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McMillan MT, Soares KC. Advances in Vaccine-Based Therapies for Pancreatic Cancer. J Gastrointest Cancer 2025; 56:62. [PMID: 39939414 PMCID: PMC11821674 DOI: 10.1007/s12029-025-01165-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2025] [Indexed: 02/14/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a 5-year survival rate that has improved only marginally over the past 30 years, despite numerous clinical trials. PDAC poses several unique challenges, including early metastatic spread and a predilection for liver metastasis. It is also highly resistant to anti-tumor immunity and immunotherapy due to its dense and immunosuppressive tumor microenvironment, low immunogenicity, and systemic immune suppression. PDAC has a low mutational burden, defective antigen presentation, and immune checkpoint molecule upregulation, which reduce immune recognition. Together, these factors leave PDAC as an "immune cold" tumor with minimal cytotoxic T-cell activity. Novel therapeutic approaches are urgently needed to reinvigorate anti-tumor immunity. Recent advances, such as adjuvant personalized mRNA neoantigen vaccines and mutant-KRAS targeted vaccines, have demonstrated sustained vaccine-induced T cell responses that are associated with improved recurrence-free survival in surgically resected PDAC. Combining different vaccine approaches with optimal sequencing of chemotherapy, surgery, radiotherapy, and other immunotherapies may further enhance outcomes. PDAC vaccines represent a promising strategy for overcoming PDAC's resistance to conventional therapies, with ongoing trials exploring their potential to improve long-term survival.
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Affiliation(s)
- Matthew T McMillan
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical School, 1275 York Ave, C887, New York, NY, 10065, USA
| | - Kevin C Soares
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical School, 1275 York Ave, C887, New York, NY, 10065, USA.
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2
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Morimoto S, Tanaka Y, Nakata J, Fujiki F, Hasegawa K, Nakajima H, Nishida S, Tsuboi A, Hosen N, Kagawa N, Maruno M, Myoui A, Enomoto T, Izumoto S, Sekimoto M, Hashimoto N, Yoshimine T, Kumanogoh A, Oji Y, Oka Y, Sugiyama H. Spontaneous high clonal expansion of Wilms' tumor gene 1-specific cytotoxic T-lymphocytes in patients with Wilms' tumor gene 1-expressing solid tumor. Cancer Immunol Immunother 2024; 74:15. [PMID: 39509060 PMCID: PMC11543974 DOI: 10.1007/s00262-024-03862-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 10/09/2024] [Indexed: 11/15/2024]
Abstract
Wilms' tumor protein 1 (WT1)-targeted immunotherapy has been used in patients with leukemia and solid tumors. However, the spontaneous WT1-specific immune response before WT1 peptide vaccination in patients with WT1-expressing tumors (PTs) remains unclear. Therefore, we investigated whether WT1-specific cytotoxic CD8+ T-lymphocytes (CTLs) are clonally expanded in the peripheral blood outside of tumor sites. Clonal expansion of WT1126 peptide (a.a.126-134)-specific CTLs (WT1126-CTLs) was compared between seven PTs and five healthy volunteers (HVs), and their T-cell receptors (TCRs) were analyzed at the single-cell level. Overall, 433 and 351 TCR β-chains of WT1126-CTLs were detected from PTs and HVs, respectively, and complementarity-determining region 3 was sequenced for clonality analysis. The frequencies of WT1126-CTLs were higher in human leukocyte antigen (HLA)-A*02:01+ PTs than in HLA-A*02:01+ HVs, although the difference was not statistically significant. WT1126-CTLs of differentiated types, including memory and effector, were higher in PTs than in HVs; whereas, those of the naïve type were higher in HVs than in PTs. WT1126-CTL clonality was significantly higher in PTs than in HVs. Furthermore, the frequency of effector WT1126-CTLs positively correlated with WT1126-CTL clonality in PTs; whereas, the frequency of naïve phenotype WT1126-CTLs tended to be negatively correlated with clonality. In conclusion, these results suggest that the WT1 protein in tumor cells is highly immunogenic, thereby stimulating endogenous naïve-type WT1126-CTLs and enabling them to clonally expand and differentiate into effector-type WT1126-CTLs.
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Affiliation(s)
- Soyoko Morimoto
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan.
| | - Yukie Tanaka
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Molecular Microbiology and Immunology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
| | - Jun Nakata
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fumihiro Fujiki
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kana Hasegawa
- Laboratory of Cellular Immunotherapy, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, Japan
- Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Hiroko Nakajima
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sumiyuki Nishida
- Strategic Global Partnership & X (Cross)-Innovation Initiative Graduate School of Medicine, Osaka University and Osaka University Hospital, Osaka, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Center for Advanced Modalities and Drug Delivery System, Osaka University, Osaka, Japan
| | - Akihiro Tsuboi
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoki Hosen
- Laboratory of Cellular Immunotherapy, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, Japan
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan
| | - Naoki Kagawa
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Motohiko Maruno
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Neurosurgery, Yukioka Hospital, Osaka, Japan
| | - Akira Myoui
- Medical Center for Translational Research, Department of Medical Innovation, Osaka University Hospital, Osaka, Japan
| | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
- Center for Genetic Medicine, Itami City Hospital, Hyogo, Japan
| | - Shuichi Izumoto
- Department of Neurosurgery, Hyogo College of Medicine, Hyogo, Japan
- Department of Neurosurgery, Kindai University Nara Hospital, Nara, Japan
| | - Mitsugu Sekimoto
- Department of Gastroenterological Surgery Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Surgery, Minoh City Hospital, Osaka, Japan
| | - Naoya Hashimoto
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Neurosurgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiki Yoshimine
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
- Endowed Research Department of Clinical Neuroengineering, Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
- Iseikai Medical Corporation, Osaka, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yusuke Oji
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshihiro Oka
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
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3
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Netto D, Frizziero M, Foy V, McNamara MG, Backen A, Hubner RA. Systemic Therapy for Metastatic Pancreatic Cancer-Current Landscape and Future Directions. Curr Oncol 2024; 31:5206-5223. [PMID: 39330013 PMCID: PMC11430697 DOI: 10.3390/curroncol31090385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/22/2024] [Accepted: 08/25/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence. A paucity of strong predictive risk factors mean screening programmes are difficult to implement. Historically, a lack of identifiable and actionable driver mutations, coupled with a relatively immunosuppressed tumour microenvironment, has led to a reliance on cytotoxic chemotherapy. The NAPOLI-3 trial has reported data supporting consideration of NALIRIFOX as a new first-line standard of care. Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.
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Affiliation(s)
- Daniel Netto
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Melissa Frizziero
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Victoria Foy
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Mairéad G. McNamara
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Alison Backen
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Richard A. Hubner
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
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Gugulothu KN, Anvesh Sai P, Suraparaju S, Karuturi SP, Pendli G, Kamma RB, Nimmagadda K, Modepalli A, Mamilla M, Vashist S. WT1 Cancer Vaccine in Advanced Pancreatic Cancer: A Systematic Review. Cureus 2024; 16:e56934. [PMID: 38665761 PMCID: PMC11043900 DOI: 10.7759/cureus.56934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Advanced pancreatic cancer is one of the prominent contributors to cancer-related mortality globally. Chemotherapy, especially gemcitabine, is generally used for the treatment of advanced pancreatic cancer. Despite the treatment, the fatality rate for advanced pancreatic cancer is alarmingly high. Thus, the dire need for better treatment alternatives has drawn focus to cancer vaccinations. The Wilms tumor gene (WT1), typically associated with Wilms tumor, is found to be excessively expressed in some cancers, such as pancreatic cancer. This characteristic feature is harvested to develop cancer vaccines against WT1. This review aims to systematically summarize the clinical trials investigating the efficacy and safety of WT1 vaccines in patients with advanced pancreatic cancer. An extensive literature search was conducted on databases Medline, Web of Science, ScienceDirect, and Google Scholar using the keywords "Advanced pancreatic cancer," "Cancer vaccines," "WT1 vaccines," and "Pulsed DC vaccines," and the results were exclusively studied to construct this review. WT1 vaccines work by introducing peptides from the WT1 protein to trigger an immune response involving cytotoxic T lymphocytes via antigen-presenting cells. Upon activation, these lymphocytes induce apoptosis in cancer cells by specifically targeting those with increased WT1 levels. WT1 vaccinations, which are usually given in addition to chemotherapy, have demonstrated clinically positive results and minimal side effects. However, there are several challenges to their widespread use, such as the immunosuppressive nature of tumors and heterogeneity in expression. Despite these limitations, the risk-benefit profile of cancer vaccines is encouraging, especially for the WT1 vaccine in the treatment of advanced pancreatic cancer. Considering the fledgling status of their development, large multicentric, variables-matched, extensive analysis across diverse demographics is considered essential.
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Affiliation(s)
| | | | - Sonika Suraparaju
- Internal Medicine, Sri Padmavathi Medical College for Women, Tirupati, IND
| | | | - Ganesh Pendli
- Internal Medicine, PES Institute of Medical Sciences and Research, Kuppam, IND
| | - Ravi Babu Kamma
- Internal Medicine, Sri Venkata Sai (SVS) Medical College, Mahabubnagar, IND
| | | | - Alekhya Modepalli
- Internal Medicine, Sri Padmavathi Medical College for Women, Tirupati, IND
| | - Mahesh Mamilla
- Internal Medicine, Sri Venkateswara Medical College, Tirupati, IND
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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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6
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Jiang C, Li J, Zhang W, Zhuang Z, Liu G, Hong W, Li B, Zhang X, Chao CC. Potential association factors for developing effective peptide-based cancer vaccines. Front Immunol 2022; 13:931612. [PMID: 35967400 PMCID: PMC9364268 DOI: 10.3389/fimmu.2022.931612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/29/2022] [Indexed: 11/26/2022] Open
Abstract
Peptide-based cancer vaccines have been shown to boost immune systems to kill tumor cells in cancer patients. However, designing an effective T cell epitope peptide-based cancer vaccine still remains a challenge and is a major hurdle for the application of cancer vaccines. In this study, we constructed for the first time a library of peptide-based cancer vaccines and their clinical attributes, named CancerVaccine (https://peptidecancervaccine.weebly.com/). To investigate the association factors that influence the effectiveness of cancer vaccines, these peptide-based cancer vaccines were classified into high (HCR) and low (LCR) clinical responses based on their clinical efficacy. Our study highlights that modified peptides derived from artificially modified proteins are suitable as cancer vaccines, especially for melanoma. It may be possible to advance cancer vaccines by screening for HLA class II affinity peptides may be an effective therapeutic strategy. In addition, the treatment regimen has the potential to influence the clinical response of a cancer vaccine, and Montanide ISA-51 might be an effective adjuvant. Finally, we constructed a high sensitivity and specificity machine learning model to assist in designing peptide-based cancer vaccines capable of providing high clinical responses. Together, our findings illustrate that a high clinical response following peptide-based cancer vaccination is correlated with the right type of peptide, the appropriate adjuvant, and a matched HLA allele, as well as an appropriate treatment regimen. This study would allow for enhanced development of cancer vaccines.
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Affiliation(s)
- Chongming Jiang
- Department of Medicine, Baylor College of Medicine, Houston TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
- *Correspondence: Chongming Jiang, ; Cheng-Chi Chao,
| | - Jianrong Li
- Department of Medicine, Baylor College of Medicine, Houston TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
| | - Wei Zhang
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | | | - Geng Liu
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | - Wei Hong
- Department of Medicine, Baylor College of Medicine, Houston TX, United States
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
- Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, United States
| | - Bo Li
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | - Xiuqing Zhang
- Institute of Super Cell, BGI-Shenzhen, Shenzhen, China
| | - Cheng-Chi Chao
- Department of Pipeline Development, Biomap, Inc, San Francisco, CA, United States
- *Correspondence: Chongming Jiang, ; Cheng-Chi Chao,
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Emerging concepts in designing next-generation multifunctional nanomedicine for cancer treatment. Biosci Rep 2022; 42:231373. [PMID: 35638450 PMCID: PMC9272595 DOI: 10.1042/bsr20212051] [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: 01/24/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 11/17/2022] Open
Abstract
Nanotherapy has emerged as an improved anticancer therapeutic strategy to circumvent the harmful side effects of chemotherapy. It has been proven to be beneficial to offer multiple advantages, including their capacity to carry different therapeutic agents, longer circulation time and increased therapeutic index with reduced toxicity. Over time, nanotherapy evolved in terms of their designing strategies like geometry, size, composition or chemistry to circumvent the biological barriers. Multifunctional nanoscale materials are widely used as molecular transporter for delivering therapeutics and imaging agents. Nanomedicine involving multi-component chemotherapeutic drug-based combination therapy has been found to be an improved promising approach to increase the efficacy of cancer treatment. Next-generation nanomedicine has also utilized and combined immunotherapy to increase its therapeutic efficacy. It helps in targeting tumor immune response sparing the healthy systemic immune function. In this review, we have summarized the progress of nanotechnology in terms of nanoparticle designing and targeting cancer. We have also discussed its further applications in combination therapy and cancer immunotherapy. Integrating patient-specific proteomics and biomarker based information and harnessing clinically safe nanotechnology, the development of precision nanomedicine could revolutionize the effective cancer therapy.
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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: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 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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9
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Development of Peptide-Based Vaccines for Cancer. JOURNAL OF ONCOLOGY 2022; 2022:9749363. [PMID: 35342400 PMCID: PMC8941562 DOI: 10.1155/2022/9749363] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 02/23/2022] [Indexed: 12/14/2022]
Abstract
Peptides cancer vaccines are designed based on the epitope peptides that can elicit humoral and cellular immune responses targeting tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs). In order to develop a clinically safe and more effective vaccine for the future, several issues need to be addressed, and these include the selection of optimal antigen targets, adjuvants, and immunization regimens. Another emerging approach involves the use of personalized peptide-based vaccines based on neoantigens to enhance antitumor response. Rationally designed combinatorial therapy is currently being investigated with chemotherapeutic drugs or immune checkpoint inhibitor therapies to improve the efficacy. This review discusses an overview of the development of peptide-based vaccines, the role of adjuvants, and the delivery systems for peptide vaccines as well as combinatorial therapy as potential anticancer strategies.
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Nishida S, Morimoto S, Oji Y, Morita S, Shirakata T, Enomoto T, Tsuboi A, Ueda Y, Yoshino K, Shouq A, Kanegae M, Ohno S, Fujiki F, Nakajima H, Nakae Y, Nakata J, Hosen N, Kumanogoh A, Oka Y, Kimura T, Sugiyama H. Cellular and Humoral Immune Responses Induced by an HLA Class I-restricted Peptide Cancer Vaccine Targeting WT1 Are Associated With Favorable Clinical Outcomes in Advanced Ovarian Cancer. J Immunother 2022; 45:56-66. [PMID: 34874330 PMCID: PMC8654282 DOI: 10.1097/cji.0000000000000405] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 10/22/2021] [Indexed: 11/25/2022]
Abstract
The HLA-A*24:02-restricted peptide vaccine targeting Wilms' tumor 1 (WT1) (WT1 vaccine) is a promising therapeutic strategy for ovarian cancer; however, its efficacy varies among patients. In this study, we analyzed WT1-specific immune responses in patients with advanced or recurrent ovarian cancer that was refractory to standard chemotherapies and their associations with clinical outcomes. In 25 patients, the WT1 vaccine was administered subcutaneously weekly for 3 months and biweekly thereafter until disease progression or severe adverse events. We assessed Wilms' tumor 1-specific cytotoxic T lymphocytes (WT1-CTLs) and Wilms' tumor 1 peptide-specific immunoglobulin G (WT1235-IgG). After vaccination, the percentage of tetramer high-avidity population of WT1-CTLs among CD8+ T lymphocytes (%tet-hi WT1-CTL) and the WT1235-IgG titer increased significantly, although the values were extremely low or below the limit of detection before vaccination (%tet-hi WT1-CTL: 0.003%-0.103%.; WT1235-IgG: <0.05-0.077 U/mL). Patients who had %tet-hi WT1-CTL of ≥0.25% (n=6) or WT1235-IgG of ≥0.10 U/mL (n=12) had a significantly longer progression-free survival than those of patients in the other groups. In addition, an increase in WT1235-IgG corresponded to a significantly longer progression-free survival (P=0.0496). In patients with systemic inflammation, as evidenced by elevated C-reactive protein levels, the induction of tet-hi WT1-CTL or WT1235-IgG was insufficient. Decreased serum albumin levels, multiple tumor lesions, poor performance status, and excess ascites negatively influenced the clinical effectiveness of the WT1 vaccine. In conclusion, the WT1 vaccine induced antigen-specific cellular and humoral immunity in patients with refractory ovarian cancer. Both %tet-hi WT1-CTL and WT1235-IgG levels are prognostic markers for the WT1 vaccine.
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Affiliation(s)
| | | | | | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto
| | | | - Takayuki Enomoto
- Obstetrics and Gynecology, Osaka University Graduates School of Medicine
- Department of Obstetrics and Gynecology, Niigata University Medical School, Niigata
| | | | - Yutaka Ueda
- Obstetrics and Gynecology, Osaka University Graduates School of Medicine
| | - Kiyoshi Yoshino
- Obstetrics and Gynecology, Osaka University Graduates School of Medicine
- Department of Obstetrics and Gynecology, University of Occupational and Environmental Health, Kita-Kyushu, Fukuoka Prefecture
| | | | | | - Satoshi Ohno
- Cancer Immunotherapy
- Clinical Research Support Center, Shimane University Faculty of Medicine, Izumo, Shimane Prefecture, Japan
| | | | | | - Yoshiki Nakae
- Departments of Respiratory Medicine and Clinical Immunology
| | | | | | - Atsushi Kumanogoh
- Departments of Respiratory Medicine and Clinical Immunology
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka Prefecture
| | - Yoshihiro Oka
- Cancer Stem Cell Biology
- Department of Immunopathology, Immunology Frontier Research Center, Osaka University
| | - Tadashi Kimura
- Obstetrics and Gynecology, Osaka University Graduates School of Medicine
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11
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Ota S, Miyashita M, Yamagishi Y, Ogasawara M. Baseline immunity predicts prognosis of pancreatic cancer patients treated with WT1 and/or MUC1 peptide-loaded dendritic cell vaccination and a standard chemotherapy. Hum Vaccin Immunother 2021; 17:5563-5572. [PMID: 34919493 PMCID: PMC8903979 DOI: 10.1080/21645515.2021.2003645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/15/2021] [Accepted: 11/04/2021] [Indexed: 12/15/2022] Open
Abstract
The prognosis of patients with advanced pancreatic cancer is poor despite the recent introduction of immune checkpoint inhibitors. Therefore, the development of new therapeutic approaches is urgently required. In the present phase I/II study, we have evaluated the safety, the efficacy and the prognostic factors of Wilms' tumor 1 (WT1) and/or mucin 1 (MUC1) peptide-loaded dendritic cell (DC) vaccination in combination with a chemotherapy employing gemcitabine plus nab-paclitaxel or a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Forty-eight eligible patients were enrolled and received the vaccinations approximately every 2-4 weeks at least seven times. No severe adverse events related to the vaccinations were observed. Median progression free survival and overall survival were 8.1 months and 15.1 months, respectively. DC vaccinations augmented tumor specific immunity which might be related to clinical outcome. The multivariate analyses demonstrated that WT1 or MUC1-specific interferonɤ enzyme-linked immunospot number prior to DC vaccination was an independent prognostic factor related to overall survival. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and has clinical benefits for patients in advanced stage of PDAC. The precise evaluation of the baseline antitumor specific immunity is critical to predict clinical outcome.
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Affiliation(s)
- Shuichi Ota
- Department of Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Mamiko Miyashita
- Institute for Artificial Organ, Transplantation and Cell Therapy, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Yuka Yamagishi
- Cell Processing Center, Sapporo Hokuyu Hospital, Sapporo, Japan
| | - Masahiro Ogasawara
- Department of Internal Medicine, Sapporo Hokuyu Hospital, Sapporo, Japan
- Institute for Artificial Organ, Transplantation and Cell Therapy, Sapporo Hokuyu Hospital, Sapporo, Japan
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12
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Kiryu S, Ito Z, Suka M, Bito T, Kan S, Uchiyama K, Saruta M, Hata T, Takano Y, Fujioka S, Misawa T, Yamauchi T, Yanagisawa H, Sato N, Ohkusa T, Sugiyama H, Koido S. Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma. BMC Cancer 2021; 21:1197. [PMID: 34758773 PMCID: PMC8582170 DOI: 10.1186/s12885-021-08911-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Both activated tumor-infiltrating lymphocytes (TILs) and immune-suppressive cells, such as regulatory T cells (Tregs), in the tumor microenvironment (TME) play an important role in the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). METHODS The densities of TILs, programmed death receptor 1 (PD-1) + T cells, and forkhead box P3 (Foxp3) + T cells were analyzed by immunohistochemical staining. The associations of the immunological status of the PDAC microenvironment with overall survival (OS) time and disease-free survival (DFS) time were evaluated. RESULTS PDAC patients with a high density of TILs in the TME or PD-1-positive T cells in tertiary lymphoid aggregates (TLAs) demonstrated a significantly better prognosis than those with a low density of TILs or PD-1-negativity, respectively. Moreover, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than those with low levels of Foxp3-expressing T cells. Importantly, even with a high density of the TILs in TME or PD-1-positive T cells in TLAs, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than patients with low levels of Foxp3-expressing T cells. A PDAC TME with a high density of TILs/high PD-1 positivity/low Foxp3 expression was an independent predictive marker associated with superior prognosis. CONCLUSION Combined assessment of TILs, PD-1+ cells, and Foxp3+ T cells in the TME may predict the prognosis of PDAC patients following surgical resection.
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Affiliation(s)
- Sachie Kiryu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Machi Suka
- Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461 Japan
| | - Tsuuse Bito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Shin Kan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Kan Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461 Japan
| | - Taigo Hata
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Yuki Takano
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Shuichi Fujioka
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Takeyuki Misawa
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
| | - Takashi Yamauchi
- Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461 Japan
| | - Hiroyuki Yanagisawa
- Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461 Japan
| | - Nobuhiro Sato
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Toshifumi Ohkusa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Haruo Sugiyama
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita-city, Osaka, 565-0871 Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, 163-1 Kashiwa-shita, Kashiwa, Chiba, 277-8567 Japan
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13
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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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14
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Nakajima H, Nakata J, Imafuku K, Hayashibara H, Isokawa K, Udaka K, Fujiki F, Morimoto S, Hasegawa K, Hosen N, Hashii Y, Nishida S, Tsuboi A, Oka Y, Oji Y, Sogo S, Sugiyama H. Identification of mouse helper epitopes for WT1-specific CD4 + T cells. Cancer Immunol Immunother 2021; 70:3323-3335. [PMID: 34272593 DOI: 10.1007/s00262-021-03003-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 06/28/2021] [Indexed: 11/25/2022]
Abstract
Helper T lymphocytes (HTLs) play a central role in cancer immunity because they can not only help the induction and proliferation of cytotoxic T lymphocytes (CTLs) but also their differentiation into cytotoxic CD4+ T cells and directly kill the target cells.This study describes the identification of three novel mouse Th epitope peptides, WT135-52, WT186-102 and WT1294-312, derived from WT1 protein, which is the most potent tumor-associated antigen. Compared to immunization with WT1 CTL peptide alone, immunization with the addition of these WT1-specific Th peptides strongly induced WT1-specific CTLs, continued to maintain them, and efficiently rejected the challenge of WT1-expressing tumor cells. Importantly, the majority of WT1-specific CTLs induced by the co-immunization with WT1 CTL and the WT1-specific Th peptides were CD44+CD62L- effector memory CD8+ T cells, which played a central role in tumor rejection. Establishment of mouse models suitable for the analysis of the detailed mechanism of these functions of HTLs is very important. These results clearly showed that WT1-specific HTLs perform an essential function in WT1-specific tumor immunity. Therefore, the WT1-specific Th peptides identified here should make a major contribution to elucidation of the mutual roles of WT1-specific CTLs and HTLs in cancer immunity in in vivo mouse models.
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Affiliation(s)
- Hiroko Nakajima
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita-city, Osaka, 565-0871, Japan.
| | - Jun Nakata
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kanako Imafuku
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiromu Hayashibara
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuki Isokawa
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Keiko Udaka
- Department of Immunology, School of Medicine, Kochi University, Kochi, Japan
| | - Fumihiro Fujiki
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita-city, Osaka, 565-0871, Japan
| | - Soyoko Morimoto
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kana Hasegawa
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita-city, Osaka, 565-0871, Japan
| | - Naoki Hosen
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshiko Hashii
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sumiyuki Nishida
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Akihiro Tsuboi
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshihiro Oka
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Immunopathology, WPI, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan
| | - Yusuke Oji
- Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shinji Sogo
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita-city, Osaka, 565-0871, Japan
- Immunology Research Unit, Department of Medical Innovations, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita-city, Osaka, 565-0871, Japan
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15
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Miyazawa M, Katsuda M, Kawai M, Hirono S, Okada KI, Kitahata Y, Yamaue H. Advances in immunotherapy for pancreatic ductal adenocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:419-430. [PMID: 33742512 DOI: 10.1002/jhbp.944] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Advances in immunotherapy against advanced cancers can be considered stunning and epoch-making. Meanwhile, efficacy of immune-based therapies, especially immune checkpoint inhibitors, remains insufficient in pancreatic ductal adenocarcinoma, differing from other immunogenic cancers. To date, neither immunotherapies targeting immune system acceleration nor release of immunologic brakes have been able to overcome the robust immune barrier in the pancreatic tumor microenvironment, which is characterized by rich fibrotic stroma and accumulation of immunosuppressive myeloid cells. However, by receiving an immune checkpoint blockade, patients with abundant tumor-infiltrating lymphocytes in pancreatic ductal adenocarcinoma clearly have better prognosis, and patients with mismatch repair deficiency have achieved better outcomes, albeit in a small population of pancreatic ductal adenocarcinoma. We overview recent preclinical and clinical studies that have been concerned with immune-based therapies including cancer vaccine and immune checkpoint inhibitors. By providing a deep insight into the immunosuppressive tumor microenvironment, we suggest the possibility of comprehensive immune intensification that could reverse the tumor microenvironment, making it conducive to cytotoxic T lymphocyte activity for overcoming pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Motoki Miyazawa
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Masahiro Katsuda
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Manabu Kawai
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Seiko Hirono
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Ken-Ichi Okada
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yuji Kitahata
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
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16
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Abstract
Pancreatic cancer is a tumor with a high degree of malignancy, morbidity, and mortality. Immunotherapy is another important treatment for pancreatic cancer in addition to surgery and chemotherapy, but its application in pancreatic cancer is very limited, which is related to the unique biological behavior of pancreatic cancer and the tumor microenvironment. The immunosuppressive microenvironment of pancreatic cancer is highly heterogeneous and presents challenges for immunotherapy. The transformation of tumor immunosuppressive microenvironment contributes to the response to tumor immunotherapy, such that the tumor undergoes functional reprogramming to change from immunologically "cold" to immunologically "hot." In this review, we summarized the research and progress in immunotherapy for pancreatic cancer, including immune checkpoint inhibitors, vaccines, adoptive T cell therapy, oncolytic viruses, and immunomodulators, and suggest that individualized, combination, and precise therapy should be the main direction of future immunotherapy in pancreatic cancer.
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Affiliation(s)
- Jia Wu
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang Province, China
| | - Jianting Cai
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang Province, China.
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17
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Mandili G, Curcio C, Bulfamante S, Follia L, Ferrero G, Mazza E, Principe M, Cordero F, Satolli MA, Spadi R, Evangelista A, Giordano D, Viet D, Cappello P, Novelli F. In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination. J Immunother Cancer 2020; 8:jitc-2020-001071. [PMID: 33115943 PMCID: PMC7594541 DOI: 10.1136/jitc-2020-001071] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in survival, confirming the suppressive environment of PDA. As CT has immune-modulating properties, we investigated the effect of gemcitabine (GEM) in antitumor effector responses to TAA in patients with PDA. METHODS The IgG antibody repertoire in patients with PDA before and after CT was profiled by serological proteome analysis and ELISA and their ability to activate complement-dependent cytotoxicity (CDC) was measured. Peripheral T cells were stimulated in vitro with recombinant TAA, and specific proliferation, IFN-γ/IL-10 and CD8+/Treg ratios were measured. Mice that spontaneously developed PDA were treated with GEM and inoculated with an ENO1 (α-Enolase) DNA vaccine. In some experimental groups, the effect of depleting CD4, CD8 and B cells by specific antibodies was also evaluated. RESULTS CT increased the number of TAA recognized by IgG and their ability to activate CDC. Evaluation of the IFN-γ/IL-10 ratio and CD8+/Treg ratios revealed that CT treatment shifted T cell responses to ENO1, G3P (glyceraldheyde-3-phosphate dehydrogenase), K2C8 (keratin, type II cytoskeletal 8) and FUBP1 (far upstream binding protein 1), four of the most recognized TAA, from regulatory to effector. In PDA mice models, treatment with GEM prior to ENO1 DNA vaccination unleashed CD4 antitumor activity and strongly impaired tumor progression compared with mice that were vaccinated or GEM-treated alone. CONCLUSIONS Overall, these data indicate that, in PDA, CT enhances immune responses to TAA and renders them suitable targets for IT.
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Affiliation(s)
- Giorgia Mandili
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Claudia Curcio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Sara Bulfamante
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Laura Follia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Computer Science Department, University of Turin, Turin, Italy
| | - Giulio Ferrero
- Computer Science Department, University of Turin, Turin, Italy
| | - Emanuela Mazza
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Moitza Principe
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | | | - Maria Antonietta Satolli
- Department of Surgical Sciences, University of Turin, Torino, Italy.,Centro Oncologico Ematologico Subalpino, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Rosella Spadi
- Centro Oncologico Ematologico Subalpino, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Andrea Evangelista
- Servizio di Epidemiologia Clinica, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
| | - Daniele Giordano
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Duy Viet
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy .,Centro Ricerche Medicina Sperimentale, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
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18
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Nakata J, Isohashi K, Morimoto S, Itou R, Kamiya T, Matsuura A, Nakajima H, Fujiki F, Nishida S, Hasii Y, Hasegawa K, Nakatsuka S, Hosen N, Tsuboi A, Oka Y, Kumanogoh A, Shibano M, Munakata S, Oji Y, Hatazawa J, Sugiyama H. Enhanced immune reaction resulting from co-vaccination of WT1 helper peptide assessed on PET-CT. Medicine (Baltimore) 2020; 99:e22417. [PMID: 32991475 PMCID: PMC7523872 DOI: 10.1097/md.0000000000022417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
It has become evident that positron emission tomography/computed tomography (PET-CT) using 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) (FDG PET-CT) can detect anti-tumor immune response induced by various immunotherapies. To evaluate whether FDG PET-CT could detect anti-cancer immune response caused by cancer vaccine therapy, we performed a retrospective analysis of FDG PET-CT imaging of patients who were treated with Wilms Tumor 1 (WT1) vaccine therapy in Osaka University during July 2008 and June 2018. Increased FDG uptakes were detected in WT1-vaccinated skin and their draining lymph nodes during the repeated vaccination. While the FDG uptakes seemed to decrease with time after the cessation of WT1 peptide vaccinations, persistence of FDG uptakes for years in WT1-vaccinated skin were also observed in 2 cases who showed good clinical course. Moreover, the FDG uptakes of patients treated with the combination vaccine of WT1 specific cytotoxic T cell (CTL) and helper peptides were significantly stronger than of those treated with the WT1 CTL peptide alone. Since it is evident that the combination vaccine can induce a more robust anti-tumor immunity than can CTL peptide vaccine alone, the FDG uptakes in WT1-vaccinated skin might reflect the degree of immune response. These results suggest that PET-CT might be a good tool for prediction of anti-tumor immune response induced by WT1 vaccine therapy. Larger scale prospective studies therefore seem to be warranted.
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Affiliation(s)
- Jun Nakata
- Department of Clinical Laboratory and Biomedical Sciences
| | | | - Soyoko Morimoto
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine
| | - Ryota Itou
- Department of Pathology, Sakai City General Hospital
| | - Takashi Kamiya
- Department of Nuclear Medicine and Tracer Kinetics, Osaka
| | - Ai Matsuura
- Department of Hematology, Sakai City General Hospital
| | - Hiroko Nakajima
- Department of Cancer Immunology, Osaka University Graduate School of Medicine
| | - Fumihiro Fujiki
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine
| | - Sumiyuki Nishida
- Department of Respiratory Medicine and clinical immunology, Osaka University Graduate School of Medicine
| | - Yoshiko Hasii
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine
| | | | | | - Naoki Hosen
- Department of Hematology and Oncology, Osaka University Graduate School of Medicine
| | - Akihiro Tsuboi
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine
| | - Yoshihiro Oka
- Department of Cancer Stem Cell Biology
- Department of Immunopathology, WP1 Immunology Frontier Research Center, Osaka University, Suita city, Osaka, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and clinical immunology, Osaka University Graduate School of Medicine
- Department of Immunopathology, WP1 Immunology Frontier Research Center, Osaka University, Suita city, Osaka, Japan
| | | | | | - Yusuke Oji
- Department of Clinical Laboratory and Biomedical Sciences
| | - Jun Hatazawa
- Department of Nuclear Medicine and Tracer Kinetics, Osaka
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine
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19
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Kan S, Bito T, Shimabuku M, Taguchi J, Ohkusa T, Shimodaira S, Sugiyama H, Koido S. Impact of mature dendritic cells pulsed with a novel WT1 helper peptide on the induction of HLA‑A2‑restricted WT1‑reactive CD8+ T cells. Int J Oncol 2020; 57:1047-1056. [PMID: 32945369 DOI: 10.3892/ijo.2020.5110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 07/31/2020] [Indexed: 11/06/2022] Open
Abstract
The proliferation and activation of CD4+ T helper 1 (Th1) cells and CD8+ cytotoxic T lymphocytes (CTLs) that produce interferon‑γ (IFN‑γ) is an essential action of effective cancer vaccines. Recently, a novel Wilms' tumor 1 (WT1) helper peptide (WT1 HP34‑51; amino acid sequence, WAPVLDFAPPGASAYGSL) applicable for various human leukocyte antigen (HLA) subtypes (HLA‑DR, HLA‑DP and HLA‑DQ) was reported to increase peptide immunogenicity; however, the function of WT1 HP34‑51 remains unclear. In the present study, mature dendritic cells (mDCs) pulsed with WT1 HP34‑51 (mDC/WT1 HP34‑51) activated not only WT1‑specific CD4+ T cells but also CD8+ T cells that produced IFN‑γ following stimulation with immature dendritic cells (imDCs) pulsed with WT1 killer peptide (imDC/WT1 KP37‑45) in an HLA‑A*02:01‑ or HLA‑A*02:06‑restricted manner. Furthermore, the activated WT1‑reactive CD4+ Th1 cells were predominantly effector memory (EM) T cells. In 5 of 12 (41.7%) patients with cancer carrying the HLA‑A*02:01 or HLA‑A*02:06 allele, WT1‑reactive CD8+ T cells stimulated with mDC/WT1 HP34‑51 enhanced their levels of WT1 KP37‑45‑specific IFN‑γ production, with an increase >10%. Simultaneous activation of CD4+ and CD8+ T cells occurred more often when stimulation with mDC/WT1 HP34‑51 was combined with imDC/WT1 KP37‑45 restimulation. These results indicated that the novel mDC/WT1 HP34‑51 combination induced responses by WT1‑specific EM CD4+ Th1 cells and HLA‑A*02:01‑ or HLA‑A*02:06‑restricted CD8+ CTLs, suggesting its potential as a WT1‑targeting cancer vaccine.
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Affiliation(s)
- Shin Kan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
| | - Tsuuse Bito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
| | - Masamori Shimabuku
- Tokyo Midtown Center for Advanced Medical Science and Technology, Tokyo 107‑6206, Japan
| | - Junichi Taguchi
- Tokyo Midtown Center for Advanced Medical Science and Technology, Tokyo 107‑6206, Japan
| | - Toshifumi Ohkusa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
| | - Shigetaka Shimodaira
- Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa 920‑0293, Japan
| | - Haruo Sugiyama
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka 565‑0871, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277‑8567, Japan
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20
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Zhang L, Huang Y, Lindstrom AR, Lin TY, Lam KS, Li Y. Peptide-based materials for cancer immunotherapy. Theranostics 2019; 9:7807-7825. [PMID: 31695802 PMCID: PMC6831480 DOI: 10.7150/thno.37194] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 09/29/2019] [Indexed: 12/21/2022] Open
Abstract
Peptide-based materials hold great promise as immunotherapeutic agents for the treatment of many malignant cancers. Extensive studies have focused on the development of peptide-based cancer vaccines and delivery systems by mimicking the functional domains of proteins with highly specific immuno-regulatory functions or tumor cells fate controls. However, a systemic understanding of the interactions between the different peptides and immune systems remains unknown. This review describes the role of peptides in regulating the functions of the innate and adaptive immune systems and provides a comprehensive focus on the design, categories, and applications of peptide-based cancer vaccines. By elucidating the impacts of peptide length and formulations on their immunogenicity, peptide-based immunomodulating agents can be better utilized and dramatic breakthroughs may also be realized. Moreover, some critical challenges for translating peptides into large-scale synthesis, safe delivery, and efficient cancer immunotherapy are posed to improve the next-generation peptide-based immunotherapy.
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Affiliation(s)
| | | | | | | | | | - Yuanpei Li
- Department of Biochemistry and Molecular Medicine, UC Davis NCI-designated Comprehensive Cancer Center, University of California Davis, Sacramento, California 95817, United States
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21
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Elaileh A, Saharia A, Potter L, Baio F, Ghafel A, Abdelrahim M, Heyne K. Promising new treatments for pancreatic cancer in the era of targeted and immune therapies. Am J Cancer Res 2019; 9:1871-1888. [PMID: 31598392 PMCID: PMC6780661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 08/05/2019] [Indexed: 06/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality among men and women in the United States. Its incidence has been on the rise, with a projected two-fold increase by 2030. PDAC carries a poor prognosis due to a lack of effective screening tools, limited understanding of pathophysiology, and ineffective treatment modalities. Recently, there has been a revolution in the world of oncology with the advent of novel treatments to combat this disease. However, the 5-year survival of PDAC remains unchanged at a dismal 8%. The aim of this review is to bring together several studies and identify various recent modalities that have been promising in treating PDAC.
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Affiliation(s)
- Ahmed Elaileh
- Department of General Surgery, Houston Methodist HospitalHouston, Texas, USA
| | - Ashish Saharia
- Department of General Surgery, Houston Methodist HospitalHouston, Texas, USA
| | - Lucy Potter
- Department of General Surgery, Houston Methodist HospitalHouston, Texas, USA
| | - Flavio Baio
- Department of General Surgery, Houston Methodist HospitalHouston, Texas, USA
| | - Afnan Ghafel
- Department of Radiology, The University of JordanAmman, Jordan
| | - Maen Abdelrahim
- Department of General Surgery, Houston Methodist HospitalHouston, Texas, USA
| | - Kirk Heyne
- Department of General Surgery, Houston Methodist HospitalHouston, Texas, USA
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22
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Ito Z, Kan S, Bito T, Horiuchi S, Akasu T, Yoshida S, Kajihara M, Hokari A, Saruta M, Yoshida N, Kobayashi M, Ohkusa T, Shimodaira S, Okamoto M, Sugiyama H, Koido S. Predicted Markers of Overall Survival in Pancreatic Cancer Patients Receiving Dendritic Cell Vaccinations Targeting WT1. Oncology 2019; 97:135-148. [DOI: 10.1159/000500359] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 04/15/2019] [Indexed: 11/19/2022]
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23
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Abstract
PURPOSE OF REVIEW Despite all efforts, pancreatic ductal adenocarcinoma (PDAC) remains a disease that causes substantial morbidity and mortality, with a 5-year survival rate of 7%. Innovative paradigms for treating PDAC are urgently needed. RECENT FINDINGS We discuss the advances and difficulties in using immunotherapy and developing immunotherapeutic vaccines for PDAC. Current excitement about antigen-specific immunotherapy has been propelled by advances in multiple areas, such as next-generation sequencing to identify neoantigens and manufacturing to produce immunotherapeutic vaccines. Antigen-specific immunotherapy is being actively explored in clinical trials. As the field of immunotherapy matures and as our understanding of the complex interactions between tumor and host develops, we hope to identify new methods for treating and managing PDAC.
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Affiliation(s)
- Annie A Wu
- Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 488, Baltimore, MD, 21287, USA
| | - Elizabeth Jaffee
- Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 488, Baltimore, MD, 21287, USA
| | - Valerie Lee
- Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 488, Baltimore, MD, 21287, USA.
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24
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Takahashi N, Zhao C, Rajan A. WT1 as an immunotherapy target for thymic epithelial tumors: a novel method to activate anti-tumor immunity. ACTA ACUST UNITED AC 2019; 3. [PMID: 31304461 PMCID: PMC6625794 DOI: 10.21037/med.2019.03.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- Nobuyuki Takahashi
- Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Chen Zhao
- Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Arun Rajan
- Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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25
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Zhang W, Lu X, Cui P, Piao C, Xiao M, Liu X, Wang Y, Wu X, Liu J, Yang L. Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer. Cancer Immunol Immunother 2019; 68:121-130. [PMID: 30306202 PMCID: PMC11028035 DOI: 10.1007/s00262-018-2257-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 10/04/2018] [Indexed: 12/22/2022]
Abstract
Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-γ assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer.
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Affiliation(s)
- Wen Zhang
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 South Lane, Panjiayuan, Chaoyang District, Beijing, 100021, China
| | - Xu Lu
- Department of Oncology, Beijing Biohealthcare Biotechnology Co.,Ltd, FL2, Building 3, Park B, Shunyi District Airport High Tech Zoon, Beijing, 101300, China
| | - Peilin Cui
- Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
| | - Chunmei Piao
- Department of Oncology, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing, 100029, China
| | - Man Xiao
- Department of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, 571199, China
| | - Xuesong Liu
- Department of Oncology, Beijing Biohealthcare Biotechnology Co.,Ltd, FL2, Building 3, Park B, Shunyi District Airport High Tech Zoon, Beijing, 101300, China
| | - Yue Wang
- Department of Oncology, Beijing Biohealthcare Biotechnology Co.,Ltd, FL2, Building 3, Park B, Shunyi District Airport High Tech Zoon, Beijing, 101300, China
| | - Xuan Wu
- Department of Oncology, Beijing Biohealthcare Biotechnology Co.,Ltd, FL2, Building 3, Park B, Shunyi District Airport High Tech Zoon, Beijing, 101300, China
| | - Jingwei Liu
- Department of Oncology, Beijing Biohealthcare Biotechnology Co.,Ltd, FL2, Building 3, Park B, Shunyi District Airport High Tech Zoon, Beijing, 101300, China.
| | - Lin Yang
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 South Lane, Panjiayuan, Chaoyang District, Beijing, 100021, China.
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26
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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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27
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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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28
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Lee J, Kang TH, Yoo W, Choi H, Jo S, Kong K, Lee SR, Kim SU, Kim JS, Cho D, Kim J, Kim JY, Kwon ES, Kim S. An Antibody Designed to Improve Adoptive NK-Cell Therapy Inhibits Pancreatic Cancer Progression in a Murine Model. Cancer Immunol Res 2018; 7:219-229. [PMID: 30514792 DOI: 10.1158/2326-6066.cir-18-0317] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 09/12/2018] [Accepted: 11/28/2018] [Indexed: 11/16/2022]
Abstract
Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer. Despite the usefulness of NK cells, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK-cell-homing protein, named NK-cell-recruiting protein-conjugated antibody (NRP-body). The effect of NRP-body on infiltration of NK cells into primary and metastatic pancreatic cancer was evaluated in vitro and in murine pancreatic ductal adenocarcinoma models. The NRP-body increased NK-cell infiltration of tumors along a CXCL16 gradient (CXCL16 is cleaved from the NRP-body by furin expressed on the surface of pancreatic cancer cells). CXCL16 induced NK-cell infiltration by activating RhoA via the ERK signaling cascade. Administration of the NRP-body to pancreatic cancer model mice increased tumor tissue infiltration of transferred NK cells and reduced the tumor burden compared with that in controls. Overall survival of NRP-body-treated mice (even the metastasis models) was higher than that of mice receiving NK cells alone. In conclusion, increasing NK-cell infiltration into tumor tissues improved response to this cancer immunotherapy. The combination of an NRP-body with NK-cell therapy might be useful for treating pancreatic cancer.
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Affiliation(s)
- Jaemin Lee
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.,Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, South Korea
| | - Tae Heung Kang
- Department of Immunology, School of Medicine, Konkuk University, Seoul, South Korea
| | - Wonbeak Yoo
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Hyunji Choi
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Seongyea Jo
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Kyungsu Kong
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.,Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, South Korea
| | - Sang-Rae Lee
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, South Korea
| | - Sun-Uk Kim
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, South Korea
| | - Ji-Su Kim
- National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, South Korea
| | - Duck Cho
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.,Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, South Korea
| | - Janghwan Kim
- Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea
| | - Jeong-Yoon Kim
- Department of Microbiology and Molecular Biology, College of Bioscience and Biotechnology, Chungnam National University, South Korea
| | - Eun-Soo Kwon
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
| | - Seokho Kim
- Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
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29
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McGregor RJ, Chau YY, Kendall TJ, Artibani M, Hastie N, Hadoke PWF. WT1 expression in vessels varies with histopathological grade in tumour-bearing and control tissue from patients with breast cancer. Br J Cancer 2018; 119:1508-1517. [PMID: 30374123 PMCID: PMC6288121 DOI: 10.1038/s41416-018-0317-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 09/28/2018] [Accepted: 10/08/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The Wilms' tumour protein (WT1), which influences tumour development and angiogenesis, is a promising therapeutic target in breast cancer. We hypothesised that WT1 expression would vary in endothelial cells in distinct sub-classifications of breast cancer. METHODS WT1 expression and vascular density were quantified by immunohistochemical analysis of human (n = 57) and murine breast cancers. Human tumours were sub-classified by histopathological grade, ER status and HER2 enrichment. RESULTS WT1 was identified in endothelial (and epithelial and smooth muscle) cells in tumours and tumour-free tissues (controls) from patients and mice with breast cancer. WT1 expression was higher in tumours than in controls, but this was not due to increased endothelial WT1. Vascular WT1 in cancers decreased as histopathological grade increased. WT1 was higher in ER-positive versus ER-negative cancers. Strikingly, reduced WT1 expression in controls correlated with an increased Nottingham Prognostic Index score. CONCLUSIONS Expression of WT1 is increased in breast cancers but this is not limited to the vascular compartment. The association between reduced WT1 in tumour-free tissue and poor prognosis suggests a protective role for WT1 in the healthy breast.
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Affiliation(s)
| | - You-Ying Chau
- University/BHF Centre for Cardiovascular Science, Edinburgh, UK.,MRC HGU at the MRC Institute of Genetics and Molecular Medicine (IGMM), Edinburgh, UK
| | - Timothy J Kendall
- MRC HGU at the MRC Institute of Genetics and Molecular Medicine (IGMM), Edinburgh, UK.,Division of Pathology, University of Edinburgh, Edinburgh, UK
| | - Mara Artibani
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Nicholas Hastie
- MRC HGU at the MRC Institute of Genetics and Molecular Medicine (IGMM), Edinburgh, UK
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30
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Affiliation(s)
- Xuedan He
- University at Buffalo; State University of New York; Buffalo NY 14260 USA
| | - Scott I. Abrams
- Roswell Park Comprehensive Cancer Center; Department of Immunology; Buffalo NY 14263 USA
| | - Jonathan F. Lovell
- University at Buffalo; State University of New York; Buffalo NY 14260 USA
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31
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Kanai T, Ito Z, Oji Y, Suka M, Nishida S, Takakura K, Kajihara M, Saruta M, Fujioka S, Misawa T, Akiba T, Yanagisawa H, Shimodaira S, Okamoto M, Sugiyama H, Koido S. Prognostic significance of Wilms' tumor 1 expression in patients with pancreatic ductal adenocarcinoma. Oncol Lett 2018; 16:2682-2692. [PMID: 30008944 DOI: 10.3892/ol.2018.8961] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 05/16/2018] [Indexed: 02/07/2023] Open
Abstract
The only current curative treatment for patients with pancreatic ductal adenocarcinoma (PDA) is surgical resection, and certain patients still succumb to disease shortly after complete surgical resection. Wilms' tumor 1 (WT1) serves an oncogenic role in various types of tumors; therefore, in the present study, WT1 protein expression in patients with PDA was analyzed and the association with overall survival (OS) and disease-free survival (DFS) time in patients with PDA was assessed following surgical resection. A total of 50 consecutive patients with PDA who received surgical resection between January 2005 and December 2015 at the Jikei University Kashiwa Hospital (Kashiwa, Chiba, Japan) were enrolled. WT1 protein expression in PDA tissue was measured using immunohistochemical staining. Furthermore, laboratory parameters were measured within 2 weeks of surgery, and systemic inflammatory response markers were evaluated. WT1 protein expression was detected in the nucleus and cytoplasm of all PDA cells and in tumor vessels. WT1 exhibited weak staining in the nuclei of all PDA cells; however, the cytoplasmic expression of WT1 levels was classified into four groups: Negative (n=0), weak (n=19), moderate (n=23) and strong (n=8). In patients with PDA, it was demonstrated that the OS and DFS times of patients with weak cytoplasmic WT1 expression were significantly prolonged compared with those of patients with moderate-to-strong cytoplasmic WT1 expression, as determined by log-rank test (P=0.0005 and P=0.0001, respectively). Furthermore, an association between the density of WT1-expressing tumor vessels and worse OS/DFS times was detected. Multivariate analysis also indicated a significant association between the overexpression of WT1 in PDA tissue and worse OS/DFS times. To the best of our knowledge, the present study is the first to demonstrate that moderate-to-strong overexpression of WT1 in the cytoplasm of PDA cells is significantly associated with worse OS/DFS times. Therefore, overexpression of WT1 in the cytoplasm of PDA cells may impact the recurrence and prognosis of patients with PDA following surgical resection. The results further support the development of WT1-targeted therapies to prolong survival in all patients with PDA.
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Affiliation(s)
- Tomoya Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Yusuke Oji
- Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Machi Suka
- Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo 105-8571, Japan
| | - Sumiyuki Nishida
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Kazuki Takakura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Mikio Kajihara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8571, Japan
| | - Shuichi Fujioka
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Takeyuki Misawa
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Tadashi Akiba
- Department of Surgery, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan
| | - Hiroyuki Yanagisawa
- Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo 105-8571, Japan
| | - Shigetaka Shimodaira
- Department of Regenerative Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan
| | - Masato Okamoto
- Department of Advanced Immunotherapeutics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa, Chiba 277-8567, Japan.,Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Chiba 277-8567, Japan
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32
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Xu JW, Wang L, Cheng YG, Zhang GY, Hu SY, Zhou B, Zhan HX. Immunotherapy for pancreatic cancer: A long and hopeful journey. Cancer Lett 2018; 425:143-151. [PMID: 29605510 DOI: 10.1016/j.canlet.2018.03.040] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 02/28/2018] [Accepted: 03/26/2018] [Indexed: 12/11/2022]
Abstract
Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials. The current review describes the roles of immune cells and the immunosuppressive microenvironment in the development of pancreatic cancer, as well as the preclinical and clinical outcomes and benefits of recent immunotherapeutic approaches, which may help us further disclose the mechanisms of pancreatic cancer progression and the dialectical views of feasibility and effectiveness of immunotherapy in treatment of pancreatic cancer.
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Affiliation(s)
- Jian-Wei Xu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Lei Wang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Yu-Gang Cheng
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Guang-Yong Zhang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - San-Yuan Hu
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China
| | - Bin Zhou
- Department of Hepatopancreatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, 266003, China.
| | - Han-Xiang Zhan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, China.
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Correlates of immune and clinical activity of novel cancer vaccines. Semin Immunol 2018; 39:119-136. [PMID: 29709421 DOI: 10.1016/j.smim.2018.04.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 12/30/2022]
Abstract
Cancer vaccines are solely meant to amplify the pool of type 1 cytokine oriented CD4+ and CD8+ T cells that recognize tumor antigen and ultimately foster control and destruction of a growing tumor. They are not designed to deal with all aspects of immune ignorance, exclusion, suppression and escape that are generally in place in patients with cancer and may prevent the T cells to enter the tumor or to exert their effector function. This simple fact prompted for a reappraisal of the many recent trials in which therapeutic cancer vaccines have been examined as monotherapy. In this review, I focus on trials examining therapeutic cancer vaccines at different stages of existing disease. The analysis of vaccine-induced immune responses and clinical activity of therapeutic cancer vaccines revealed four levels of evidence for vaccine efficacy. The lowest levels, reflect the many trials in which the strength of the tumor-reactive T cell response of vaccinated patients is associated with better clinical outcome or change in tumor marker. The highest levels indicate occasional regressions of tumors and metastases after vaccination or reflect a stronger clinical impact of vaccine in a randomized trial. A whole series of trials in which vaccine-induced tumor immunity correlates with the clinical impact of cancer vaccines in premalignant diseases, settings of low tumor burden or tumor regressions in patients with cancer, form an attest to the fact that cancer vaccines work. While the current number of true clinical responders in each cancer trial is too low for firm conclusions on immune correlates of clinical reactivity in cancer, extrapolation of the results from vaccinated patients with pre-cancers suggest a requirement of broad type 1 T cell reactivity.
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Targeted therapies in the management of locally advanced and metastatic pancreatic cancer: a systematic review. Oncotarget 2018; 9:21613-21627. [PMID: 29765563 PMCID: PMC5940404 DOI: 10.18632/oncotarget.25085] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 03/12/2018] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer has a dismal prognosis particularly in patients presenting with unresectable tumors. We performed a bibliometric analysis of clinical trials for pancreatic cancer conducted between 2014-2016 focusing on patients that presented with unresectable (locally advanced or metastatic) tumors. We discuss a range of studies that employed FOLFIRINOX, the gemcitabine + nab-paclitaxel combination and studies that used molecularly-targeted therapy. Major areas of focus have been dual targeting of EGFR and VEGFR, immunotherapy or a multimodal approach – combining chemotherapy with radiotherapy. We also point out the need for molecular selection for low prevalence subtypes. Key insights sourced from these pivotal trials should improve clinical outcomes for this devastating cancer.
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Abstract
Despite the identification of some efficient drugs for the treatment of metastatic pancreatic cancer, this tumor remains one of the most lethal cancers and is characterized by a strong resistance to therapies. Pancreatic cancer has some unique features including the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma, which is both a physical barrier to drug penetration and a dynamic entity involved in immune system control. Therefore, the immune system has been hypothesized to play an important role in pancreatic cancer. Thus, therapies acting on innate or adaptive immunity are being investigated. Here, we review the literature, report the most interesting results and hypothesize future treatment directions.
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Affiliation(s)
- Francesca Aroldi
- UO Oncologia, Poliambulanza Foundation, Via Bissolati 57, 25124 Brescia, Italy
| | - Alberto Zaniboni
- UO Oncologia, Poliambulanza Foundation, Via Bissolati 57, 25124 Brescia, Italy
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36
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Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners. Cancers (Basel) 2018; 10:cancers10020051. [PMID: 29462900 PMCID: PMC5836083 DOI: 10.3390/cancers10020051] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 02/07/2018] [Accepted: 02/14/2018] [Indexed: 12/21/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor. ENO1 is also recognized by T cells in PDA patients, so we developed a DNA vaccine that targets ENO1. This efficiently induces many immunological processes (antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells), which significantly increase the survival of genetically engineered mice that spontaneously develop pancreatic cancer. Although promising, the ENO1 DNA vaccine does not completely eradicate the tumor, which, after an initial growth inhibition, returns to proliferate again, especially when Tregs and MDSC ensue in the tumor mass. This led us to develop possible strategies for combinatorial treatments aimed to broaden and sustain the antitumor immune response elicited by DNA vaccination. Based on the data we have obtained in recent years, this review will discuss the biological bases of possible combinatorial treatments (chemotherapy, PI3K inhibitors, tumor-associated macrophages, ENO1 inhibitors) that could be effective in amplifying the response induced by the immune vaccination in PDA.
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Nishida S, Ishikawa T, Egawa S, Koido S, Yanagimoto H, Ishii J, Kanno Y, Kokura S, Yasuda H, Oba MS, Sato M, Morimoto S, Fujiki F, Eguchi H, Nagano H, Kumanogoh A, Unno M, Kon M, Shimada H, Ito K, Homma S, Oka Y, Morita S, Sugiyama H. Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase II Randomized Study. Cancer Immunol Res 2018; 6:320-331. [PMID: 29358173 DOI: 10.1158/2326-6066.cir-17-0386] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/17/2017] [Accepted: 01/09/2018] [Indexed: 11/16/2022]
Abstract
We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it with gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01- or HLA-A*24:02-positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival [PFS; hazard ratio (HR), 0.66; P = 0.084] and improved overall survival rate at 1 year (1-year OS%; GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared with the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86; P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses. Cancer Immunol Res; 6(3); 320-31. ©2018 AACR.
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Affiliation(s)
- Sumiyuki Nishida
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
| | - Takeshi Ishikawa
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shinichi Egawa
- Division of International Cooperation for Disaster Medicine, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
| | - Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | | | - Jun Ishii
- Division of General and Gastroenterological Surgery, Department of Surgery, Toho University Faculty of Medicine, Tokyo, Japan
| | - Yoshihide Kanno
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Satoshi Kokura
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroaki Yasuda
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mari Saito Oba
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Maho Sato
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Soyoko Morimoto
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fumihiro Fujiki
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masanori Kon
- Department of Surgery, Kansai Medical University, Hirakata, Japan
| | - Hideaki Shimada
- Division of General and Gastroenterological Surgery, Department of Surgery, Toho University Faculty of Medicine, Tokyo, Japan
| | - Kei Ito
- Department of Gastroenterology, Sendai City Medical Center, Sendai, Japan
| | - Sadamu Homma
- Division of Oncology, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Yoshihiro Oka
- Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
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38
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Oji Y, Inoue M, Takeda Y, Hosen N, Shintani Y, Kawakami M, Harada T, Murakami Y, Iwai M, Fukuda M, Nishida S, Nakata J, Nakae Y, Takashima S, Shirakata T, Nakajima H, Hasegawa K, Kida H, Kijima T, Morimoto S, Fujiki F, Tsuboi A, Morii E, Morita S, Sakamoto J, Kumanogoh A, Oka Y, Okumura M, Sugiyama H. WT1 peptide-based immunotherapy for advanced thymic epithelial malignancies. Int J Cancer 2018; 142:2375-2382. [DOI: 10.1002/ijc.31253] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 11/19/2017] [Accepted: 12/07/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Yusuke Oji
- Department of Functional Diagnostic Science; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Masayoshi Inoue
- Division of Thoracic Surgery, Department of Surgery; Kyoto Prefectural University of Medicine; Kyoto Prefecture Japan
| | - Yoshito Takeda
- Department of Respiratory Medicine and Clinical Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Naoki Hosen
- Department of Cancer Stem Cell Biology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Yasushi Shintani
- Department of General Thoracic Surgery; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | | | - Takuya Harada
- Department of Functional Diagnostic Science; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Yui Murakami
- Department of Functional Diagnostic Science; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Miki Iwai
- Department of Functional Diagnostic Science; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Mari Fukuda
- Department of Cancer Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Sumiyuki Nishida
- Department of Respiratory Medicine and Clinical Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Jun Nakata
- Department of Cancer Immunotherapy; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Yoshiki Nakae
- Internal Medicine, Nissay Hospital; Osaka Prefecture Japan
| | - Satoshi Takashima
- Department of Respiratory Medicine and Clinical Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Toshiaki Shirakata
- Department of Respiratory Medicine and Clinical Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Hiroko Nakajima
- Department of Cancer Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Kana Hasegawa
- Department of Cancer Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Hiroshi Kida
- Department of Respiratory Medicine and Clinical Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Takashi Kijima
- Division of Respiratory Medicine, Department of Internal Medicine; Hyogo College of Medicine; Hyōgo Prefecture Japan
| | - Soyoko Morimoto
- Department of Cancer Immunotherapy; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Fumihiro Fujiki
- Department of Cancer Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Akihiro Tsuboi
- Department of Cancer Immunotherapy; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Eiichi Morii
- Department of Pathology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics; Kyoto University Graduate School of Medicine; Kyoto Prefecture Japan
| | | | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Yoshihiro Oka
- Department of Respiratory Medicine and Clinical Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
- Department of Cancer Stem Cell Biology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Meinoshin Okumura
- Department of General Thoracic Surgery; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology; Osaka University Graduate School of Medicine; Osaka Prefecture Japan
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39
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Emerging trends in the immunotherapy of pancreatic cancer. Cancer Lett 2017; 417:35-46. [PMID: 29242097 DOI: 10.1016/j.canlet.2017.12.012] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 11/20/2017] [Accepted: 12/07/2017] [Indexed: 12/23/2022]
Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the U.S., claiming approximately 43,000 lives every year. Much like other solid tumors, PC evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive tumor microenvironment (TME). Therefore, targeting and reinstating the patient's immune system could serve as a powerful therapeutic tool. Indeed, immunotherapy has emerged in recent years as a potential adjunct treatment for solid tumors including PC. Immunotherapy modulates the host's immune response to tumor-associated antigens (TAAs), eradicates cancer cells by reducing host tolerance to TAAs and provides both short- and long-term protection against the disease. Passive immunotherapies like monoclonal antibodies or engineered T-cell based therapies directly target tumor cells by recognizing TAAs. Active immunotherapies, like cancer vaccines, on the other hand elicit a long-lasting immune response via activation of the patient's immune cells against cancer cells. Several immunotherapy strategies have been tested for anti-tumor responses alone and in combination with standard care in multiple preclinical and clinical studies. In this review, we discuss various immunotherapy strategies used currently and their efficacy in abrogating self-antigen tolerance and immunosuppression, as well as their ability to eradicate PC.
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40
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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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41
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Bendjama K, Quemeneur E. Modified Vaccinia virus Ankara-based vaccines in the era of personalized immunotherapy of cancer. Hum Vaccin Immunother 2017; 13:1997-2003. [PMID: 28846477 DOI: 10.1080/21645515.2017.1334746] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
While interest in immunotherapies is renewed by the successful introduction of immune checkpoint blocking agent in the clinic, advances in genome sequencing are opening new possibilities in the design of increasingly personalized vaccines. Personalization of medicine can now be realistically contemplated at the single patient level. Unlike the previous generation of cancer vaccines, neoantigen directed vaccines would target truly specific tumor antigens resulting from acquired tumor genome mutations. Immune response induced by this next generation vaccine would not be subject to self-tolerance and will likely result to enhanced efficacy. Nevertheless, this new technologies can hold to their promises only if sponsors manage to meet several scientific, technical, logistical and regulatory challenges. In particular manufacturers will have to design, manufacture, and deliver to the patient a new pharmaceutical grade in a matters of weeks. In this paper, we briefly review current technologies currently tried at the translation of personalized vaccines and explore the possibilities offered by the Modified Vaccinia virus Ankara in this next wave of cancer vaccines.
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42
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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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43
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Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study. Breast Cancer Res Treat 2017; 162:479-488. [PMID: 28176175 PMCID: PMC5332485 DOI: 10.1007/s10549-017-4130-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 01/20/2017] [Indexed: 12/23/2022]
Abstract
Purpose This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms’ tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients. Methods Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab–chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A–C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination. Results Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely. Conclusions Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab–chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4130-y) contains supplementary material, which is available to authorized users.
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44
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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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45
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Silva APS, Coelho PV, Anazetti M, Simioni PU. Targeted therapies for the treatment of non-small-cell lung cancer: Monoclonal antibodies and biological inhibitors. Hum Vaccin Immunother 2016; 13:843-853. [PMID: 27831000 PMCID: PMC5404364 DOI: 10.1080/21645515.2016.1249551] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The usual treatments for patients with non-small-cell lung cancer (NSCLC), such as advanced lung adenocarcinoma, are unspecific and aggressive, and include lung resection, radiotherapy and chemotherapy. Recently, treatment with monoclonal antibodies and biological inhibitors has emerged as an effective alternative, generating effective results with few side effects. In recent years, several clinical trials using monoclonal antibodies presented potential benefits to NSCLC, and 4 of them are already approved for the treatment of NSCLC, such as cetuximab, bevacizumab, nivolumab and pembrolizumab. Also, biological inhibitors are attractive tolls for biological applications. Among the approved inhibitors are crizotinib, erlotinib, afatinib and gefitinib, and side effects are usually mild to intense. Nevertheless, biological molecule treatments are under development, and several new monoclonal antibodies and biological inhibitors are in trial to treat NSCLC. Also under trial study are as follows: anti-epidermal growth factor receptor (EGFR) antibodies (nimotuzumab and ficlatuzumab), anti-IGF 1 receptor (IGF-1R) monoclonal antibody (figitumumab), anti-NR-LU-10 monoclonal antibody (nofetumomab) as well as antibodies directly affecting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule (ipilimumab and tremelimumab), to receptor activator of nuclear factor-kappa B ligand (RANKL) (denosumab) or to polymerase enzyme (veliparib and olaparib). Among new inhibitors under investigation are poly-ADP ribose polymerase (PARP) inhibitors (veliparib and olaparib) and phosphatidylinositol 3-kinase (PI3K) inhibitor (buparlisib). However, the success of immunotherapies still requires extensive research and additional controlled trials to evaluate the long-term benefits and side effects.
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Affiliation(s)
- Ana P S Silva
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil
| | - Priscila V Coelho
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil
| | - Maristella Anazetti
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil.,b Department of Health Science , Faculty DeVry Metrocamp , Campinas , SP , Brazil
| | - Patricia U Simioni
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil.,c Department of Genetics , Evolution and Bioagents, Institute of Biology, University of Campinas (UNICAMP) , Campinas , SP , Brazil.,d Department of Biochemistry and Microbiology , Institute of Biosciences, Universidade Estadual Paulista, UNESP , Rio Claro , SP , Brazil
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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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47
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Koido S, Okamoto M, Shimodaira S, Sugiyama H. Wilms’ tumor 1 (WT1)-targeted cancer vaccines to extend survival for patients with pancreatic cancer. Immunotherapy 2016; 8:1309-1320. [PMID: 27993090 DOI: 10.2217/imt-2016-0031] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Despite novel chemotherapy treatments, pancreatic ductal adenocarcinoma (PDA) remains a lethal disease. New targeted cancer vaccines may represent a viable option for patients with PDA. The Wilms’ tumor 1 (WT1) antigen is one of the most widely expressed tumor-associated antigens in various types of tumors, including PDA. Recent reports have indicated that WT1-targeted cancer vaccines for patients with PDA mediated a potent antitumor effect when combined with chemotherapy in preclinical and clinical studies. This review summarizes the early-phase clinical trials of WT1-targeted cancer vaccines (peptide vaccines and dendritic cell-based vaccines) for PDA. Moreover, we will discuss future strategies for PDA treatments using WT1-specific cancer vaccines combined with immune checkpoint therapies to maximize the clinical effectiveness of PDA treatments.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City, Chiba 277-8567, Japan
- Institute of Clinical Medicine & Research, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan
| | - Masato Okamoto
- Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Tokyo 108-8641, Japan
| | | | - Haruo Sugiyama
- Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan
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48
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Syndecan-4 as a biomarker to predict clinical outcome for glioblastoma multiforme treated with WT1 peptide vaccine. Future Sci OA 2016; 2:FSO96. [PMID: 28116121 PMCID: PMC5241910 DOI: 10.4155/fsoa-2015-0008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 01/04/2016] [Indexed: 12/18/2022] Open
Abstract
AIM In cancer immunotherapy, biomarkers are important for identification of responsive patients. This study was aimed to find biomarkers that predict clinical outcome of WT1 peptide vaccination. MATERIALS & METHODS Candidate genes that were expressed differentially between long- and short-term survivors were identified by cDNA microarray analysis of peripheral blood mononuclear cells that were extracted from 30 glioblastoma patients (discovery set) prior to vaccination and validated by quantitative RT-PCR using discovery set and different 23 patients (validation set). RESULTS SDC-4 mRNA expression levels distinguished between the long- and short-term survivors: 1-year survival rates were 64.0 and 18.5% in SDC4-low and -high patients, respectively. CONCLUSION SDC-4 is a novel predictive biomarker for the efficacy of WT1 peptide vaccine.
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49
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Takahashi H, Shimodaira S, Ogasawara M, Ota S, Kobayashi M, Abe H, Morita Y, Nagai K, Tsujitani S, Okamoto M, Suzuki Y, Nakanishi Y, Yonemitsu Y. Lung adenocarcinoma may be a more susceptive subtype to a dendritic cell-based cancer vaccine than other subtypes of non-small cell lung cancers: a multicenter retrospective analysis. Cancer Immunol Immunother 2016; 65:1099-111. [PMID: 27448677 PMCID: PMC11029687 DOI: 10.1007/s00262-016-1872-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 07/17/2016] [Indexed: 01/09/2023]
Abstract
OBJECTIVE The J-SICT DC Vaccine Study Group provides dendritic cell (DC) vaccines for compassionate use under unified cell production and patient treatment regimens. We previously reported beneficial effects of DC vaccines on the overall survival of 62 patients with advanced non-small cell lung cancer (NSCLC) in a single-center analysis. Here, we extended analysis to 260 patients with NSCLC who were treated at six centers. METHODS Of the 337 patients who met the inclusion criteria, we analyzed 260 patients who received ≥5 peptide-pulsed DC vaccinations once every 2 weeks. RESULTS The mean survival time (MST) from diagnosis was 33.0 months (95 % confidence interval [CI]: 27.9-39.2), and that from time of first vaccination was 13.8 months (95 % CI 11.4-16.8). An erythema reaction at the injection site that was ≥30 mm in diameter was correlated most strongly with overall survival from the first vaccine (≥30 vs. < 30 mm: MST 20.4 vs. 8.8 months, P < 0.001). We reported a similar finding in our previous analysis of patients with advanced pancreatic cancer. Interestingly, although such findings were common between patients with adenocarcinoma and those with other subtypes, the former group experienced significantly prolonged overall survival and a higher response rate for erythema (56.3 vs. 37.3 %, respectively, P = 0.014). CONCLUSIONS This is the first multicenter study that suggests a possible clinical benefit of DC vaccines for patients with advanced NSCLC, especially those with adenocarcinoma. These findings suggest a specific potential responder population for DC vaccines and warrant further investigation in well-controlled prospective randomized trials.
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Affiliation(s)
- Hidenori Takahashi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
- R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Seren Clinic Fukuoka, Fukuoka, 810-0001, Japan
| | - Shigetaka Shimodaira
- Cell Processing Center, Shinshu University Hospital, Matsumoto, Nagano, 390-8621, Japan
| | - Masahiro Ogasawara
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido, 003-0006, Japan
| | - Shuichi Ota
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido, 003-0006, Japan
| | | | | | | | - Kazuhiro Nagai
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, 852-8501, Japan
| | - Shunichi Tsujitani
- Tottori University Hospital Cancer Center, Tottori, Yonago, 683-8504, Japan
| | - Masato Okamoto
- Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Tokyo, 108-8641, Japan
| | - Yukio Suzuki
- Division of Clinical Medicine, Research and Education Center for Clinical Pharmacy, Kitasato University School of Pharmacy, Tokyo, 108-8641, Japan
| | - Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan
| | - Yoshikazu Yonemitsu
- R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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50
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Oji Y, Hashimoto N, Tsuboi A, Murakami Y, Iwai M, Kagawa N, Chiba Y, Izumoto S, Elisseeva O, Ichinohasama R, Sakamoto J, Morita S, Nakajima H, Takashima S, Nakae Y, Nakata J, Kawakami M, Nishida S, Hosen N, Fujiki F, Morimoto S, Adachi M, Iwamoto M, Oka Y, Yoshimine T, Sugiyama H. Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide. Int J Cancer 2016; 139:1391-401. [PMID: 27170523 PMCID: PMC5089562 DOI: 10.1002/ijc.30182] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 04/20/2016] [Accepted: 04/26/2016] [Indexed: 02/01/2023]
Abstract
We previously evaluated Wilms’ tumor gene 1 (WT1) peptide vaccination in a large number of patients with leukemia or solid tumors and have reported that HLA‐A*24:02 restricted, 9‐mer WT1‐235 peptide (CYTWNQMNL) vaccine induces cellular immune responses and elicits WT1‐235‐specific cytotoxic T lymphocytes (CTLs). However, whether this vaccine induces humoral immune responses to produce WT1 antibody remains unknown. Thus, we measured IgG antibody levels against the WT1‐235 peptide (WT1‐235 IgG antibody) in patients with glioblastoma multiforme (GBM) receiving the WT1 peptide vaccine. The WT1‐235 IgG antibody, which was undetectable before vaccination, became detectable in 30 (50.8%) of a total of 59 patients during 3 months of WT1 peptide vaccination. The dominant WT1‐235 IgG antibody subclass was Th1‐type, IgG1 and IgG3. WT1‐235 IgG antibody production was significantly and positively correlated with both progression‐free survival (PFS) and overall survival (OS). Importantly, the combination of WT1‐235 IgG antibody production and positive delayed type‐hypersensitivity (DTH) to the WT1‐235 peptide was a better prognostic marker for long‐term OS than either parameter alone. These results suggested that WT1‐235 peptide vaccination induces not only WT1‐235‐specific CTLs as previously described but also WT1‐235‐specific humoral immune responses associated with antitumor cellular immune response. Our results indicate that the WT1 IgG antibody against the WT1 peptide may be a useful predictive marker, with better predictive performance in combination with DTH to WT1 peptide, and provide a new insight into the antitumor immune response induction in WT1 peptide vaccine‐treated patients. What's new? The Wilms' tumor gene 1 (WT1) antigen is a promising target for immunotherapeutic strategies against glioblastoma multiforme (GBM), a brain tumor with poor survival rates. The present study shows that vaccination with WT1‐235 peptide can induce WT1‐235‐specific humoral immune responses in GBM patients. WT1‐235 IgG antibody production was significantly associated with prolonged progression‐free survival and overall survival. Survival times were significantly longer in GBM patients with positive delayed‐type hypersensitivity (DTH) responses to WT1 peptide. Thus, in WT1 vaccine‐treated GBM patients, especially those exhibiting positive DTH responses, WT1‐235 IgG antibody production can predict long‐term survival.
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Affiliation(s)
- Yusuke Oji
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoya Hashimoto
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Akihiro Tsuboi
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yui Murakami
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Miki Iwai
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoki Kagawa
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasuyoshi Chiba
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | | | - Olga Elisseeva
- Cell Signal Unit, Okinawa Institute of Science and Technology, Okinawa, Japan
| | | | | | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hiroko Nakajima
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Takashima
- Respiratory Medicine and Allergy, Rheumatic Disease, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Nakae
- Respiratory Medicine and Allergy, Rheumatic Disease, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Jun Nakata
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Manabu Kawakami
- Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sumiyuki Nishida
- Respiratory Medicine and Allergy, Rheumatic Disease, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Naoki Hosen
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fumihiro Fujiki
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Soyoko Morimoto
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mayuko Adachi
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Masahiro Iwamoto
- Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshihiro Oka
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.,Respiratory Medicine and Allergy, Rheumatic Disease, Osaka University Graduate School of Medicine, Osaka, Japan.,Department of Immunopathology, Immunology Frontier Research Center (World Premier International Research Center), Osaka University, Osaka, Japan
| | - Toshiki Yoshimine
- Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Haruo Sugiyama
- Department of Cancer Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
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