Novel targeted CAR-T multiple myeloma therapy

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PROJECT SUMMARY Multiple myeloma (MM), a malignancy of plasma cells (PCs), is responsible for over 12,500 deaths in the US and over 117,000 deaths worldwide annually. Over 91,000 individuals in the US and over 300,000 worldwide currently live with MM. In spite of major therapeutic advances in the past two decades, MM remains incurable and most MM patients succumb to the underlying malignancy. Recent therapies redirecting T cells via chimeric antigen receptor-T cells (CAR-Ts) or bispecific antibodies that target B Cell Maturation Antigen (BCMA) have significantly improved survival of patients with disease refractory to prior therapies. However, nearly all MM patients experience disease progression and become refractory to these BCMA-targeted T cell therapies. There is therefore an urgent unmet need to develop new targets for these potent T cell-directed MM therapies. This phase 1 SBIR application addresses that need with a novel monoclonal antibody (mAb) designated MM3. MM3 belongs to a new class of antibodies, Variable Lymphocyte Receptor B (VLRB) antibodies produced by the B cells of jawless vertebrates, lamprey and hagfish, and specifically binds to a distinctive form of a well-validated MM therapeutic target, multimeric forms of the CD38 cell surface protein, with no detectable binding to CD38 monomers. CD38 multimers are uniquely expressed by PCs and MM tumors, whereas CD38 monomers are expressed by numerous other normal cell types, including NK and T cell immune effectors. CAR-T cells that utilize MM3 as target recognition domain therefore avoid potential “on-target/off-tumor” toxicity associated with binding to monomeric CD38, “fratricide” among CAR-T cells that express both monomeric CD38 and CAR antigen binding domains that bind monomeric CD38, and depletion of NK and T cell immune effectors. Multimeric CD38 is highly expressed by the tumor cells of relapsed-refractory MM (RRMM) patients refractory to proteasome and/or immunomodulator drugs. Although downregulation of CD38 expression is one of several mechanisms of resistance to anti-CD38 mAb therapy, e.g., daratumumab, high levels of CD38 and multimeric CD38 expression return within 3 to 6 months of anti-CD38 mAb therapy discontinuation, and MM tumor cells of over 87% of RRMM patients express high levels of CD38 multimers detected with MM3. MM3 human CAR-T cells have been produced and shown with in vitro assays to direct CAR-T killing only to cells that express multimeric CD38. This application will extend those results by: (1) producing MM3 CAR-T cells with T cell preparations derived from healthy human volunteers and from patients relapsed following anti-BCMA CAR-T therapy and evaluating in vitro target-specific activation and cytotoxicity against a MM cell line and autologous MM tumor cells from anti-BCMA CAR-T relapsed MM patients, and (2) evaluating the in vivo anti-tumor efficacy of MM3 CAR-T cells with MISTRG6 “humanized” mice engrafted with a human MM tumor cell line. These phase 1 studies will be followed by phase 2 in vivo evaluations of MM3 CAR-Ts produced with RRMM patient T cells against tumors from those same patients in the MISTRG6 model and by GMP production of MM3 CAR lentivirus and MM3 CAR-T cells, and IND-enabling pharmacology/toxicology studies to support first in human clinical trials of this new CAR-T therapy for MM patients that have failed all other therapies.