Among the most powerful cancer-killing immune cells are “killer” T cells, which identify and eliminate malignant cells with remarkable specificity. However, cancer cells can deploy a host of mechanisms to limit T cell function, including via pathways that can lead to “exhaustion” and repressed killing capability. Interestingly, Dr. Zak and his team recently developed an assay to identify exhaustion-reversing molecules and found multiple drugs already in the clinic can rescue the function of killer T cells. These drugs have previously not been tested for the purpose of enhancing immunotherapy. However, the team’s recent results in preclinical models of persistent viral infection and cancer suggest that these drugs positively regulate the survival and proliferation of killer T cells by modulating their molecular properties.
In this project, Dr. Zak is investigating the mechanism by which these potential exhaustion-reversing molecules elicit beneficial effects on killer T cells and immune responses against cancer. In collaboration with clinical oncologists, he will also analyze the killer T cells from patients who are enrolled in a clinical trial of small molecules in combination with checkpoint immunotherapy, but who did not respond to checkpoint immunotherapy alone. The profiles of these patients’ T cells will be analyzed over the course of treatment to determine any connections with clinical responses. Overall, his work seeks to reveal new ways of rescuing T cell exhaustion and test which of these approaches perform in the clinic. The results may expand the range of therapeutics to complement immunotherapy.
Projects and Grants
Pharmacological expansion of self-renewing CD8 T cells to enhance immune checkpoint blockade therapy
The Scripps Research Institute | All Cancers | 2020 | John R. Teijaro, Ph.D.
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