Development TACI and Bcma Dual-Antigen Targeted Immunotherapy for Multiple Myeloma

Introduction: Despite recent advances in treatment for multiple myeloma(MM), there remains a need for novel therapeutic approaches. Recently, we have reported that antigen-specific CD8⁺ cytotoxic T lymphocytes (CTL) with anti-MM activity can be induce by immunogenic peptides to XBP1 (X-box binding protein 1), CD138 (Syndecan-1) and CS1 (SLAMF7). Based on these results, multicenter Phase 1/2a trials are completed in patients with smoldering multiple myeloma (SMM) (JAMA Oncol.2018) and on-going in patients with SMM or triple negative breast cancer, alone and in combination with checkpoint inhibitors, lenalidomide, and HDAC6 inhibitor. We here expand the breadth and extent of MM-specific immunotherapies by targeting additional tumor-associated antigens, including B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), TNF receptor family proteins which are involved in maturation of B-cells and highly expressed in MM. Purpose: We aim to develop a dual antigen targeted immunotherapeutic approach to induce central memory-specific anti-MM immunity and improve patient outcome. Results: We demonstrated that engineered BCMA_72-80 (YLMFLLRKI) and BCMA_54-62 (YILWTCLGL) peptides can evoke BCMA-specific CTL and their specific activities against MM (Bae et al. 2019). Here, we report the identification of a novel heteroclitic TACI peptide with improved HLA-A2 binding/stability compared to the native TACI peptides. The heteroclitic TACI peptide induces antigen-specific memory CD8⁺ CTL with robust anti-tumor activities (CD107a degranulation, Granzyme B upregulation, Th1 cytokine production) against HLA-A2⁺ MM (U266, McCAR) cells, but not against HLA-A2^- MM (OPM2, RPMI) nor HLA-A2⁺ breast cancer (MDA-MB231) cells. In response to HLA-A2⁺ MM cells, the heteroclitic TACI peptide-specific CTL showed the antigen-specific proliferation of CD8⁺ CTL expressing costimulatory molecules (CD28 > 41BB > CD40L), which was directly associated with functional anti-tumor activity. These results suggest that the heteroclitic TACI peptide identified is a potential novel therapeutic option to effectively generate TACI-specific CD8⁺ memory CTL targeting MM. In on-going studies, we are evaluating a combination of immunogenic heteroclitic peptides specific to BCMA and TACI to induce highly functional antigen-specific immune responses by CD8⁺ Tc and CD4⁺ Th cells to efficiently target tumor cells. Conclusions: A novel heteroclitic TACI peptide can induce MM-specific central memory CD8⁺ CTL with robust poly-functional anti-tumor activities. These results provide the framework for therapeutic application targeting combination TACI and BCMA antigens in MM patients, alone and in combination with checkpoint inhibitors, epigenetic regulators and immune modulators, to both enhance anti-MM immunity and improve patient outcome.