Improving response durability after CAR T cell therapy for multiple myeloma

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PROJECT SUMMARY / ABSTRACT (PROJECT 3) Multiple myeloma (MM) is a hematologic malignancy of bone marrow plasma cells. Even though MM is almost universally fatal, modern therapy has markedly improved survival. Among the most promising new MM therapies are CAR T cells targeting B cell maturation antigen (BCMA). Despite high response rates in patients with advanced disease, however, almost all patients eventually relapse after current-generation anti-BCMA CAR T cells. This proposal furthers a long-term goal to prevent late relapse in MM patients after initial response to CAR T cell therapy. In most cases, BCMA expression is retained at relapse, suggesting loss of anti-BCMA immune surveillance as the primary mode of treatment failure. We and others have found that features of the T cells used for CAR T cell manufacturing predict clinical outcomes, that CAR T cells can occasionally proliferate at late timepoints post-infusion to control progressive disease, and that features of the bone marrow microenvironment predict relapse risk after anti-BCMA CAR T cells. This proposal undertakes new approaches to prevent late MM relapse after CAR T cell therapy; the approache to the clinical and pre-clinical studies is rooted in these prior observations. We will conduct a clinical trial to test the safety and feasibility of therapy with anti-BCMA CAR T cells manufactured from marrow-infiltrating lymphocytes (MIL) rather than the peripheral blood lymphocytes traditionally used in CAR T cell manufacturing. We hypothesize that the BM-homing capability of MILs will enhance trafficking and persistence of CAR T cells in BM. We will also pre-clinically develop two new approaches to modulate CAR T cell activity in vivo post infusion. (1) We will introduce a modified IL-2 receptor into CAR T cells to enable selective post-infusion in vivo stimulation with a pharmacologically administered and orthogonally modified IL-2 ligand (orthoIL2); we hypothesize that orthoIL2 can prevent late relapse by maintaining in vivo anti- BCMA immune surveillance. (2) We will develop BCMA-encoding mRNA-containing lipid nanoparticles (mRNA- LNPs) to present BCMA in the context of antigen-presenting cells outside the immunosuppressive MM microenvironment; we hypothesize that BCMA-encoding mRNA-LNPs can prolong in vivo anti-BCMA immune surveillance, providing an approach to post-infusion modulation of CAR T cell activity that could be rapidly and cost-effectively translated in combination with established, FDA-approved anti-BCMA CAR T cell therapies. Collectively, our proposed studies will generate clinical and pre-clinical data to support the development of early- phase clinical trials promising new approaches to prevent relapse after CAR T cell therapy for MM, which is the primary clinical problem facing the field. In addition, findings from our studies could be readily translated to other cancer types, including solid tumors.