High-dimensional analysis of the T cell response in multiple myeloma and the potential efficacy of harnessing tumor-reactive CD8 T cells

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Abstract Multiple myeloma is an incurable malignancy of plasma cells in the bone marrow increasingly being treated by immunotherapies with improved response and survival over traditional chemotherapy, however an unexplored potential immunotherapy is the adoptive transfer of tumor-specific CD8+ T cells. Here, we investigated the tumor-specific CD8+ T cell response in highly progressed multiple myeloma patients. We predicted neoantigens and tumor-associated antigens for each patient and grew out tumor-specific CD8 T cells from patient TIL’s using autologous B cells loaded with the predicted epitopes. We then utilized TetTCR-SeqHD, a high-throughput tetramer-based workflow, to isolate paired tumor-specific T cell receptor (TCR) sequence and antigen specificities. We subsequently transduced and functionally validated these TCR specificities and their cytotoxicity in vitro. In addition, we performed single-cell transcriptomic and proteomic analyses on TIL’s and peripheral blood T cells before and after immunomodulatory treatment to capture high-dimensional data on the cellular states of the T cell response and their response to stimulation. We observed T cells within the tumor were largely exhausted, but that patients had neoantigen-specific CD8+ T cell populations present responding to a broad array of antigens suggesting adoptive transfer of tumor-specific CD8 T cells is potentially efficacious. Last, we measured TCR repertoire changes and identified T cell clones that had expanded. We also found a number of peripheral blood T cells markers that correlated with treatment response in our patients. Next, we aim to transfer transduced tumor-specific T cells into PDX mouse models to measure preclinical therapeutic potential. Supported by grants from CRI-STAR and NIH R01