The Role of Diffuse Large B-Cell Lymphoma Genome Complexity in Shaping Immune Responses to Anti-CD19 Chimeric Antigen Receptor T-Cell Therapies
Abstract
This proposal addresses the fiscal year 2022 Peer Reviewed Cancer Research Program (PRCRP) Topic Area: Lymphoma; and Military Health Focus Area: Gaps in Cancer Research That May Affect Mission Readiness. Lymphomas are cancers arising from B- and T-lymphocytes that are key components of the immune system. Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, affecting 25,000 Americans annually, including many patients of active military age. This aggressive, rapidly progressive malignancy inherently prevents mission readiness for any affected Service Member. Cure is achieved for many DLBCL patients with aggressive frontline treatment combining multiple chemotherapy agents and monoclonal antibodies. Many other patients, however, require additional treatments for relapsed or refractory (rel/ref) disease. Unfortunately, a majority of rel/ref DLBCL patients are failed by currently available therapies and will die from their disease. A new kind of immunotherapy called chimeric antigen receptor (CAR) T cells is radically reshaping our approach to rel/ref DLBCL, able to produce long-term remissions in about 40% of those treated. Reasons for CAR-T treatment failures, however, remain incompletely understood. CAR-T cells are derived from each patient s own immune system, and it is known that dysfunction of these cells is a reason for treatment failure in some patients. Many treatment failures are not explained by these factors, however, and in particular the ways by which lymphoma tumors themselves are able to avoid clearance by CAR-T cells is poorly understood. We recently undertook the first ever comprehensive look at genomic factors in DLBCL tumors treated with CAR-T cells. We employed whole-genome sequencing, which allowed us to investigate acquired genomic changes in tumors that are missed by other techniques. In particular, complex changes of tumor DNA such as rearrangements of chromosomes and fingerprints left behind in DNA by particular mutational processes were captured by our sophisticated techniques, fueled by the particular expertise of our investigative team. We found specific genomic changes associate very strongly with CAR-T treatment failures, demonstrating that tumor-intrinsic factors are key mediators of responses. Mechanisms by which this occurs, however, remain to be determined. In this proposal we will identify how specific mutational patterns in DLBCL genomes prevent CAR-T efficacy. Specifically, we will more clearly define genomic patterns associated with poor CAR-T responses and cross-compare their effects on additional treatment options available to these patients. We also will determine the way in which genomic factors lead to reprogramming of the immune cells that infiltrate DLBCL tumors, which are key drivers of both response and resistance to CAR-T therapy. Finally, we will employ sophisticated laboratory systems including accurate animal models to define the specific mechanisms that mediate outcomes so that new therapies able to overcome resistance can be developed on a more rational basis. Patients affected by this project are all those not cured by frontline DLBCL therapy, because CAR-T treatments are now available to increasing numbers of patients but need to be made to work long term for more than 40% of those treated. Immediate benefits to patients include bringing forward specific factors readily identifiable in tumors that allow clinicians to best identify those patients likely to be failed by CAR-T cells so that alternative approaches can be pursued instead. Over a longer term, we expect to inform development of novel therapies able to overcome the resistance mechanisms we characterize. The Overarching Challenge addressed by this proposal is Therapeutics: Advance Immunotherapy Across the Different PRCRP Topic Areas. CAR-T therapies are either available or under development for multiple additional malignancies. We expect the results of this proj
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310750
Entities
People
- Jonathan Schatz
Organizations
- United States Army
- University of Miami