Journal Articles

Neoantigen-based therapy

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

Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome

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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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Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow

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Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides. We employ IPAW to analyze two proteomics data sets acquired from A431 cells and five normal human tissues using extended (pH range, 3-10) high-resolution isoelectric focusing (HiRIEF) pre-fractionation and TMT-based peptide quantitation. The IPAW results provide evidence for the translation of pseudogenes, lncRNAs, short ORFs, alternative ORFs, N-terminal extensions, and intronic sequences. Moreover, our quantitative analysis indicates that protein production from certain pseudogenes and lncRNAs is tissue specific.

Author Info: (1) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (2) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska

Author Info: (1) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (2) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (3) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (4) Department of Biochemistry and Biophysics, The Arrhenius Laboratories for Natural Sciences, Science for Life Laboratory, Stockholm University, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (5) Department of Oncology-Pathology, NBIS (National Bioinformatics Infrastructure Sweden), Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (6) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (7) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. (8) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. rui.mamede-branca@ki.se. (9) Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Tomtebodavagen 23A, 171 65, Stockholm, Sweden. janne.lehtio@ki.se.

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Anti-cancer vaccine therapy for hematologic malignancies: An evolving era

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The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity.

Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: mnahas1@bidmc.harvard.edu. (2) Department of Medicine, Beth Israel Deaconess Medical Center, Boston

Author Info: (1) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. Electronic address: mnahas1@bidmc.harvard.edu. (2) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. (3) Department of Medicine, Case Western Reserve University, Cleveland, OH, USA. (4) Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

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Temozolomide-associated Hypermutation in Gliomas

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Low-grade gliomas cause considerable morbidity and most will recur after initial therapy. At recurrence, low-grade gliomas can undergo transformation to high-grade gliomas (grade III or grade IV), which are associated with worse prognosis. Temozolomide (TMZ) provides survival benefit in patients with glioblastomas (GBMs) but its value in patients with low-grade gliomas is less clear. A subset of TMZ-treated, IDH-mutant, low-grade astrocytomas recur as more malignant tumors with thousands of de novo, coding mutations bearing a signature of TMZ-induced hypermutation. Preliminary studies raise the hypothesis that TMZ-induced hypermutation may contribute to malignant transformation, although with highly variable latency. On the other hand, hypermutated gliomas have radically altered genomes that present new opportunities for therapeutic intervention. In light of these findings and the immunotherapy clinical trials they inspired, how do patients and providers approach the risks and benefits of TMZ therapy? This review discusses what is known about the mechanisms and consequences of TMZ-induced hypermutation and outstanding questions regarding its clinical significance.

Author Info: (1) Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA. (2) Department of Radiation Oncology, University of California, San Francisco, San Francisco

Author Info: (1) Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA. (2) Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA. (3) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA. (4) Samaritan Pastega Regional Cancer Center, Corvallis, OR. (5) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA. (6) Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA.

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A Recurrent Mutation in Anaplastic Lymphoma Kinase with Distinct Neoepitope Conformations

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The identification of recurrent human leukocyte antigen (HLA) neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction of T Cell Epitopes for Cancer Therapy, to analyze sequencing data from neuroblastoma patients and identify a recurrent anaplastic lymphoma kinase mutation (ALK R1275Q) that leads to two high affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self-epitope is excluded from binding due to steric hindrance in the MHC groove. To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. Subsequent determination of the X-ray structure of an HLA-A*01:01 bound neoepitope validates atomic features seen in our Rosetta models with respect to key residues relevant for MHC stability and T cell receptor recognition. Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. This work provides a rational approach toward high-throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy.

Author Info: (1) Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. (2) Department of Biomolecular Engineering, University of California, Santa

Author Info: (1) Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. (2) Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States. (3) Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. (4) Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States. (5) Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. Department of Computer Science, University of California, Santa Cruz, Santa Cruz, CA, United States. (6) Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. (7) Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, United States. (8) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. (9) Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States. (10) Division of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, United States. (11) Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States. Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA, United States. (12) Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States. Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA, United States. (13) Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, United States.

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Therapeutic cancer vaccines: From initial findings to prospects

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With the approval of the first therapeutic cancer vaccine by US Food and Drug Administration, numerous therapeutic cancer vaccines have been under clinical trials with an inspiring antitumor immune response in cancer patients. Though there is no therapeutic cancer vaccine showing clinical efficacy in phase III trials, recent advances in personalized cancer vaccine based on neoantigens have emerged as an efficient way to induce tumor regression. In this review, we discuss the selection methods of tumor specific antigen and mainly focus on the development of therapeutic cancer vaccine strategies. Besides, we highlight the newly developed personalized cancer vaccine as a novel therapeutic approach for cancer patients. Finally, we outline the recent development of therapeutic cancer vaccine in clinical trials.

Author Info: (1) Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 13

Author Info: (1) Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China. Electronic address: sqoxaid@163.com. (2) School of Life Sciences, Fudan University, Shanghai 200032, China. Electronic address: izhangcd@163.com. (3) Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China. Electronic address: wuxianghua2018@163.com.

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