Perumal et al. analyzed DNA and RNA sequencing data from 184 patients with newly diagnosed or relapsed multiple myeloma (MM). Mutations and predicted neoantigens were detected in both populations; both were more frequent in the relapsed subgroup. Although most mutations were private, shared neoantigens were identified in the NRAS, KRAS, and IRF4 oncogenic driver genes. In 3 patients with relapsed MM whose T cell responses were analyzed, neoantigen-specific T cell activation, TCR expansion, and cytotoxicity following immunotherapy (checkpoint blockade and others) + ASCT treatment was shown and led to clinical responses (including one CR).
PURPOSE: Somatic mutations in cancer cells can give rise to novel protein sequences that can be presented by antigen-presenting cells as neoantigens to the host immune system. Tumor neoantigens represent excellent targets for immunotherapy, due to their specific expression in cancer tissue. Despite the widespread use of immunomodulatory drugs and immunotherapies that recharge T and NK cells, there has been no direct evidence that neoantigen-specific T-cell responses are elicited in multiple myeloma. EXPERIMENTAL DESIGN: Using next-generation sequencing data we describe the landscape of neo-antigens in 184 patients with multiple myeloma and successfully validate neoantigen-specific T cells in patients with multiple myeloma and support the feasibility of neoantigen-based therapeutic vaccines for use in cancers with intermediate mutational loads such as multiple myeloma. RESULTS: In this study, we demonstrate an increase in neoantigen load in relapsed patients with multiple myeloma as compared with newly diagnosed patients with multiple myeloma. Moreover, we identify shared neoantigens across multiple patients in three multiple myeloma oncogenic driver genes (KRAS, NRAS, and IRF4). Next, we validate neoantigen T-cell response and clonal expansion in correlation with clinical response in relapsed patients with multiple myeloma. This is the first study to experimentally validate the immunogenicity of predicted neoantigens from next-generation sequencing in relapsed patients with multiple myeloma. CONCLUSIONS: Our findings demonstrate that somatic mutations in multiple myeloma can be immunogenic and induce neoantigen-specific T-cell activation that is associated with antitumor activity in vitro and clinical response in vivo. Our results provide the foundation for using neoantigen targeting strategies such as peptide vaccines in future trials for patients with multiple myeloma.
Author Info: (1) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New
Author Info: (1) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (2) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (3) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, New York. (4) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (5) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, New York. (6) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (7) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Center for Computational Immunology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (8) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (9) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (10) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (11) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, New York. (12) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (13) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (14) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Center for Computational Immunology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (15) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (16) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. (17) Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York. samir.parekh@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
