewed interest in this field. Further, the combination of tumour peptide vaccines with checkpoint blockades may improve patient outcomes. In this review, we discuss the development of tumour peptide vaccines and the new technological progress, from universalization to personalization, to highlight the substantial promise of tumour peptide vaccines in clinical cancer immunotherapy.
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Affiliation(s)
- Minjun Ma
- Department of Gastrology, The First People's Hospital of Fuyang of Hangzhou, Hangzhou, China
| | - Jingwen Liu
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Shenghang Jin
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Lan Wang
- Linhai Center for Disease Control and Prevention, Linhai, China
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13
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Waki K, Kawano K, Tsuda N, Komatsu N, Yamada A. CD4/CD8 ratio is a prognostic factor in IgG nonresponders among peptide vaccine-treated ovarian cancer patients. Cancer Sci 2020; 111:1124-1131. [PMID: 32058620 PMCID: PMC7156874 DOI: 10.1111/cas.14349] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 01/01/2023] Open
Abstract
The identification of useful biomarkers is an urgent issue in cancer treatment, particularly for immunotherapy, as only some patients experience benefits from this treatment. The early induction of the IgG response has been reported as a useful biomarker of favorable prognosis for cancer patients treated with a personalized peptide vaccination, but a portion of these patients (IgG nonresponders) fail to achieve an early induction of IgG response yet experience long-term survival. It is thus necessary to identify other biomarkers of favorable prognosis among these patients. Here we report the usefulness of classical T-cell markers (ie, the CD8 content and the CD4/CD8 ratio in peripheral blood) in IgG nonresponders among advanced or recurrent ovarian cancer patients treated with a personalized peptide vaccination. Among IgG nonresponders (n = 25), the overall survival (OS) of the increased-CD8 group (n = 7) was significantly longer than that of the decreased-CD8 group (n = 18; P = .018), and the OS of the patients with a decreased CD4/CD8 ratio (n = 10) was significantly longer than that of the patients with an increased ratio (n = 15; P = .0055). Thus, an increased content of CD8 and a decreased CD4/CD8 ratio are each favorable prognosis markers in IgG nonresponders treated with a personalized peptide vaccination.
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Affiliation(s)
- Kayoko Waki
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Kouichiro Kawano
- Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Japan
| | - Naotake Tsuda
- Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Japan
| | - Nobukazu Komatsu
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan
| | - Akira Yamada
- Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
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14
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Lambert A, Schwarz L, Borbath I, Henry A, Van Laethem JL, Malka D, Ducreux M, Conroy T. An update on treatment options for pancreatic adenocarcinoma. Ther Adv Med Oncol 2019; 11:1758835919875568. [PMID: 31598142 PMCID: PMC6763942 DOI: 10.1177/1758835919875568] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Accepted: 08/19/2019] [Indexed: 12/24/2022] Open
Abstract
Pancreatic cancer is one of the most lethal solid organ tumors. Due to the rising incidence, late diagnosis, and limited treatment options, it is expected to be the second leading cause of cancer deaths in high income countries in the next decade. The multidisciplinary treatment of this disease depends on the stage of cancer at diagnosis (resectable, borderline, locally advanced, and metastatic disease), and combines surgery, chemotherapy, chemoradiotherapy, and supportive care. The landscape of multidisciplinary pancreatic cancer treatment is changing rapidly, especially in locally advanced disease, and the number of treatment options in metastatic disease, including personalized medicine, innovative targets, immunotherapy, therapeutic vaccines, adoptive T-cell transfer, or stemness inhibitors, will probably expand in the near future. This review summarizes the current literature and provides an overview of how new therapies or new therapeutic strategies (neoadjuvant therapies, conversion surgery) will guide multidisciplinary disease management, future clinical trials, and, hopefully, will increase overall survival.
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Affiliation(s)
- Aurélien Lambert
- Department of Medical Oncology, Institut de Cancérologie de Lorraine and Université de Lorraine, Nancy, France
| | - Lilian Schwarz
- Department of Digestive Surgery, Rouen University Hospital and Université de Rouen Normandie, France
| | - Ivan Borbath
- Department of Gastroenterology and Digestive Oncology, Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels, Belgium
| | - Aline Henry
- Department of Supportive Care in Oncology, Institut de Cancérologie de Lorraine, Nancy, France
| | - Jean-Luc Van Laethem
- Department of Gastroenterology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Belgium
| | - David Malka
- Department of Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Michel Ducreux
- Department of Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Thierry Conroy
- Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, 50519 Vandoeuvre-lès-Nancy CEDEX, France
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15
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Nakahara Y, Kouro T, Igarashi Y, Kawahara M, Sasada T. Prospects for a personalized peptide vaccine against lung cancer. Expert Rev Vaccines 2019; 18:703-709. [DOI: 10.1080/14760584.2019.1635461] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Yoshiro Nakahara
- Department of Respiratory Medicine, Kanagawa Cancer Center, Yokohama, Japan
| | - Taku Kouro
- Department of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Yuka Igarashi
- Department of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Mamoru Kawahara
- Department of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Tetsuro Sasada
- Department of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine Center, Kanagawa Cancer Center, Yokohama, Japan
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16
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Singh RR, Goldberg J, Varghese AM, Yu KH, Park W, O'Reilly EM. Genomic profiling in pancreatic ductal adenocarcinoma and a pathway towards therapy individualization: A scoping review. Cancer Treat Rev 2019; 75:27-38. [PMID: 30927677 PMCID: PMC6504563 DOI: 10.1016/j.ctrv.2019.03.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 03/20/2019] [Accepted: 03/21/2019] [Indexed: 12/11/2022]
Abstract
CONTEXT Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations. OBJECTIVE A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC. METHOD A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008. RESULTS A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability. CONCLUSION Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.
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Affiliation(s)
- Ritu R Singh
- Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai St. Luke's and Mount Sinai West, New York, NY 10019, USA.
| | - Johanna Goldberg
- MSK Library, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - Anna M Varghese
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Kenneth H Yu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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17
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Ducreux M, Seufferlein T, Van Laethem JL, Laurent-Puig P, Smolenschi C, Malka D, Boige V, Hollebecque A, Conroy T. Systemic treatment of pancreatic cancer revisited. Semin Oncol 2018; 46:28-38. [PMID: 30638624 DOI: 10.1053/j.seminoncol.2018.12.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 12/19/2018] [Indexed: 12/25/2022]
Abstract
Pancreatic cancer is considered to be one of the most aggressive cancers. For unknown reasons, the incidence of pancreatic cancer is slowly rising and so too are mortality rates. Over 75% of patients are diagnosed with locally advanced disease or with metastases; and more than 95% of patients have metastases at diagnosis or will develop metastases during their follow-up. Despite recent improvements in the therapy of pancreatic cancer, initially with demonstration of the activity of the FOLFIRINOX regimen and subsequently the approval of nab-paclitaxel in combination with gemcitabine, prognosis remains poor and the 5-year survival rate is less than 5%. To date, neither personalized medicine nor immunotherapy, the 2 recent revolutions of cancer treatment, have delivered major positive results in the treatment of pancreatic cancer; and it is especially clear that immune checkpoint inhibitors will not become a major tool in the treatment of pancreatic cancer. There are many ongoing studies, including those exploring combinations of chemotherapy with immunotherapy. Vaccines or T cells modified with a chimeric antigen receptor (CAR-T cells) could also play a role in the treatment of cancer in the future. The aim of this review is to discuss recent improvements in standard of care, major obstacles to overcome, recent results of new treatment combinations, and the most interesting innovative approaches.
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Affiliation(s)
- Michel Ducreux
- Département de Médecine Oncologique, Gustave Roussy Cancer Center Grand Paris, Université Paris Saclay, France.
| | | | - Jean-Luc Van Laethem
- Department of Gastroenterology and Digestive oncology, Erasme University Hospital, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Pierre Laurent-Puig
- Assistance Publique-Hôpitaux de Paris, Department of Biology, European Georges Pompidou Hospital, Paris, France
| | - Cristina Smolenschi
- Département de Médecine Oncologique, Gustave Roussy Cancer Center Grand Paris, France
| | - David Malka
- Département de Médecine Oncologique, Gustave Roussy Cancer Center Grand Paris, France
| | - Valérie Boige
- Département de Médecine Oncologique, Gustave Roussy Cancer Center Grand Paris, France
| | - Antoine Hollebecque
- Département de Médecine Oncologique, Gustave Roussy Cancer Center Grand Paris, France; Département d'Innovation Thérapeutique, Gustave Roussy Cancer Center Grand Paris, France
| | - Thierry Conroy
- Département d'oncologie médicale, Institut de Cancérologie de Lorraine, Université de Lorraine, Nancy, France
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18
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Uchida A, Kawasaki E, Tojikubo M, Tamai H, Sagara Y, Nakano Y, Uji Y, Masuda M, Yamaguchi T, Yutani S. Development of Lobular Panniculitis Long After Completing the Personalized Peptide Vaccine Therapy. AMERICAN JOURNAL OF CASE REPORTS 2018; 19:1530-1535. [PMID: 30587844 PMCID: PMC6322063 DOI: 10.12659/ajcr.912418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Patient: Female, 64 Final Diagnosis: Lobular panniculitis Symptoms: Subcutaneous indurations Medication: — Clinical Procedure: Skin biopsy/Administration of prednisolone Specialty: Oncology
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Affiliation(s)
- Aira Uchida
- Department of Diabetes and Endocrinology, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | - Eiji Kawasaki
- Department of Diabetes and Endocrinology, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | - Masayuki Tojikubo
- Department of Diabetes and Endocrinology, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | - Hidekazu Tamai
- Department of Diabetes and Endocrinology, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | - Yoko Sagara
- Department of Diabetes and Endocrinology, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | - Yuko Nakano
- Department of Diabetes and Endocrinology, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | - Yoshitaka Uji
- Department of Digestive Surgery, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | - Masanori Masuda
- Department of Diagnostic Pathology, Shin-Koga Hospital, Kurume, Fukuoka, Japan
| | | | - Shigeru Yutani
- Cancer Vaccine Center, Kurume University, Kurume, Fukuoka, Japan
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19
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Young K, Hughes DJ, Cunningham D, Starling N. Immunotherapy and pancreatic cancer: unique challenges and potential opportunities. Ther Adv Med Oncol 2018; 10:1758835918816281. [PMID: 30574212 PMCID: PMC6299311 DOI: 10.1177/1758835918816281] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 10/31/2018] [Indexed: 12/13/2022] Open
Abstract
Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) continues to have the worst 5-year survival of any malignancy. With 338,000 new cases diagnosed and over 300,000 deaths per year globally there is an urgent unmet need to improve the therapeutic options available. Novel immunotherapies have shown promising results across multiple solid tumours, in a number of cases surpassing chemotherapy as a first-line therapeutic option. However, to date, trials of single-agent immunotherapies in PDAC have been disappointing and PDAC has been labelled as a nonimmunogenic cancer. This lack of response may in part be attributed to PDAC’s unique tumour microenvironment (TME), consisting of a dense fibrotic stroma and a scarcity of tumour infiltrating lymphocytes. However, as our understanding of the PDAC TME evolves, it is becoming apparent that the problem is not simply the immune system failing to recognize the cancer. There is a highly complex interplay between stromal signals, the immune system and tumour cells, at times possibly restraining tumour growth and at others supporting growth and metastasis. Understanding this complexity will enable the development of rational combinations with immunotherapy, priming the TME to offer immunotherapy the best chance of success. This review seeks to describe the unique challenges of the PDAC TME, the potential opportunities it may afford and the trials in progress capitalizing on recent insights in this area.
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Affiliation(s)
- Kate Young
- The Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, London, UK
| | - Daniel J Hughes
- The Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, London, UK
| | - David Cunningham
- The Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, London, UK
| | - Naureen Starling
- Consultant Medical Oncologist, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK
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20
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Wang X, Qi Y, Kong X, Zhai J, Li Y, Song Y, Wang J, Feng X, Fang Y. Immunological therapy: A novel thriving area for triple-negative breast cancer treatment. Cancer Lett 2018; 442:409-428. [PMID: 30419345 DOI: 10.1016/j.canlet.2018.10.042] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/25/2018] [Accepted: 10/25/2018] [Indexed: 11/19/2022]
Abstract
Triple-negative breast cancer (TNBC) refers to cancers that are low in expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tends to behave more aggressively than other types of breast cancer. Unlike other breast cancer subtypes (ie, ER-positive, HER2-positive subtypes), there are no approved targeted treatments available, other than the administration of chemotherapy. Immunotherapy is a new kind of treatment approach for TNBC when compared with the surgical treatment, chemotherapy, endocrine therapy, and molecular targeting therapy. The present article reviews the research progresses of immunotherapy for TNBC in recent years. The full text structure covers molecular classification of TNBC, active immunotherapy of TNBC, passive immunotherapy of TNBC, oncolytic immunotherapy and the prospect of immunotherapy for TNBC.
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Affiliation(s)
- Xiangyu Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Department of Laboratory Medicine, Mayo Clinic, Rochester, MN, 55902, USA
| | - Yihang Qi
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jie Zhai
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yalun Li
- Department of Breast Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, China
| | - Yan Song
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Xiaoli Feng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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21
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Therapeutic cancer vaccines: From initial findings to prospects. Immunol Lett 2018; 196:11-21. [DOI: 10.1016/j.imlet.2018.01.011] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 12/30/2017] [Accepted: 01/24/2018] [Indexed: 12/15/2022]
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22
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Sahin IH, Askan G, Hu ZI, O’Reilly EM. Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity? Ann Oncol 2017; 28:2950-2961. [PMID: 28945842 PMCID: PMC5834032 DOI: 10.1093/annonc/mdx503] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The genomic-plasticity of the immune system creates a broad immune repertoire engaged to tackle cancer cells. Promising clinical activity has been observed with several immune therapy strategies in solid tumors including melanoma, lung, kidney, and bladder cancers, albeit as yet immunotherapy-based treatment approaches in pancreatic ductal adenocarcinoma (PDAC) remain to have proven value. While translational and early clinical studies have demonstrated activation of antitumor immunity, most recent late-phase clinical trials have not confirmed the early promise in PDAC except in MSI-High PDAC patients. These results may in part be explained by multiple factors, including the poorly immunogenic nature of PDAC along with immune privilege, the complex tumor microenvironment, and the genetic plasticity of PDAC cells. These challenges have led to disappointments in the field, nonetheless they have also advanced our understanding that may tailor the future steps for immunotherapy for PDAC. Therefore, there is significant hope that progress is on the horizon.
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Affiliation(s)
- I H Sahin
- Department of Medicine, Emory University School of Medicine, Atlanta
| | - G Askan
- Department of Pathology, Pathology, Memorial Sloan Kettering Cancer Center, New York
| | - Z I Hu
- Department of Medicine, Icahn School of Medicine, Mount Sinai Health System, New York
| | - E M O’Reilly
- Department of Pathology, Pathology, Memorial Sloan Kettering Cancer Center, New York
- Department of Medicine, Weill Cornell Medicine, New York, USA
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23
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Beatty GL, Eghbali S, Kim R. Deploying Immunotherapy in Pancreatic Cancer: Defining Mechanisms of Response and Resistance. Am Soc Clin Oncol Educ Book 2017; 37:267-278. [PMID: 28561678 DOI: 10.1200/edbk_175232] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The immune reaction to pancreatic ductal adenocarcinoma (PDAC) is a strong prognostic determinant of clinical outcomes and may be a promising therapeutic target. We use multiplex immunohistochemistry to illustrate distinct patterns of T-cell and myeloid cell infiltration seen in PDAC that have therapeutic implications and discuss the current state of immunotherapy in this disease. Based on collective findings from clinical and preclinical studies, two conceptual models have emerged for applying immunotherapy in PDAC that involve (1) restoring elements of T-cell immunosurveillance and (2) redirecting myeloid cells to condition tumors with increased sensitivity to cytotoxic therapies. Overall, the success of immunotherapy in PDAC will most likely rely on strategic combinations of therapies that are informed by well-designed correlative analyses that consider the spatial heterogeneity of immune responses detected in malignant tissues.
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Affiliation(s)
- Gregory L Beatty
- From the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Shabnam Eghbali
- From the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Rebecca Kim
- From the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Department of Medicine, Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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24
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Wada S, Yada E, Ohtake J, Sasada T. Personalized peptide vaccines for cancer therapy: current progress and state of the art. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2017. [DOI: 10.1080/23808993.2017.1403286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Satoshi Wada
- Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama, Japan
| | - Erica Yada
- Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama, Japan
| | - Junya Ohtake
- Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama, Japan
| | - Tetsuro Sasada
- Cancer Immunotherapy, Kanagawa Cancer Center, Asahi-ku, Yokohama, Japan
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25
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Sakamoto S, Yamada T, Terazaki Y, Yoshiyama K, Sugawara S, Takamori S, Matsueda S, Shichijo S, Yamada A, Noguchi M, Itoh K, Hattori N, Kohno N, Sasada T. Feasibility Study of Personalized Peptide Vaccination for Advanced Small Cell Lung Cancer. Clin Lung Cancer 2017; 18:e385-e394. [PMID: 28416261 DOI: 10.1016/j.cllc.2017.03.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/15/2017] [Accepted: 03/15/2017] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The prognosis of patients with small cell lung cancer (SCLC) remains very poor. Therefore, the development of new therapeutic approaches, including immunotherapies, is desirable. PATIENTS AND METHODS We conducted a phase II study of personalized peptide vaccination (PPV), in which a maximum of 4 human leukocyte antigen-matched peptides were selected from 31 pooled peptides according to the pre-existing peptide-specific IgG responses before vaccination. The PPV was subcutaneously administered. RESULTS Forty-six patients were enrolled (median age, 63 years; 40 patients were men). Grade 1 (n = 13), 2 (n = 10), or 3 (n = 1) skin reactions at the injection sites were observed; however, no other severe adverse events related to the PPV were observed. The median survival time was 466, 397, 401, and 107 days in the subgroups with 0 (n = 5), 1 (n = 15), 2 (n = 12), and ≥ 3 (n = 14) previous chemotherapy regimens, respectively. Peptide-specific IgG responses to the vaccinated peptides were augmented in 70% and 95% of patients after 1 and 2 vaccination cycles, respectively. The overall survival (OS) of patients with augmented IgG responses to a greater number of nonvaccinated peptides after the second cycle of vaccination was significantly longer (median survival time, 1237 days vs. 382 days; P = .010). In addition, augmentation of IgG responses specific to 6 peptides, including Lck-derived peptides, was significantly related to better OS (P < .05, in each peptide). CONCLUSION These results suggest the feasibility of PPV for SCLC patients from the viewpoints of safety, immune boosting, and possible prolongation of OS. Therefore, further evaluation of PPV for advanced SCLC in prospective randomized trials is warranted.
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Affiliation(s)
- Shinjiro Sakamoto
- Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan; Cancer Vaccine Center, Kurume University, Kurume, Japan; Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| | - Teppei Yamada
- Cancer Vaccine Center, Kurume University, Kurume, Japan; Department of Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Yasuhiro Terazaki
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Koichi Yoshiyama
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Shunichi Sugawara
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan
| | - Shinzo Takamori
- Department of Surgery, Kurume University School of Medicine, Kurume, Japan
| | | | | | - Akira Yamada
- Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Masanori Noguchi
- Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Japan
| | - Kyogo Itoh
- Cancer Vaccine Center, Kurume University, Kurume, Japan
| | - Noboru Hattori
- Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | - Tetsuro Sasada
- Cancer Vaccine Center, Kurume University, Kurume, Japan; Kanagawa Cancer Center Research Institute, Yokohama, Japan
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Chen J, Xiao-Zhong G, Qi XS. Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis. J Immunol Res 2017; 2017:8282391. [PMID: 28265583 PMCID: PMC5318641 DOI: 10.1155/2017/8282391] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 12/15/2016] [Indexed: 02/08/2023] Open
Abstract
Specific immunotherapies, including vaccines with autologous tumor cells and tumor antigen-specific monoclonal antibodies, are important treatments for PC patients. To evaluate the clinical outcomes of PC-specific immunotherapy, we performed a systematic review and meta-analysis of the relevant published clinical trials. The effects of specific immunotherapy were compared with those of nonspecific immunotherapy and the meta-analysis was executed with results regarding the overall survival (OS), immune responses data, and serum cancer markers data. The pooled analysis was performed by using the random-effects model. We found that significantly improved OS was noted for PC patients utilizing specific immunotherapy and an improved immune response was also observed. In conclusion, specific immunotherapy was superior in prolonging the survival time and enhancing immunological responses in PC patients.
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Affiliation(s)
- Jiang Chen
- Department of Gastroenterology, Shenyang General Hospital of PLA, No. 83 Wenhua Road Shenyang City, Liaoning 110016, China
| | - Guo Xiao-Zhong
- Department of Gastroenterology, Shenyang General Hospital of PLA, No. 83 Wenhua Road Shenyang City, Liaoning 110016, China
| | - Xing-Shun Qi
- Department of Gastroenterology, Shenyang General Hospital of PLA, No. 83 Wenhua Road Shenyang City, Liaoning 110016, China
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27
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Zhang B, Dong Y, Liu J, Lian Z, Liang L, Chen W, Luo X, Pei S, Mo X, Zhang L, Huang W, Ouyang F, Guo B, Liang C, Zhang S. Immunotherapy for patients with advanced pancreatic carcinoma: a promising treatment. Oncotarget 2017; 8:5703-5716. [PMID: 27992378 PMCID: PMC5351583 DOI: 10.18632/oncotarget.13968] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 12/12/2016] [Indexed: 12/11/2022] Open
Abstract
There are limited data on the safety and efficacy of immunotherapy for patients with advanced pancreatic cancer (APC). A meta-analysis of single-arm trials is proposed to assess the efficacy and safety of immunotherapy for APC. Eighteen relevant studies involving 527 patients were identified. The pooled disease control rate (DCR), overall survival (OS), progression free survival (PFS), and 1-year survival rate were estimated as 59.32%, 7.90 months, 4.25 months, and 30.12%, respectively. Subgroup analysis showed that the pooled OS, PFS, and 1-year survival rate were significantly higher for autologous activated lymphocyte therapy compared with peptide-based vaccine therapy (OS: 8.28 months vs. 7.40 months; PFS: 6.04 months vs. 3.86 months; 1-year survival rate: 37.17% vs. 19.74%). Another subgroup analysis demonstrated that the pooled endpoints were estimated as obviously higher for immunotherapy plus chemotherapy compared with immunotherapy alone (DCR: 62.51% vs. 47.63%; OS: 8.67 months vs. 4.91 months; PFS: 4.91 months vs. 3.34 months; 1-year survival rate: 32.32% vs. 21.43%). Of the included trials, seven trials reported no treatment related adverse events , five trials reported (16.6 ± 3.9) % grade 3 adverse events and no grade 4 adverse events. In conclusion, immunotherapy is safe and effective in the treatment of APC.
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Affiliation(s)
- Bin Zhang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Yuhao Dong
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Jing Liu
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Zhouyang Lian
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Long Liang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Wenbo Chen
- Department of Radiology, Huizhou Municipal Central Hospital, Huizhou, Guangdong, P.R. China
| | - Xiaoning Luo
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Shufang Pei
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Xiaokai Mo
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Lu Zhang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Wenhui Huang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- School of medicine, South China University of Technology, Guangzhou, Guangdong, P.R. China
| | - Fusheng Ouyang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Baoliang Guo
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
- Graduate College, Southern Medical University, Guangzhou, Guangdong, P.R. China
| | - Changhong Liang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
| | - Shuixing Zhang
- Department of Radiology, Guangdong General Hospital/Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P.R. China
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Wada S, Yada E, Ohtake J, Fujimoto Y, Uchiyama H, Yoshida S, Sasada T. Current status and future prospects of peptide-based cancer vaccines. Immunotherapy 2016; 8:1321-1333. [PMID: 27993087 DOI: 10.2217/imt-2016-0063] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Cancer immunotherapy has attracted attention worldwide owing to the recent development of immune checkpoint inhibitors. However, these therapies have shown limited efficacy, and further advancements are needed before these modalities can progress to widespread use. Immune checkpoint inhibitors are a type of nonspecific cancer immunotherapy, and antitumor effects are only observed when cancer-specific T cells are found within the nonspecifically activated T-cell group. In order to facilitate the development of potent immunotherapies, selective enhancement of cancer-specific T cells is essential. In this report, we discuss current and future perspectives, including the latest clinical trials of cancer-specific immunotherapies, particularly cancer peptide vaccines.
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Affiliation(s)
- Satoshi Wada
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
| | - Erika Yada
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
| | - Junya Ohtake
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
| | - Yuki Fujimoto
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
| | - Hidemi Uchiyama
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
| | - Shintaro Yoshida
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
| | - Tetsuro Sasada
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao Asahi-ku, Yokohama, Kanagawa 241-8515, Japan
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Sakamoto S, Yoshitomi M, Yutani S, Terazaki Y, Yoshiyama K, Ioji T, Matsueda S, Yamada A, Takamori S, Itoh K, Hattori N, Kohno N, Sasada T. Evaluation of prognostic significance of granulocyte-related factors in cancer patients undergoing personalized peptide vaccination. Hum Vaccin Immunother 2016; 11:2784-9. [PMID: 26325075 PMCID: PMC5054776 DOI: 10.1080/21645515.2015.1075107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Since cancer vaccines do not always elicit beneficial effects in treated patients, identification of biomarkers for predicting clinical outcomes would be highly desirable. We previously reported that abnormal granulocytes present in peripheral blood mononuclear cells (PBMC) may contribute to poor prognosis in advanced prostate cancer patients receiving personalized peptide vaccination (PPV). In the current study, we examined whether soluble factors derived from granulocytes, such as matrix metalloproteinase 9 (MMP-9), myeloperoxidase (MPO), and arginase 1 (ARG1), and inhibitory cytokine TGFβ in pre-vaccination plasma were useful for predicting prognosis after PPV in advanced cancer patients. In biliary tract cancer (n=25), multivariate Cox regression analysis demonstrated that patients with higher plasma MMP-9 levels had a significantly worse overall survival (OS) [hazard ratio (HR) = 4.637, 95% confidence interval (CI) = 1.670 - 12.877, P = 0.003], whereas MPO, ARG1, or TGFβ levels were not correlated with OS. Similarly, patients with higher MMP-9 levels showed worse prognosis than those with lower MMP-9 levels in other types of advanced cancers, including non-small cell lung cancer (n=32, P = 0.037 by log-rank test), and pancreatic cancer (n=41, P = 0.042 by log-rank test). Taken together, plasma MMP-9 levels before vaccination might be potentially useful as a biomarker for selecting advanced cancer patients who would benefit from PPV.
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Affiliation(s)
- Shinjiro Sakamoto
- a Research Center for Innovative Cancer Therapy; Kurume University ; Kurume , Japan.,b Cancer Vaccine Center; Kurume University ; Kurume , Japan.,c Department of Molecular and Internal Medicine ; Institute of Biomedical & Health Sciences; Hiroshima University ; Hiroshima , Japan
| | - Munehiro Yoshitomi
- d Department of Surgery ; Kurume University School of Medicine ; Kurume , Japan
| | - Shigeru Yutani
- b Cancer Vaccine Center; Kurume University ; Kurume , Japan
| | - Yasuhiro Terazaki
- d Department of Surgery ; Kurume University School of Medicine ; Kurume , Japan
| | - Koichi Yoshiyama
- d Department of Surgery ; Kurume University School of Medicine ; Kurume , Japan
| | - Tetsuya Ioji
- b Cancer Vaccine Center; Kurume University ; Kurume , Japan
| | | | - Akira Yamada
- a Research Center for Innovative Cancer Therapy; Kurume University ; Kurume , Japan
| | - Shinzo Takamori
- d Department of Surgery ; Kurume University School of Medicine ; Kurume , Japan
| | - Kyogo Itoh
- b Cancer Vaccine Center; Kurume University ; Kurume , Japan
| | - Noboru Hattori
- c Department of Molecular and Internal Medicine ; Institute of Biomedical & Health Sciences; Hiroshima University ; Hiroshima , Japan
| | - Nobuoki Kohno
- c Department of Molecular and Internal Medicine ; Institute of Biomedical & Health Sciences; Hiroshima University ; Hiroshima , Japan
| | - Tetsuro Sasada
- b Cancer Vaccine Center; Kurume University ; Kurume , Japan.,e Kanagawa Cancer Center Research Institute ; Yokohama , Japan
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30
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Kotteas E, Saif MW, Syrigos K. Immunotherapy for pancreatic cancer. J Cancer Res Clin Oncol 2016; 142:1795-805. [PMID: 26843405 DOI: 10.1007/s00432-016-2119-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 01/18/2016] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Pancreatic cancer is among the most lethal malignancies resistant to conventional therapies. The vast majority of patients is diagnosed with advanced/metastatic disease and consequently has grim prognosis. Despite the available options with nab-paclitaxel and gemcitabine or 5-fluorouracil/leucovorin/oxaliplatin, chemotherapy offers a modest survival benefit. Targeted therapy in combination with chemotherapy has not shown significant improvement in treatment outcomes. The urgent need for new therapies has turned the spotlights on immunotherapy. Immunotherapy in pancreatic cancer recruits and activates T cells which recognize tumor-specific antigens. RESULTS Preclinical models have demonstrated that chemotherapy or targeted therapy works synergistically with immunotherapy. A growing body of evidence has already been gathered regarding the efficacy of checkpoint inhibitors, vaccines, adoptive T cell therapy, monoclonal antibodies, and cytokines in patients with pancreatic cancer. CONCLUSIONS Many ongoing trials are aiming to identify treatments which could combine efficacy with limited toxicity. In this article, we review the available data concerning multiple aspects of immunotherapy in pancreatic cancer.
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Affiliation(s)
- Elias Kotteas
- Oncology Unit, 3rd Department of Internal Medicine, Sotiria General Hospital, Athens University School of Medicine, 152 Mesogeion Avenue, Athens, Greece.
| | - Muhammad Wasif Saif
- Section of GI and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA
| | - Konstantinos Syrigos
- Oncology Unit, 3rd Department of Internal Medicine, Sotiria General Hospital, Athens University School of Medicine, 152 Mesogeion Avenue, Athens, Greece
- Yale School of Medicine, New Haven, CT, USA
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Uchida D, Shiraha H, Kato H, Sawahara H, Nagahara T, Iwamuro M, Kataoka J, Horiguchi S, Watanabe M, Takaki A, Nouso K, Nasu Y, Kumon H, Yamamoto K. Synergistic anti-pancreatic cancer immunological effects by treatment with reduced expression in immortalized cells/dickkopf-3 protein and peripheral blood mononuclear cells. J Gastroenterol Hepatol 2016; 31:1154-9. [PMID: 26643412 DOI: 10.1111/jgh.13259] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 10/26/2015] [Accepted: 11/16/2015] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Reduced expression in immortalized cells/dickkopf-3 (REIC/DKK3) is a reported tumor suppressor gene and has potential to become an innovative therapy for various cancers. We examined the antitumor immunological effects of human REIC/DKK3 protein against pancreatic cancer. METHODS Activation of extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 by REIC/DKK3 protein was assessed in human peripheral blood mononuclear cells using immunoblotting. Pancreatic cancer cell lines (AsPC-1 and MIA Paca-2) were cocultured with peripheral blood mononuclear cells, and the anticancer effects of REIC/DKK3 protein were assessed using the methyl thiazole tetrazolium, cytotoxicity, and enzyme-linked immunospot assays. The antitumor immunological effects of the combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells were also assessed in a pancreatic cancer model using non-obese diabetic/severe combined immunodeficiency mice. RESULTS The REIC/DKK3 protein activated extracellular signal-regulated kinases 1 and 2, mammalian target of rapamycin, and signal transducer and activator of transcription 3 in peripheral blood mononuclear cells. REIC/DKK3 protein inhibited in vitro cancer cell viability and enhanced cytotoxicity when incubated with peripheral blood mononuclear cells. REIC/DKK3 protein induced significant production of interferon gamma from lymphocytes incubated with pancreatic cancer cells, indicating that CD8+ T cells were activated in the peripheral blood mononuclear cells when cocultured with AsPC-1 and MIA Paca-2 in the presence of REIC/DKK3 protein. Combined treatment with REIC/DKK3 protein and peripheral blood mononuclear cells produced in vivo anticancer immunostimulatory effects on pancreatic cancer cells. CONCLUSIONS The REIC/DKK3 protein and peripheral blood mononuclear cells synergistically enhanced anticancer immunological effects against pancreatic cancer cells. The observed immunomodulatory effect of combined treatment likely occurs in adenovirus-mediated REIC/DKK3 gene therapy and provides important clues to the therapeutic mechanisms involving immune cells.
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Affiliation(s)
- Daisuke Uchida
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hidenori Shiraha
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hironari Kato
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroaki Sawahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Teruya Nagahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Junro Kataoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shigeru Horiguchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masami Watanabe
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Innovation Center Okayama for Nanobio-targeted Therapy, Okayama University, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiro Nouso
- Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yasutomo Nasu
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiromi Kumon
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Innovation Center Okayama for Nanobio-targeted Therapy, Okayama University, Okayama, Japan
| | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Sakamoto S, Noguchi M, Yamada A, Itoh K, Sasada T. Prospect and progress of personalized peptide vaccinations for advanced cancers. Expert Opin Biol Ther 2016; 16:689-98. [PMID: 26938083 DOI: 10.1517/14712598.2016.1161752] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The field of cancer immunotherapy has made dramatic progress in the past 20 years, in part due to the identification of numerous tumor-associated antigens (TAAs). We have developed a novel immunotherapeutic approach called the personalized peptide vaccine (PPV), in which a maximum of four human leukocyte antigen (HLA)-matched vaccine peptides are selected based on the pre-existing host immunity before vaccination. AREAS COVERED This review describes recent progress in the use of PPV for various types of advanced cancer. EXPERT OPINION Although various approaches for therapeutic cancer immunotherapies, including peptide-based vaccines, have been developed and clinically examined, the diverse and heterogeneous characteristics of tumor cells and host immunity seem to limit their therapeutic efficacy. Selection of suitable peptide vaccines for individual patients based on the pre-existing host immunity before vaccination could resolve this limitation and could be a rational approach for developing effective cancer vaccines.
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Affiliation(s)
- Shinjiro Sakamoto
- a Research Center for Innovative Cancer Therapy , Kurume University , Kurume , Japan.,b Cancer Vaccine Center , Kurume University , Kurume , Japan.,c Department of Molecular and Internal Medicine School of Medicine, Graduate School of Biomedical and Health Sciences , Hiroshima University , Hiroshima , Japan
| | - Masanori Noguchi
- a Research Center for Innovative Cancer Therapy , Kurume University , Kurume , Japan
| | - Akira Yamada
- a Research Center for Innovative Cancer Therapy , Kurume University , Kurume , Japan
| | - Kyogo Itoh
- b Cancer Vaccine Center , Kurume University , Kurume , Japan
| | - Tetsuro Sasada
- b Cancer Vaccine Center , Kurume University , Kurume , Japan.,d Kanagawa Cancer Center Research Institute , Yokohama , Japan
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Miyauchi K, Tsuchikawa T, Wada M, Abiko T, Kyogoku N, Shichinohe T, Miyahara Y, Kageyama S, Ikeda H, Shiku H, Hirano S. Clinical relevance of antigen spreading pattern induced by CHP-MAGE-A4 cancer vaccination. Immunotherapy 2016; 8:527-40. [PMID: 26888315 DOI: 10.2217/imt-2016-0007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
AIM To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as a surrogate marker of patient survival. MATERIALS & METHODS 12 patients who had been injected with 300 μg of CHP-MAGE-A4 and 0.5 Klinische Einheit of OK-432 in more than five vaccinations were analyzed. RESULTS Increases in the anti-MAGE-A4-specific antibody response were observed in eight patients (66.7%), compared with six patients (50%) for anti-NY-ESO-1 and five patients (41.7%) for anti-MAGE-A3 after five vaccinations. We identified frequent antigen spreading following MAGE-A4 vaccinations without associations with the clinical response or patient prognosis. CONCLUSION Antigen spreading pattern might reflect tumor shrinkage as a response to treatment and treatment history (clinical trial registration number: UMIN000001999).
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Affiliation(s)
- Kengo Miyauchi
- Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Masataka Wada
- Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Takehiro Abiko
- Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Noriaki Kyogoku
- Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Toshiaki Shichinohe
- Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Yoshihiro Miyahara
- Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shinichi Kageyama
- Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hiroaki Ikeda
- Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hiroshi Shiku
- Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
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Jimenez-Luna C, Prados J, Ortiz R, Melguizo C, Torres C, Caba O. Current Status of Immunotherapy Treatments for Pancreatic Cancer. J Clin Gastroenterol 2016; 50:836-848. [PMID: 27505403 DOI: 10.1097/mcg.0000000000000623] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer (PC) is a lethal disease representing the seventh most frequent cause of death from cancer worldwide. Resistance of pancreatic tumors to current treatments leads to disappointing survival rates, and more specific and effective therapies are urgently needed. In recent years, immunotherapy has been proposed as a promising approach to the treatment of PC, and encouraging results have been published by various preclinical and clinical studies. This review provides an overview of the latest developments in the immunotherapeutic treatment of PC and summarizes the most recent and important clinical trials.
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Affiliation(s)
- Cristina Jimenez-Luna
- *Institute of Biopathology and Regenerative Medicine (IBIMER) ‡Department of Biochemistry and Molecular Biology I, Universidad de Granada, Granada †Department of Health Sciences, Universidad de Jaen, Jaen, Spain
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Paniccia A, Merkow J, Edil BH, Zhu Y. Immunotherapy for pancreatic ductal adenocarcinoma: an overview of clinical trials. Chin J Cancer Res 2015; 27:376-91. [PMID: 26361407 DOI: 10.3978/j.issn.1000-9604.2015.05.01] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 04/08/2015] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and current therapeutic strategies are often unsatisfactory. Identification and development of more efficacious therapies is urgently needed. Immunotherapy offered encouraging results in preclinical models during the last decades, and several clinical trials have explored its therapeutic application in PDAC. The aim of this review is to summarize the results of clinical trials conducted to evaluate the future perspective of immunotherapy in the treatment of PDAC.
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Affiliation(s)
- Alessandro Paniccia
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Justin Merkow
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Barish H Edil
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Yuwen Zhu
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Cid-Arregui A, Juarez V. Perspectives in the treatment of pancreatic adenocarcinoma. World J Gastroenterol 2015; 21:9297-9316. [PMID: 26309356 PMCID: PMC4541382 DOI: 10.3748/wjg.v21.i31.9297] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/12/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and, in most cases, PDAC is diagnosed at advanced disease stages, when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize, which involve essential adaptive changes in cellular metabolism, signaling, adhesion and immunoediting. In addition, PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades, gemcitabine has been the reference for the systemic treatment of PDAC. However, recently, a regimen combining fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC, with survival outcomes of 11.3 and 8.5 mo on phase III trials, respectively, over single-agent gemcitabine. With the pending issue of their higher toxicities, these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition, the efficacy of oral fluoropyrimidine (S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past, with only one drug (erlotinib) approved to date. Besides, a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise, immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.
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Mohammed A, Janakiram NB, Pant S, Rao CV. Molecular Targeted Intervention for Pancreatic Cancer. Cancers (Basel) 2015; 7:1499-542. [PMID: 26266422 PMCID: PMC4586783 DOI: 10.3390/cancers7030850] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies.
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Affiliation(s)
- Altaf Mohammed
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Shubham Pant
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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Pol J, Bloy N, Buqué A, Eggermont A, Cremer I, Sautès-Fridman C, Galon J, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Peptide-based anticancer vaccines. Oncoimmunology 2015; 4:e974411. [PMID: 26137405 PMCID: PMC4485775 DOI: 10.4161/2162402x.2014.974411] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 10/06/2014] [Indexed: 02/07/2023] Open
Abstract
Malignant cells express antigens that can be harnessed to elicit anticancer immune responses. One approach to achieve such goal consists in the administration of tumor-associated antigens (TAAs) or peptides thereof as recombinant proteins in the presence of adequate adjuvants. Throughout the past decade, peptide vaccines have been shown to mediate antineoplastic effects in various murine tumor models, especially when administered in the context of potent immunostimulatory regimens. In spite of multiple limitations, first of all the fact that anticancer vaccines are often employed as therapeutic (rather than prophylactic) agents, this immunotherapeutic paradigm has been intensively investigated in clinical scenarios, with promising results. Currently, both experimentalists and clinicians are focusing their efforts on the identification of so-called tumor rejection antigens, i.e., TAAs that can elicit an immune response leading to disease eradication, as well as to combinatorial immunostimulatory interventions with superior adjuvant activity in patients. Here, we summarize the latest advances in the development of peptide vaccines for cancer therapy.
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Key Words
- APC, antigen-presenting cell
- CMP, carbohydrate-mimetic peptide
- EGFR, epidermal growth factor receptor
- FDA, Food and Drug Administration
- GM-CSF, granulocyte macrophage colony stimulating factor
- HPV, human papillomavirus
- IDH1, isocitrate dehydrogenase 1 (NADP+), soluble
- IDO1, indoleamine 2, 3-dioxygenase 1
- IFNα, interferon α
- IL-2, interleukin-2
- MUC1, mucin 1
- NSCLC, non-small cell lung carcinoma
- PADRE, pan-DR binding peptide epitope
- PPV, personalized peptide vaccination
- SLP, synthetic long peptide
- TAA, tumor-associated antigen
- TERT, telomerase reverse transcriptase
- TLR, Toll-like receptor
- TRA, tumor rejection antigen
- WT1
- carbohydrate-mimetic peptides
- immune checkpoint blockers
- immunostimulatory cytokines
- survivin
- synthetic long peptides
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Affiliation(s)
- Jonathan Pol
- Gustave Roussy Cancer Campus; Villejuif, France
- INSERM, U1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers; Paris, France
| | - Norma Bloy
- Gustave Roussy Cancer Campus; Villejuif, France
- INSERM, U1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers; Paris, France
- Université Paris-Sud/Paris XI
| | - Aitziber Buqué
- Gustave Roussy Cancer Campus; Villejuif, France
- INSERM, U1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers; Paris, France
| | | | - Isabelle Cremer
- INSERM, U1138; Paris, France
- Equipe 13; Center de Recherche des Cordeliers; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
| | - Catherine Sautès-Fridman
- INSERM, U1138; Paris, France
- Equipe 13; Center de Recherche des Cordeliers; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
| | - Jérôme Galon
- INSERM, U1138; Paris, France
- Université Pierre et Marie Curie/Paris VI; Paris, France
- Laboratory of Integrative Cancer Immunology, Center de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
| | - Eric Tartour
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- INSERM; U970; Paris, France
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus; Villejuif, France
- INSERM; U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- INSERM, U1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France
- Metabolomics and Cell Biology Platforms; Gustave Roussy Cancer Campus; Villejuif, France
| | - Lorenzo Galluzzi
- Gustave Roussy Cancer Campus; Villejuif, France
- INSERM, U1138; Paris, France
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Center de Recherche des Cordeliers; Paris, France
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
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Huang H, Cao K, Malik S, Zhang Q, Li D, Chang R, Wang H, Lin W, Van Doren J, Zhang K, Du Z, Zheng X. Combination of 12-O-tetradecanoylphorbol-13-acetate with diethyldithiocarbamate markedly inhibits pancreatic cancer cell growth in 3D culture and in immunodeficient mice. Int J Mol Med 2015; 35:1617-24. [PMID: 25847449 PMCID: PMC4432920 DOI: 10.3892/ijmm.2015.2163] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 03/03/2015] [Indexed: 11/08/2022] Open
Abstract
The aim of the present study was to determine the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and diethyldithiocarbamate (DDTC) alone or in combination on human pancreatic cancer cells cultured in vitro and grown as xenograft tumors in nude mice. Pancreatic cancer cells were treated with either DDTC or TPA alone, or in combination and the number of viable cells was then determined by trypan blue ecxlusion assay and the number of apoptotic cells was determined by morphological assessment by staining the cells with propidium idiode and examining them under a fluorescence microscope. Treatment with DDTC or TPA alone inhibited the growth and promoted the apoptosis of pancreatic cancer cells in a concentration-dependent manner. These effects were more prominent following treatment with TPA in combination with DDTC than following treatment with either agent alone in PANC-1 cells in monolayer cultures and in 3 dimensional (3D) cultures. The potent effects of the combination treatment on PANC-1 cells were associated with the inhibition of nuclear factor-κB (NF-κB) activation and the decreased expression of Bcl-2 induced by DDTC, as shown by NF-κB-dependent reporter gene expression assay and western blot analysis. Furthermore, treatment of nude mice with DDTC + TPA strongly inhibited the growth of PANC-1 xenograft tumors. The results of the present study indicate that the administration of TPA and DDTC in combination may be an effective strategy for inhibiting the growth of pancreatic cancer.
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Affiliation(s)
- Huarong Huang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
| | - Kajia Cao
- Department of Nasopharyngeal Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Saquib Malik
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Qiuyan Zhang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
| | - Dongli Li
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
| | - Richard Chang
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Huaqian Wang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
| | - Weiping Lin
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
| | - Jeremiah Van Doren
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Kun Zhang
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
| | - Zhiyun Du
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
| | - Xi Zheng
- Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, Guangdong 510006, P.R. China
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Trials of vaccines for pancreatic ductal adenocarcinoma: Is there any hope of an improved prognosis? Surg Today 2015; 46:139-48. [PMID: 25649538 DOI: 10.1007/s00595-015-1120-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 01/06/2015] [Indexed: 02/06/2023]
Abstract
Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.
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Waki K, Yamada T, Yoshiyama K, Terazaki Y, Sakamoto S, Matsueda S, Komatsu N, Sugawara S, Takamori S, Itoh K, Yamada A. PD-1 expression on peripheral blood T-cell subsets correlates with prognosis in non-small cell lung cancer. Cancer Sci 2014; 105:1229-35. [PMID: 25117757 PMCID: PMC4462362 DOI: 10.1111/cas.12502] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 08/04/2014] [Accepted: 08/05/2014] [Indexed: 01/08/2023] Open
Abstract
PD-1 expression in peripheral blood T-cells has been reported in several kinds of cancers, including lung cancer. However, the relationship between PD-1 expression in peripheral blood T-cells and prognosis after treatment with a cancer vaccine has not been reported. To elucidate this relationship, we analyzed PD-1 expression in the peripheral blood T-cells of patients with non-small cell lung cancer. The blood samples used in this study were obtained from patients enrolled in phase II clinical trials of a personalized peptide vaccine. Seventy-eight samples obtained before and after a single vaccination cycle (consisting of six or eight doses) were subjected to the analysis. PD-1 was expressed on lymphocytes in the majority of samples. The relative contents of PD1(+) CD4(+) T-cells against total lymphocytes before and after the vaccination cycle correlated with overall survival (OS) with a high degree of statistical significance (P < 0.0001 and P = 0.0014). A decrease in PD-1(+) CD8(+) T-cells after one cycle of vaccination also correlated with longer OS (P = 0.032). The IgG response to the non-vaccinated peptides suggested that the epitope spreading seemed to occur more frequently in high-PD-1(+) CD4(+) T-cell groups. Enrichment of CD45RA(-) CCR7(-) effector-memory phenotype cells in PD-1(+) T-cells in PBMCs was also shown. These results suggest that PD-1 expression on the peripheral blood T-cell subsets can become a new prognostic marker in non-small cell lung cancer patients treated with personalized peptide vaccination.
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Affiliation(s)
- Kayoko Waki
- Cancer Vaccine Development Division, Kurume University Research Center for Innovative Cancer Therapy, Kurume, Japan
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Tanase CP, Neagu AI, Necula LG, Mambet C, Enciu AM, Calenic B, Cruceru ML, Albulescu R. Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics. World J Gastroenterol 2014; 20:10790-10801. [PMID: 25152582 PMCID: PMC4138459 DOI: 10.3748/wjg.v20.i31.10790] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/07/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.
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Francis T, Graf A, Hodges K, Kennedy L, Hargrove L, Price M, Kearney K, Francis H. Histamine regulation of pancreatitis and pancreatic cancer: a review of recent findings. Hepatobiliary Surg Nutr 2014; 2:216-26. [PMID: 24570946 DOI: 10.3978/j.issn.2304-3881.2013.08.06] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 07/25/2013] [Indexed: 12/11/2022]
Abstract
The pancreas is a dynamic organ that performs a multitude of functions within the body. Diseases that target the pancreas, like pancreatitis and pancreatic cancer, are devastating and often fatal to the suffering patient. Histamine and histamine receptors (H1-H4HRs) have been found to play a critical role in biliary diseases. Accordingly, the biliary tract and the pancreas share similarities with regards to morphological, phenotypical and functional features and disease progression, studies related the role of H1-H4HRs in pancreatic diseases are important. In this review, we have highlighted the role that histamine, histidine decarboxylase (HDC), histamine receptors and mast cells (the main source of histamine in the body) play during both pancreatitis and pancreatic cancer. The objective of the review is to demonstrate that histamine and histamine signaling may be a potential therapeutic avenue towards treatment strategies for pancreatic diseases.
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Affiliation(s)
- Taylor Francis
- Medicine, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
| | - Allyson Graf
- Research, Central Texas Veteran's Health Care System, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA ; Scott & White Digestive Disease Research Center, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
| | - Kyle Hodges
- Scott & White Digestive Disease Research Center, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
| | - Lindsey Kennedy
- Scott & White Digestive Disease Research Center, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
| | - Laura Hargrove
- Scott & White Digestive Disease Research Center, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
| | - Mattie Price
- Scott & White Digestive Disease Research Center, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
| | - Kate Kearney
- Scott & White Digestive Disease Research Center, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
| | - Heather Francis
- Medicine, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA ; Research, Central Texas Veteran's Health Care System, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA ; Scott & White Digestive Disease Research Center, Scott and White Healthcare, Texas A&M HSC, Temple, TX, USA
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