Immunogenomics to decipher mediators of resistance to immune-mediated therapies in Multiple Myeloma

Aim/goals:

We will interrogate the genome of Multiple Myeloma (MM) cells and the tumor microenvironment of patients treated with immune-based therapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BITEs) to elucidate tumor- and immune-mediated causes of resistance.

• Aim1: Establish at the single cell level the transcriptomic, immunophenotypic and epigenomic “dictionary” of myeloma infiltrating immune cells (T cells) and their interactome with tumoral cells in patients treated with immune-based therapies.
• Aim 2: Define the TCR repertoire, clonotypic diversity and the dynamics of antigen-dependent responses associated with T cell clonal expansion in MM patients treated with immune-based therapies.

Summary:

Immune-based therapies have demonstrated very encouraging responses in heavily pre-treated multiple myeloma (MM) patients. However, the cellular and molecular predictors of clinical response are not fully understood as well as the mediators of acquired resistance remain elusive. In this proposal, we aim to delve deeper into the molecular and cellular crosstalk between MM cancer cells and the immune microenvironment to elucidate the immune-mediated causes of resistance, identify potential means to reverse tolerance, and help propagate an anti-tumor specific memory T-cells immunity. The data generated from this project could guide the selection of combination therapies, minimize the use of ineffective therapeutics, and support future T cells engineering studies to enhance the efficacy and durability of immunotherapy in MM. While this proposal will be mainly centered on the study of symptomatic MM, we anticipate that the approaches and deliverables are in large transferable and adaptable to other hematological malignancies where novel immune-based strategies are currently used.