Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma

Abstract

Pivotal clinical trials of B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent FDA approval. Despite their success, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART-cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We demonstrated that CAFs inhibit CART-cell anti-tumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and SLAMF7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, we generated CART cells targeting both MM cells and CAFs. Our dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We demonstrate for the first time that dual targeting both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.

CAR T cell therapy and the tumor microenvironment: Current challenges and opportunities

“…30 It has been demonstrated that CAFs inhibit CAR T cell functions in preclinical models through complex multi-directional mechanisms that involve TGF-b as well contact cell-to-cell-mediated mechanisms. 31 Another major physical constraint that leads to T cell exclusion from the TME is the aberrant vasculature of solid tumors that contributes to tissue hypoxia and limits T cell extravasation into the TME. Hypoxia promotes recruitment of immunosuppressive cells through secretion of various chemokines but also upregulates expression of CTLA4 or lymphocyte activation gene 3 protein (LAG3) on regulatory T (Treg) cells and programmed cell death 1 (PD-1) ligand 1 (PD-L1) on myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor cells.…”

“…83 Recently, it was reported that SLAMF7 is expressed on CAFs and that targeting SLAMF7 in combination with targeting tumor cells is a potential strategy to reverse TME-induced CAR T cell inhibition. 31…”

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

“…Interestingly, other CAR-NK cell strategies take advantage of the ligand shared expression between cancer cells and MDSCs, such as NKG2D-CAR-NK cells and PD-L1-CAR-NK cells that can kill both cell types ( 285 , 286 ). Similarly, dual FAP/SLAMF7-CAR-T therapies are novel approaches for targeting CAFs, surmounting the suppressor function of these cells over CAR effectors, and eliminating MM cells at the same time ( 287 ). Meanwhile, TAM-specific CAR-T cells, targeting folate receptor β (FRβ), reduce the number of TAMs in the TME while decreasing tumor cells’ proliferation rate.…”

Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors

“…Recently, cancer-associated fibroblasts were shown to inhibit CAR T-cell anti-MM activity and to promote MM progression. At the same time, novel CAR T-cells targeting both MM cells and cancer-associated fibroblasts significantly improved the effector functions of CAR T-cells in MM and represent novel strategy to overcome CAR T-cell therapy resistance ( 325 ).…”