Developing adoptive T cell therapy for lung adenocarcinoma in genetically engineered mouse models
Leah Schmidt1, Jacob Lee1, Oanh Tran1, Jennifer Hotes2, Philip Greenberg1,2*
1University of Washington, 2Fred Hutchinson Cancer Research Center
Adoptive transfer of T cells engineered to recognize cancer cells is an evolving immunotherapeutic approach that has seen success against hematologic cancers in the clinic. However, application of this strategy to solid tumors is still in the early stages of exploration. Extending the utility of T cell therapy to solid cancers will likely require incorporating strategies to enhance function as well as approaches to mitigate toxicity. Antibody-based checkpoint blockade therapy has shown promising results in lung cancer in the clinic, providing the first evidence that immunotherapeutic approaches can be efficacious against this disease. However, only a fraction of patients exhibit beneficial responses to these therapies. Thus, the biological factors underlying responses to these and other immunotherapeutic strategies must be further elucidated in tractable and clinically relevant cancer models. A genetically engineered mouse model of lung cancer, relying on conditional activation of oncogenic Kras and inactivation of the tumor suppressor p53, allows for in situ development of tumors that histologically and transcriptionally recapitulate human disease alongside a fully competent immune system. We are targeting tumor-associated antigens (TAAs) in lung cancer by administering TCR-engineered T cells to tumor-bearing mice in this model. We are evaluating the obstacles limiting the ability of transferred tumor-specific T cells to home to tumors, persist, and remain functional, as well as assessing the potential toxicities of such therapies. Previous work by others in this lung cancer model has shown that T cells specific for model tumor antigens rapidly lose function and acquire markers of exhaustion. We will characterize the molecular events leading to the acquisition of dysfunction, and will explore genetic engineering strategies to enhance and sustain anti-tumor immune responses without inducing toxicity.
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