Nanobody-based IL-18-armored BCMA/BAFF-R dual-CAR T Cells to Overcome Treatment Failure in Multiple Myeloma

Description

We have recently evaluated IL-18-secreting dual-CAR T cells targeting BCMA and BAFF-R in a syngeneic mouse model of multiple myeloma as a comprehensive approach to simultaneously overcome multiple CAR T cell failure mechanisms. Engineered IL-18 secretion by BCMA and BAFF-R-targeting CAR T cells enabled elimination of antigen-low myeloma, stimulated macrophage killing of myeloma cells, activated the myeloma immune microenvironment, and enhanced NFkB signaling to promote T cell survival and function. Importantly, this high activity was achieved without toxicity in syngeneic mice, suggesting safety of this approach. Towards the goal of clinical translation and simplifying our design into a single vector approach, we have generated and validated nanobody-based CAR T cells targeting human BCMA and BAFF-R. We now plan to optimize dual-targeting BCMA/BAFF-R nanobody-based CAR T cells in dual-CAR and tandem-CAR formats and pair these CAR configurations with engineered IL-18 secretion. We hypothesize that CAR T cells generated with a compact, tandem-nanobody-CAR encoded by a single vector design will overcome antigen-low escape, heterogeneous target antigen expression, and the immune suppressive myeloma microenvironment.