T cell-based therapies (both bispecific T cell engagers (TCE) and chimeric antigen-receptor-T (CAR-T) have led to impressive rates of tumor regression in myeloma (MM). However, MM patients remain at risk of recurrent disease and require long-term therapy, indicating an unmet need to achieve unmaintained responses and cures. This proposal involves collaboration between investigators with expertise in MM immunobiology (MVD) and T cell therapy (PG). The underlying hypothesis is that the inability of current therapies to fully eradicate a distinct subpopulation of tumor cells and prevent tumor repopulation underlies the lack of curative potential. We posit that specific immune targeting of tumor compartments with repopulation potential and stemness pathways will be key to achieving durable unmaintained tumor regressions and cures. Current T cell therapies do not target these compartments or the underlying “stemness” pathways, which may underlie the risk of recurrence. These pathways are particularly relevant for high-risk MM subtypes such as t(4:14), which exhibit altered B cell differentiation and distinct epigenetic alterations. We will pursue preclinical studies that will identify optimal approaches for novel T cell therapies as well as T cell engagers (TCE) to target persister cells and stemness pathways in MM and set the stage for first-in-human trials of novel T cell therapies as well as T cell engagers (TCE). These studies will have direct implications to improve immunotherapy in MM but may also provide new approaches for other cancers and autoimmune diseases.
Targeting Long-lived and Persister Compartment in t(4:14) MM with new T Cell Engagers
Madhav V. Dhodapkar, MBBS
Professor
Fred Hutch Cancer Center
Kavita M. Dhodapkar, MBBS
Professor
Fred Hutch Cancer Center
Studies in the Dhodapkar lab will characterize immune alterations in patients with t(4:14) myeloma, particularly in the context of antigen-specific immunity and underlying aging-associated immune alterations. These will build on these studies to evaluate T cell redirection with bispecific T cell engagers in preclinical models. The underlying hypothesis is testing the capacity of these T cell engagers to target persister cells.
Targeting myeloma stem cells and eradicating disease with engineered T cells specific for SOX2
Dr. Phil Greenberg
Professor
Fred Hutch Cancer Center
Current therapies for MM can now produce dramatic responses, but ultimately most of even the best responders can be expected to relapse and progress. This in large part may reflect the failure of these therapies to target myeloma stem cells, which can repopulate the tumor and ultimately lead to resistance. Stem cells require expression of a distinct set of specific genes to sustain their stem-like state, and one of these genes is SOX2, which has been linked to oncogenesis and cancer stem cells, with over-expression detected in more than 20 human malignancies, and is generally associated with a worse prognosis and chemotherapy resistance. We have generated T cells that can recognize SOX2 and propose to isolate a high affinity TCR that we will use to engineer T cells for a new cellular therapy of myeloma. We will use synthetic biology to impart these T cells with novel properties that enhance function and will evaluate activity in preclinical models to optimize design before advancing the approach to clinical trials.