Bone Marrow Mesenchymal Stromal Cells can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis.

Purpose: The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSCs) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTLs) and daratumumab-redirected NK cells through the upregulation of anti-apoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune-escape on T cells engineered to express chimeric antigen receptors (CAR T cells). Experimental Design: We tested the cytolytic ability of a panel of ten BCMA-, CD38- and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in presence versus absence of BMMSCs. Results: While BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38- and CD138-specific CAR T cells in a cell-cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of co-stimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of anti-apoptotic proteins Survivin, Mcl-1, and XIAP. Conclusions: These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggests that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of anti-apoptotic proteins upregulated in MM cells through BMMSC interactions.