Journal Articles

Neoantigen-based therapy

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

Immune Surveillance by Natural IgM is Required For Early Neoantigen Recognition and Initiation of Adaptive Immunity

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Early recognition of neoantigen-expressing cells is complex, involving multiple immune cell types. In this study, in vivo, we examined how antigen-presenting cell (APC) subtypes coordinate and induce an immunological response against neoantigen-expressing cells, particularly in the absence of a pathogen-associated molecular pattern (PAMP), which is normally required to license APCs to present foreign or self-antigens as immunogens. Using two reductionist models of neoantigen-expressing cells and two cancer models, we demonstrated that natural IgM is essential for the recognition and initiation of adaptive immunity against neoantigen-expressing cells. Natural IgM antibodies form a cellular immune complex with the neoantigen-expressing cells. This immune complex licenses surveying monocytes to present neoantigens as immunogens to CD4+ T cells. Helper CD4+ T cells, in turn, use CD40L to license cross-presenting CD40+ Batf3+ dendritic cells to elicit a cytotoxic T cell response against neoantigen-expressing cells. Any break along this immunological chain reaction results in the escape of neoantigen-expressing cells. This study demonstrates the surprising, essential role of natural IgM as the initiator of a sequential signaling cascade involving multiple immune cell subtypes. This sequence is required to coordinate an adaptive immune response against neoantigen-expressing cells.

Author Info: (1) National Jewish Health, Denver, Colorado, United States. (2) National Jewish Health, Denver, Colorado, United States. (3) National Jewish Health, Pediatrics, Denver, Colorado, United States

Author Info: (1) National Jewish Health, Denver, Colorado, United States. (2) National Jewish Health, Denver, Colorado, United States. (3) National Jewish Health, Pediatrics, Denver, Colorado, United States. (4) National Jewish Health, 2930, Denver, Colorado, United States. (5) University of Colorado, Denver, Colorado, United States. (6) University of Colorado, Denver, Colorado, United States. (7) National Jewish Health, Pediatrics & Immunology, Denver, Colorado, United States. (8) National Jewish, Denver, Colorado, United States ; jakubzickc@njhealth.org.

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Complex pattern of immune evasion in MSI colorectal cancer

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Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation, and 54% of these mutations were predicted to abrogate function. Mutations affecting the HLA class I transactivator NLRC5 were observed as a potential new immune evasion mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in MMR-deficient cancers were associated with decreased levels of HLA class I antigen expression. In summary, the majority of MMR-deficient cancers display mutations interfering with HLA class I antigen presentation that reflect active immune surveillance and immunoselection during tumor development. Clinical studies focusing on immune checkpoint blockade in MSI cancer should account for the broad variety of immune evasion mechanisms as potential biomarkers of therapy success.

Author Info: (1) Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg

Author Info: (1) Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Germany. (2) Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Germany. (3) Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Germany. (4) Department of Applied Tumour Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Collaboration Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Germany.

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Cancer immunotherapy: broadening the scope of targetable tumours

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Cancer immunotherapy has experienced remarkable advances in recent years. Striking clinical responses have been achieved for several types of solid cancers (e.g. melanoma, non-small cell lung cancer, bladder cancer and mismatch repair-deficient cancers) after treatment of patients with T-cell checkpoint blockade therapies. These have been shown to be particularly effective in the treatment of cancers with high mutation burden, which places tumour-mutated antigens (neo-antigens) centre stage as targets of tumour immunity and cancer immunotherapy. With current technologies, neo-antigens can be identified in a short period of time, which may support the development of complementary, personalized approaches that increase the number of tumours amenable to immunotherapeutic intervention. In addition to reviewing the state of the art in cancer immunotherapy, we discuss potential avenues that can bring the immunotherapy revolution to a broader patient group including cancers with low mutation burden.

Author Info: (1) Department of Pathology, LUMC, Leiden, The Netherlands. (2) Department of Clinical Oncology, LUMC, Leiden, The Netherlands. (3) Department of Pathology, LUMC, Leiden, The Netherlands

Author Info: (1) Department of Pathology, LUMC, Leiden, The Netherlands. (2) Department of Clinical Oncology, LUMC, Leiden, The Netherlands. (3) Department of Pathology, LUMC, Leiden, The Netherlands n.f.de_miranda@lumc.nl.

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Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer

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Zacharakis et al. report a case of a patient with ER+HER- metastatic breast cancer, refractory to multiple lines of chemotherapy, who underwent autologous transfer of tumor-infiltrating lymphocytes that were enriched for neoantigen-specific T cells prior to infusion. The patient experienced complete and durable regression of all metastatic regions that is ongoing at >22 months after cell transfer.

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Zacharakis et al. report a case of a patient with ER+HER- metastatic breast cancer, refractory to multiple lines of chemotherapy, who underwent autologous transfer of tumor-infiltrating lymphocytes that were enriched for neoantigen-specific T cells prior to infusion. The patient experienced complete and durable regression of all metastatic regions that is ongoing at >22 months after cell transfer.

Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations-such as melanoma, smoking-induced lung cancers and bladder cancer-with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary(1-7). Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers(8-11). We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins-SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.

Author Info: (1) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD

Author Info: (1) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (3) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (4) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (5) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (6) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (7) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (8) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (9) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (10) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (11) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (12) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (13) Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. (14) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (15) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (16) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. sar@mail.nih.gov. (17) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (18) Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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Update on Tumor Neoantigens and Their Utility: Why It Is Good to Be Different

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Antitumor rejection by the immune system is a complex process that is regulated by several factors. Among these factors are the quality and quantity of mutational events that occur in cancer cells. Perhaps one of the most important types of mutations that influence antitumor immunity is the neoantigen, that is, a non-self-antigen that arises as a result of somatic mutation. Recent work has demonstrated that neoantigens hold significant promise for developing new diagnostic and therapeutic modalities. Therapeutic targeting of neoantigens is important for achieving benefit following therapy with immune checkpoint blockade agents or for cancer vaccines targeting mutations. Here, we review our understanding of neoantigens and discuss new developments in the quest to use them in cancer immunotherapy.

Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Gritstone Oncology, 5858 Horton Street, #210, Emeryville, CA 94608, USA

Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Gritstone Oncology, 5858 Horton Street, #210, Emeryville, CA 94608, USA. (3) Gritstone Oncology, 5858 Horton Street, #210, Emeryville, CA 94608, USA. (4) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chant@mskcc.org.

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Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome

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To characterize the immune profile of premalignant lesions, or polyps, in patients with the mismatch repair (MMR)-associated disease, Lynch Syndrome (LS), Chang et al. performed RNA sequencing on polyps from patients with LS and the non-MMR disease, familial adenomatous polyposis. Their analysis revealed an immune activated profile (CD4+ T cell infiltration, proinflammatory molecules, and checkpoint molecules) in LS premalignant polyps that was independent of mutational rates, neoantigen formation, or mismatch repair status, challenging the current paradigm.

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To characterize the immune profile of premalignant lesions, or polyps, in patients with the mismatch repair (MMR)-associated disease, Lynch Syndrome (LS), Chang et al. performed RNA sequencing on polyps from patients with LS and the non-MMR disease, familial adenomatous polyposis. Their analysis revealed an immune activated profile (CD4+ T cell infiltration, proinflammatory molecules, and checkpoint molecules) in LS premalignant polyps that was independent of mutational rates, neoantigen formation, or mismatch repair status, challenging the current paradigm.

Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS. Design, Setting, and Participants: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. Main Outcomes and Measures: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. Results: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling). Conclusions and Relevance: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS.

Author Info: (1) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer

Author Info: (1) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. (2) Department of Pathology, University of Texas MD Anderson Cancer Center, Houston. (3) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (4) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (5) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (6) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (7) Nouscom SRL, Rome, Italy. (8) Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston. (9) Nouscom SRL, Rome, Italy. (10) ReiThera SRL, Rome, Italy. (11) Department of Pathology, "Regina Elena" National Cancer Institute, Rome, Italy. (12) Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. (13) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. (14) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston. (15) Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston. (16) Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. (17) Nouscom SRL, Rome, Italy. CEINGE, Naples, Italy. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. (18) Nouscom SRL, Rome, Italy. (19) Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston. (20) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston. (21) Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston. Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston. Clinical Cancer Genetics Program, University of Texas MD Anderson Cancer Center, Houston. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston.

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The perfect personalized cancer therapy: cancer vaccines against neoantigens

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In the advent of Immune Checkpoint inhibitors (ICI) and of CAR-T adoptive T-cells, the new frontier in Oncology is Cancer Immunotherapy because of its ability to provide long term clinical benefit in metastatic disease in several solid and liquid tumor types. It is now clear that ICI acts by unmasking preexisting immune responses as well as by inducing de novo responses against tumor neoantigens. Thanks to theprogress made in genomics technologies and the evolution of bioinformatics, neoantigens represent ideal targets, due to their specific expression in cancer tissue and the potential lack of side effects. In this review, we discuss the promise of preclinical and clinical results with mutation-derived neoantigen cancer vaccines (NCVs) along with the current limitations from bioinformatics prediction to manufacturing an effective new therapeutic approach.

Author Info: (1) Takis, Rome, Italy. aurisicchio@takisbiotech.it. Biogem, Ariano Irpino, Italy. aurisicchio@takisbiotech.it. (2) UOSD SAFU, IRCSS Regina Elena National Cancer Institute, Rome, Italy. (3) Scientific Directorate, IRCCS

Author Info: (1) Takis, Rome, Italy. aurisicchio@takisbiotech.it. Biogem, Ariano Irpino, Italy. aurisicchio@takisbiotech.it. (2) UOSD SAFU, IRCSS Regina Elena National Cancer Institute, Rome, Italy. (3) Scientific Directorate, IRCCS Regina Elena National Cancer Institute, Rome, Italy. (4) Takis, Rome, Italy. Alleanza contro il Cancro, Rome, Italy.

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Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer

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A pilot clinical study of a new whole-cell tumor lysate dendritic cell vaccine showed that in addition to being well-tolerated, the vaccine induced a tumor antigen-specific and neoantigen-specific antitumor immune response in some patients with ovarian cancer. Patients who responded to therapy showed remission inversion and improved progression-free and overall survival. Patients who received the vaccine in combination with bevacizumab and pretreatment with cyclophosphamide were most likely to immunologically respond and benefit.

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A pilot clinical study of a new whole-cell tumor lysate dendritic cell vaccine showed that in addition to being well-tolerated, the vaccine induced a tumor antigen-specific and neoantigen-specific antitumor immune response in some patients with ovarian cancer. Patients who responded to therapy showed remission inversion and improved progression-free and overall survival. Patients who received the vaccine in combination with bevacizumab and pretreatment with cyclophosphamide were most likely to immunologically respond and benefit.

We conducted a pilot clinical trial testing a personalized vaccine generated by autologous dendritic cells (DCs) pulsed with oxidized autologous whole-tumor cell lysate (OCDC), which was injected intranodally in platinum-treated, immunotherapy-naive, recurrent ovarian cancer patients. OCDC was administered alone (cohort 1, n = 5), in combination with bevacizumab (cohort 2, n = 10), or bevacizumab plus low-dose intravenous cyclophosphamide (cohort 3, n = 10) until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccination induced T cell responses to autologous tumor antigen, which were associated with significantly prolonged survival. Vaccination also amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes. We conclude that the use of oxidized whole-tumor lysate DC vaccine is safe and effective in eliciting a broad antitumor immunity, including private neoantigens, and warrants further clinical testing.

Author Info: (1) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Department of Oncology, Lausanne University

Author Info: (1) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (3) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (4) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (5) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (7) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (8) Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (9) Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (10) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (11) Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. (12) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (13) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (14) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (15) Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (16) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (17) Immunogenetics Laboratory, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (18) Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. (19) Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. (20) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (21) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA. (23) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (24) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (25) Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (26) Laboratory of Biostatistics, School of Health Sciences, National and Kapodistrian, University of Athens, Athens, Greece. (27) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. Swiss Institute of Bioinformatics, Lausanne CH-1015, Switzerland. (28) Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (29) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland. (30) Ovarian Cancer Research Center, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. lana.kandalaft@chuv.ch. Department of Oncology, Lausanne University Hospital, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne CH-1066, Switzerland.

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Personalized vaccines for cancer immunotherapy

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Cancer is characterized by an accumulation of genetic alterations. Somatic mutations can generate cancer-specific neoepitopes that are recognized by autologous T cells as foreign and constitute ideal cancer vaccine targets. Every tumor has its own unique composition of mutations, with only a small fraction shared between patients. Technological advances in genomics, data science, and cancer immunotherapy now enable the rapid mapping of the mutations within a genome, rational selection of vaccine targets, and on-demand production of a therapy customized to a patient's individual tumor. First-in-human clinical trials of personalized cancer vaccines have shown the feasibility, safety, and immunotherapeutic activity of targeting individual tumor mutation signatures. With vaccination development being promoted by emerging innovations of the digital age, vaccinating a patient with individual tumor mutations may become the first truly personalized treatment for cancer.

Author Info: (1) Biopharmaceutical New Technologies (BioNTech) Corporation, 55131 Mainz, Germany. sahin@uni-mainz.de. TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, 55131 Mainz, Germany

Author Info: (1) Biopharmaceutical New Technologies (BioNTech) Corporation, 55131 Mainz, Germany. sahin@uni-mainz.de. TRON-Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, 55131 Mainz, Germany. University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany. (2) CI3 Cluster for Individualized Immunointervention e.V., 55131 Mainz, Germany.

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Targeting Neoantigens for Personalised Immunotherapy

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This review discusses the rapidly evolving field of immunotherapy research, focusing on the types of cancer antigens that can be recognised by the immune system and potential methods by which neoantigens can be exploited clinically to successfully target and clear tumour cells. Recent studies suggest that the likelihood of successful immunotherapeutic targeting of cancer will be reliant on immune response to neoantigens. This type of cancer-specific antigen arises from somatic variants that result in alteration of the expressed protein sequence. Massively parallel sequencing techniques now allow the rapid identification of these genomic mutations, and algorithms can be used to predict those that will be processed by the proteasome, bind to the transporter complex and encode peptides that bind strongly to individual MHC molecules. The emerging data from assessment of the immunogenicity of neoantigens suggests that only a minority of mutations will form targetable epitopes and therefore the potential for immunotherapeutic targeting will be greater in cancers with a higher frequency of protein-altering somatic variants. It is evident that neoantigens contribute to the success of some immunotherapeutic interventions and that there is significant scope for specific targeting of these antigens to develop new treatment approaches.

Author Info: (1) Genetics and Immunology Research Group, An Lochran, 10 Inverness Campus, Inverness, IV2 5NA, Scotland, UK. antonia.pritchard@uhi.ac.uk.

Author Info: (1) Genetics and Immunology Research Group, An Lochran, 10 Inverness Campus, Inverness, IV2 5NA, Scotland, UK. antonia.pritchard@uhi.ac.uk.

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