Mapping antigen-specific T-cell clonotypes that sustain durable response to T-cell Engager Therapy for Multiple Myeloma

Bispecific T cell engagers such as elranatamab have transformed outcomes for patients with relapsed refractory myeloma but localizing and activating T cells into the tumor bed and harnessing the power of the immune system to eliminate disease. They bring together activated T cells with myeloma cells expressing a target protein. While most patients will exhibit profound disease reduction, the durability of the response is variable and curative outcomes remain elusive. Discovering how non-specific activation of the immune system by these powerful agents leads to sustained tumor control in a subset of patients is a critical unmet need to better tailor these therapies. In the present project, we will explore the novel hypothesis that durable responses to bispecific T cell engagers are dependent on the secondary activation of tumor specific immune cells that recognize antigenic targets on the myeloma cell and the creation of long-term memory that may act as a barrier to prevent relapse. In a comparative analysis of patients who experience durable as compared to transient responses, we will interrogate the tumor microenvironment to quantify the number of cancer specific T cell clones that emerge with therapy. Using single cell genomics, we will isolate the pattern of the receptors of these expanded T cells and map their presence within the tumor bed using state of the art spatial technologies. Using an elegant genomic framework that we have developed, we will examine each myeloma cell within the biopsy specimens to distill out the unique cancer related targets that are created by mutations and other genetic changes that are present in the malignant cells. We will then pair the dominant T cell receptors with each of the antigen targets to determine which responses are important for driving longer term protection from relapse. Finally, we will verify the targets being recognized by genetically inserting the receptors into T cells that are co-culture with antigen expressing tumors. In an animal model, we will examine whether the addition of these specific T cells in conjunction with bispecific T cell engagers are able to more effectively fully eradicate cancer. This information will fundamentally expand our understanding of how the immune system interacts with myeloma cells, what targets and associated T cell clones are functionally most important, and allow for the incorporation of specifically targeted immune therapies to complement bispecific T cell engagers to enhance responses and potentially result in long term cures.