Project 1: Targeting Resistance to T Cell-Directed Therapy in Multiple Myeloma

Tackling mechanisms of resistance

Both chimeric antigen receptor (CAR)-T cell and bispecific antibody (BsAb) as T cell-directed therapies have yielded impressive clinical responses in people with relapsed or refractory multiple myeloma and are now available as standard care.

However, the number of durable remissions continues to be low, and most people relapse in the first 1 to 3 years.

Uncovering the underlying mechanisms of resistance is critical to improving durable remission with T cell-directed therapies.

We have identified two novel T cell-extrinsic mechanisms of resistance for mechanistic studies and therapeutic development:

Myeloma cells have intrinsic resistance to killing by entering into a dormant state.
The myeloma microenvironment suppresses T cell activity via bone marrow cancer-associated fibroblasts (BM-CAFs).

Intrinsic resistence

We and others have shown that tumor cells can enter into a dormant, nongrowing state after exposure to chemotherapy and radiation. These cells exhibit features of increased signaling in senescent, antiapoptosis pathways, but they are not permanently senescent or growth arrested. They can then reenter into proliferation and contribute to disease relapse and progression.

Thus, this therapy-induced dormancy is a novel mechanism of tumor cell intrinsic resistance to therapy.

We found that myeloma cells can adopt this senescent and myeloid-like profile after treatment. Increased presence of these therapy-induced dormancy cells in the bone marrow before CAR-T cell infusion is associated with shorter progression-free survival after CAR-T cell therapy.

Suppressing T cell activity

In addition, our group recently published findings about a novel mechanism for resistance to CAR-T cells by BM-CAFs.

Specifically, our studies indicate that BM-CAFs from people with multiple myeloma significantly inhibit CAR-T cell function in preclinical models through complex mechanisms that involve secreting suppressive cytokines and expressing inhibitory and apoptosis proteins.

This information provides a rationale for directly targeting CAFs as a strategy to improve CAR-T cell therapy.

BM-CAFs in multiple myeloma express high levels of fibroblast-activating protein (FAP) and CS1, also known as SLAMF7. Targeting both multiple myeloma cells and BM-CAFs with dual BCMA-FAP CAR-T cells or BCMA-CS1 CAR-T cells is more potent than single-targeted BCMA-CAR-T cells and is resistant to inhibition by BM-CAFs.

Our additional preliminary studies demonstrate that dual targeting of multiple myeloma cells and BM-CAFs by CAR-T cells is safe in preclinical models. Our studies also show that targeting FAP can be enhanced by using BCMA-CAR-T cells, which secrete novel FAP-directed proteins.

Hypothesis

These preliminary data informed our central hypothesis that resistance to BCMA-CAR-T cell therapy is mediated by myeloma-intrinsic mechanisms through the therapy-induced dormant multiple myeloma cells and the tumor microenvironment through CAF-mediated T-cell inhibition.

We're examining the mechanisms through which myeloma cells resist killing by T cells via the therapy-induced dormancy state.

In addition, we're working to determine the mechanisms of BM-CAF-induced BCMA-CAR-T cell dysfunction and testing strategies to overcome this resistance.