Journal Articles

Neoantigen-based therapy

Immunotherapy approaches based on patient-specific immunogenic protein-altering mutations

Immunotherapy for Non-small-cell Lung Cancer: Current Status and Future Obstacles

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Lung cancer is one of the leading causes of death worldwide. There are 2 major subtypes of lung cancer, non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Studies show that NSCLC is the more prevalent type of lung cancer that accounts for approximately 80%-85% of cases. Although, various treatment methods, such as chemotherapy, surgery, and radiation therapy have been used to treat lung cancer patients, there is an emergent need to develop more effective approaches to deal with advanced stages of tumors. Recently, immunotherapy has emerged as a new approach to combat with such tumors. The development and success of programmed cell death 1 (PD-1)/program death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockades in treating metastatic cancers opens a new pavement for the future research. The current mini review discusses the significance of immune checkpoint inhibitors in promoting the death of tumor cells. Additionally, this review also addresses the importance of tumor-specific antigens (neoantigens) in the development of cancer vaccines and major challenges associated with this therapy. Immunotherapy can be a promising approach to treat NSCLC because it stimulates host's own immune system to recognize cancer cells. Therefore, future research should focus on the development of new methodologies to identify novel checkpoint inhibitors and potential neoantigens.

Author Info: (1) Arthur G. James Cancer Hospital Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

Author Info: (1) Arthur G. James Cancer Hospital Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

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Translating Science into Survival: Report on the Third International Cancer Immunotherapy Conference

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On September 6 to 9, 2017, in Mainz, Germany, the Third International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. For the third straight year, more than 1,400 people attended the four-day event, which covered the latest advances in cancer immunology and immunotherapy. This report provides an overview of the main topics discussed. Cancer Immunol Res; 6(1); 10-13. (c)2017 AACR.

Author Info: (1) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (2) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg

Author Info: (1) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (2) TRON - Translational Oncology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. (3) Cancer Research Institute, New York, New York. abrodsky@cancerresearch.org.

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A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancer

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Mutated cancer antigens, or neoantigens, represent compelling immunological targets and appear to underlie the success of several forms of immunotherapy. While there are anecdotal reports of neoantigen-specific T cells being present in the peripheral blood and/or tumors of cancer patients, effective adoptive cell therapy (ACT) against neoantigens will require reliable methods to isolate and expand rare, neoantigen-specific T cells from clinically available biospecimens, ideally prior to clinical relapse. Here, we addressed this need using "mini-lines", large libraries of parallel T cell cultures, each originating from only 2,000 T cells. Using small quantities of peripheral blood from multiple time points in an ovarian cancer patient, we screened over 3.3 x 10(6) CD8(+) T cells by ELISPOT for recognition of peptides corresponding to the full complement of somatic mutations (n = 37) from the patient's tumor. We identified ten T cell lines which collectively recognized peptides encoding five distinct mutations. Six of the ten T cell lines recognized a previously described neoantigen from this patient (HSDL1(L25V)), whereas the remaining four lines recognized peptides corresponding to four other mutations. Only the HSDL1(L25V)-specific T cell lines recognized autologous tumor. HSDL1(L25V)-specific T cells comprised at least three distinct clonotypes and could be identified and expanded from peripheral blood 3-9 months prior to the first tumor recurrence. These T cells became undetectable at later time points, underscoring the dynamic nature of the response. Thus, neoantigen-specific T cells can be expanded from small volumes of blood during tumor remission, making pre-emptive ACT a plausible clinical strategy.

Author Info: (1) Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British

Author Info: (1) Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada. Michael Smith's Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. (2) Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada. (3) Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada. (4) Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada. (5) Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. Michael Smith's Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada. (6) Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada. Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.

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Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

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Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, where the majority of patients experienced no or minimum clinical benefits. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer-specific immune targets. Highly tumor-specific antigens, neoantigens, are generated by somatic mutations which are not present in normal cells. It is plausible that by targeting antigens with high tumor-specificity such as neoantigens, the likelihood of toxic effects is likely to be very limited. However, understanding the interaction between neoantigens and the host immune system has remained to be a big challenge. This review focuses on the potential use of neoantigen-targeted immunotherapies in cancer treatment and the recent progresses of the different strategies in predicting, identifying and validating neoantigens. Successful identification of highly tumor-specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients. This article is protected by copyright. All rights reserved.

Author Info: (1) Immunopharmacogenomics Group Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan. (2) Immunopharmacogenomics Group Cancer Precision Medicine Center, Japanese Foundation for

Author Info: (1) Immunopharmacogenomics Group Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan. (2) Immunopharmacogenomics Group Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan. (3) Department of Medicine, The University of Chicago. Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.

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Cancer Immunotherapy Targeted Glypican-3 or Neoantigens

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Immune checkpoint inhibitors have ushered a new era in cancer therapy, although other therapies or combinations thereof are still needed for the many patients for whom these drugs are ineffective. In this light, we have identified in glypican-3 an HLA-24, HLA-A2 restriction peptide with extreme cancer specificity. In this paper, we summarize results from a number of related clinical trials demonstrating that glypican-3 peptide vaccines induce specific cytotoxic T lymphocytes in most patients (UMIN Clinical Trials Registry: UMIN000001395, UMIN000005093, UMIN000002614, UMN000003696, UMIN000006357,). We also describe the current state of personalized cancer immunotherapy based on neoantigens, and assess, based on our own research and experience, the potential of such therapy to elicit cancer regression. Finally, we discuss the future direction of cancer immunotherapy. This article is protected by copyright. All rights reserved.

Author Info: (1) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa. Department of Gastroenterological Surgery, Yokohama City University Graduate School

Author Info: (1) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. (2) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa. (3) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa. (4) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. (5) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. (6) Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. (7) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center National Cancer Center, Kashiwa.

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Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Neoantigens as Vaccine Targets for Cancer

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Recent work by several groups has undoubtedly shown that we can produce cancer vaccines targeting neoantigens. However, each vaccine is essentially a single-use, patient-specific product, making this approach resource-intensive. For this reason, it is important to ask whether this approach will be any more successful than what has been attempted during the last 30 years using vaccines targeting self-epitopes. Here, we discuss what might be expected from neoantigen vaccines based on our experience in chronic viral infections, and how this new approach may be applied to cancer immunotherapy.

Author Info: (1) Departments of Urology and Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322.

Author Info: (1) Departments of Urology and Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322.

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Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Neoantigens: Nothing New in Spite of the Name

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The term "neoantigen," as applied to molecules newly expressed on tumor cells, has a long history. The groundbreaking discovery of a cancer causing virus in chickens by Rous over 100 years ago, followed by discoveries of other tumor-causing viruses in animals, suggested a viral etiology of human cancers. The search for other oncogenic viruses in the 1960s and 1970s resulted in the discoveries of Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human papilloma virus (HPV), and continues until the present time. Contemporaneously, the budding field of immunology was posing the question can the immune system of animals or humans recognize a tumor that develops from one's own tissues and what types of antigens would distinguish the tumor from normal cells. Molecules encoded by oncogenic viruses provided the most logical candidates and evidence was quickly gathered for both humoral and cellular recognition of viral antigens, referred to as neoantigens. Often, however, serologic responses to virus-bearing tumors revealed neoantigens unrelated to viral proteins and expressed on multiple tumor types, foreshadowing later findings of multiple changes in other genes in tumor cells creating nonviral neoantigens.

Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. (2) Department of Immunology, Institute for Cell Biology, University of Tuebingen, 7207

Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. (2) Department of Immunology, Institute for Cell Biology, University of Tuebingen, 72074 Tuebingen; and German Cancer Consortium, DKFZ Partner Site, D-69120 Heidelberg, Germany.

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Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Targeting the Right Antigens in the Right Patients

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Recent advances in genomic sequencing and bioinformatics have empowered a revolution in immuno-oncology that has led to numerous unambiguous demonstrations of spontaneous and therapy-induced T-cell responses in patients against a subset of immunogenic tumor-specific somatic mutations known as neoantigens. These findings raise the exciting possibility that patients could be therapeutically treated with personalized vaccines against the mutations expressed by their own tumor. A central challenge for the broader clinical application of this approach will be to define the best antigens to target, to determine the subset of patients most likely to derive significant clinical benefit, and, finally, to discover both the best method of vaccine delivery and the optimal time in the disease course to do so. A growing number of translational immunologists believe that these challenges can be overcome and this perspective will discuss strategies to achieve this.

Author Info: (1) Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037; Division of Hematology and Oncology, UCSD Moores Cancer Center

Author Info: (1) Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037; Division of Hematology and Oncology, UCSD Moores Cancer Center, San Diego, California 92123; and Cancer Vaccines Group, Human Longevity Inc., San Diego, California 92121.

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Identification and Characterization of Neoantigens As Well As Respective Immune Responses in Cancer Patients

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Cancer immunotherapy has recently emerged as a powerful tool for the treatment of diverse advanced malignancies. In particular, therapeutic application of immune checkpoint modulators, such as anti-CTLA4 or anti-PD-1/PD-L1 antibodies, have shown efficacy in a broad range of malignant diseases. Although pharmacodynamics of these immune modulators are complex, recent studies strongly support the notion that altered peptide ligands presented on tumor cells representing neoantigens may play an essential role in tumor rejection by T cells activated by anti-CTLA4 and anti-PD-1 antibodies. Neoantigens may have diverse sources as viral and mutated proteins. Moreover, posttranslational modifications and altered antigen processing may also contribute to the neoantigenic peptide ligand landscape. Different approaches of target identification are currently applied in combination with subsequent characterization of autologous and non-self T-cell responses against such neoantigens. Additional efforts are required to elucidate key characteristics and interdependences of neoantigens, immunodominance, respective T-cell responses, and the tumor microenvironment in order to define decisive determinants involved in effective T-cell-mediated tumor rejection. This review focuses on our current knowledge of identification and characterization of such neoantigens as well as respective T-cell responses. It closes with challenges to be addressed in future relevant for further improvement of immunotherapeutic strategies in malignant diseases.

Author Info: (1) Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. (2) Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich

Author Info: (1) Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. (2) Medizinische Klinik III, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany. German Cancer Consortium of Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

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Intratumoral immunotherapy: using the tumor as the remedy

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Immune checkpoint-targeted monoclonal antibodies directed at Programmed Death Receptor 1 (PD-1), Programmed Death Ligand 1 (PD-L1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) are currently revolutionizing the prognosis of many cancers. By blocking co-inhibitory receptors expressed by antitumor T cells, these antibodies can break the immune tolerance against tumor cells and allow the generation of durable cancer immunity. Benefits in overall survival over conventional therapies have been demonstrated for patients treated with these immunotherapies, leading to multiple approvals of such therapies by regulatory authorities. However, only a minority of patients develop an objective tumor response with long-term survival benefits. Moreover, the systemic delivery of immunotherapies can be responsible for severe auto-immune toxicities. This risk increases dramatically with anti-PD(L)1 and anti-CTLA-4 combinations and currently hampers the development of triple combination immunotherapies. In addition, the price of these novel treatments is probably too high to be reimbursed by health insurances for all the potential indications where immunotherapy has shown activity (i.e. in more than 30 different cancer types). Intratumoral immunotherapy is a therapeutic strategy which aims to use the tumor as its own vaccine. Upon direct injections into the tumor, a high concentration of immunostimulatory products can be achieved in situ, while using small amounts of drugs. Local delivery of immunotherapies allows multiple combination therapies, while preventing significant systemic exposure and off-target toxicities. Despite being uncertain of the dominant epitopes of a given cancer, one can therefore trigger an immune response against the relevant neo-antigens or tumor-associated antigens without the need for their characterization. Such immune stimulation can induce a strong priming of the cancer immunity locally while generating systemic (abscopal) tumor responses, thanks to the circulation of properly activated antitumor immune cells. While addressing many of the current limitations of cancer immunotherapy development, intratumoral immunotherapy also offers a unique opportunity to better understand the dynamics of cancer immunity by allowing sequential and multifocal biopsies at every tumor injection.

Author Info: (1) Departement d'Innovation Therapeutique et d'Essais Precoces, Gustave Roussy, Universite Paris-Saclay, Villejuif. INSERM U1015, Gustave Roussy, Villejuif. CIC Biotherapie IGR Curie CIC1428, Gustave Roussy Cancer

Author Info: (1) Departement d'Innovation Therapeutique et d'Essais Precoces, Gustave Roussy, Universite Paris-Saclay, Villejuif. INSERM U1015, Gustave Roussy, Villejuif. CIC Biotherapie IGR Curie CIC1428, Gustave Roussy Cancer Center, Villejuif. (2) Departement de Radiologie, Gustave Roussy, Universite Paris-Saclay, Villejuif. (3) Departement de Radiologie, Gustave Roussy, Universite Paris-Saclay, Villejuif. (4) CHU Rennes, Service Hematologie Clinique, Rennes. INSERM U1236, Rennes, France.

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