Abstract B100: Development of fargeted multiple myeloma cancer vaccine and antigen-specific T-cell immunotherapy using novel Immunogenic-engineered heteroclitic BCMA peptides
Authors: Bae Jooeun , Hideshima Teru , Tai Yu-Tzu , Munshi Nikhil , Anderson Kenneth 
Published: February 2019

Abstract
Background: Multiple myeloma (MM), the second most common hematologic malignancy in the US, is characterized by the proliferation and accumulation of clonal malignant plasma cells in the bone marrow, associated with hypercalcemia, renal dysfunction and bone disease. Despite recent advances in treatment including novel therapeutics in combination with transplantation, MM still remains incurable. We have recently developd a highly immunogenic HLA-A2-specific multipeptide cancer vaccine targeting XBP1 (X-box binding protein 1), CD138 (Syndecan-1) and CS1 (SLAMF7) antigens. In both pre-clinical studies and Phase 1/2a clinical trials in patients with smoldering multiple myeloma and triple negative breast cancer, vaccination with this multi-peptide based cancer vaccine induced antigen-specific and Th1-type anti-tumor immune responses, which were maintained for long-term within tetramer+/memory (CD45RO+) CD8 cytotoxic T lymphocytes (CTL). The immune responses were further enhanced in patients who received vaccination in combination with lenalidomide or checkpoint inhibitor. To allow for vaccination against additional tumor-associated antigens, we have recently investigated B Cell Maturation Antigen (BCMA), a cell surface antigen restricted to MM and normal plasma cells, as well as accessory dendritic cells. As the receptor for binding of B cell activating factor (BAFF) and of a proliferation-inducing ligand (APRIL), BCMA promotes MM cell growth, drug resistance, as well as survival of long lived plasma cells. Due to its restricted expression pattern, targeting of this antigen with antibodies, immunotoxins, and CAR T-cells is already ongoing in MM at present. Objective: We aimed to identify immunogenic BCMA peptides in order to generate antigen-specific CD8+ effector cytotoxic T lymphocytes against MM cells. Findings: We identified novel immunogenic HLA-A2 native and engineered heteroclitic BCMA peptides that induce tumor-specific CTL against MM. The engineered heteroclitic BCMA72-80 and BCMA54-62 peptides have improved HLA-A2 binding affinity and stability compared to their native BCMA72-80 and BCMA54-62 peptides. In preclinical studies, each of the heteroclitic BCMA peptide induced antigen specific CTL, which expressed increased T-cell activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecules. The engineered heteroclitic BCMA72-80 triggered a more robust immune response than BCMA54-62 peptide, associated with increased HLA-A2 binding affinity and stability. Importantly, the heteroclitic BCMA72-80 peptide-specific CTL induced selective and robust proliferative and cytolytic activities in response to MM patients’ tumor cells. Specifically, these tetramer+ CD8+ CTL demonstrated HLA-A2-restricted immune responses against MM, associated with CD107a degranulation, proliferation, Th-1 cytokine (IFN-γ/IL-2/TNF-α) cytokine production, perforin/granzyme B up-regulation, and increased 41BB expression. Furthermore, the heteroclitic BCMA72-80 peptide has demonstrated its immunogenicity through development central memory and effector memory CTL, which showed polyfunctional antitumor activities against MM including patients’ primary tumor cells and cell lines. This novel engineered heteroclitic BCMA72-80 peptide may therefore be useful for generation of antigen-specific and tumor-selective CTL in MM. Significance: We have identified BCMA-specific native and engineered heteroclitic peptides which induce BCMA antigen specific CD8+ CTL with robust anti-MM activity. This immunogenic BCMA peptide will be utlized in clinical protocols of vaccination and/or adoptive T-cells immunotherapy to trigger antigen-specific central and effector memory CTL anti-MM immunity.
Citation Format: Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Nikhil Munshi, Kenneth Anderson. Development of fargeted multiple myeloma cancer vaccine and antigen-specific T-cell immunotherapy using novel Immunogenic-engineered heteroclitic BCMA peptides [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B100.