Development of a Phase 1 Study Evaluating the Activity of Modular CAR T for Multiple Myeloma (MCARTY) Targeting BCMA and CD19 for Improved Persistence

BCMA directed CAR T cell therapy for multiple myeloma (MM) shows promise, but very long-term survival may be limited. Notably, BCMA CAR T persistence in MM is shorter than that seen in with CD19 CAR T cells in B cell malignancies where long-term CD19 CAR T persistence is associated with durable responses. Shorter BCMA CAR T persistence may be explained by the lower surface density of BCMA on tumour compared with that of CD19. Alternatively, CD19 CAR T persistence may be driven by recognition of continuous emergence of newly differentiated B cells. We sought to improve BCMA CAR T persistence by (a) developing a BCMA CAR with high sensitivity to BCMA, and (b) co-expression with a CD19 CAR. Notably, while CD19 is absent or expressed at low level on myeloma cells, CD19 may be expressed on a subpopulation of myeloma stem cells, providing an additional rationale for co-targeting CD19 in MM. We performed functional screening of several mid to high affinity BCMA binders in CAR format. We additionally explored whether a more stable CAR format would improve sensitivity. We explored co-expression of the new BCMA CAR with the CD19 CAR from obecabatagene autoleucel (also known as CAT19), which is known to drive long-term persistence. We also designed and started a clinical study (MCARTY, NCT04795882) testing the BCMA CAR alone or co-expressed with a CD19 CAR in patients with refractory Myeloma. The binding affinity for BCMA was determined for 13 antibody clones from a rat library, before being assessed functionally in single chain variable fragment (scFv) and fragment antigen-binding (Fab) formats in a second generation (41bbζ) CAR backbone. Noting superior target binding, functional efficacy and minimal basal activation of effector cells expressing the D8 binder in Fab format we then assessed this construct against standard BCMA targeting CARs based on the bb2121 and LCAR-B38M binders used in Ide-Cel and Cilta-Cel respectively. Compared to these competitor CARs, D8 demonstrated improved sensitivity to BCMA with improved activation, target kill, and cytokine release in a series of cocultures with plate bound antigen and cell targets expressing low level BCMA. Successful manufacture in an academic setting of dual targeting CAR T cells was achieved by double transduction of autologous CD4/CD8 selected T cells with separate lentiviral vectors titrated for equal transduction. Manufacture by CliniMACS Prodigy included AKT inhibitor VIII to reduce T cell differentiation and