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Immunotherapy using personalized T cell receptor engineered T cells

Colt Egelston, PhD

Mentor Peter Lee, MD
Award Type Career Development Award
Institution Beckman Research Institute of the City of Hope
Donor Support Funded by the Cavan Family Foundation

Immunotherapy has fundamentally changed the way we treat melanoma patients. Checkpoint blockade specifically, which unleashes T cell killing of cancer cells, has extended patient survival and significantly increased the percentage of patients that are deemed disease-free after therapy. Despite these successes, many melanoma patients still do not respond to immunotherapy; and even among those that respond initially, a significant percentage develop resistance or relapse after therapy. Barriers to the ultimate success of immunotherapy include tumor specific T cell dysfunction or the inability to generate sufficient numbers of tumor specific T cells due to immunosuppressive features of tumors. Recent research has demonstrated how these barriers emerge, showing that many melanoma tumors contain tumor specific T cells, but they lack the ability to kill cancer cells due to a state of dysfunction termed ‘T cell exhaustion’. Here we propose to use a combination of cutting-edge single cell RNA sequencing and T cell engineering methodology to generate large numbers of anti-tumor T cells. To do so, we will use single cell RNA sequencing on melanoma patient tumor infiltrating T cells to identify their T cell receptor (TCR), which allows tumor-specific T cells to recognize and kill cancer cells. We will use these TCR RNA sequences to then engineer large numbers of tumor- specific T cells (TCR-T cells) and test them for their ability to kill melanoma cancer cells from the same patient the T cell receptors were identified in. Next, we will test if any of the TCR-T cells we construct are capable of killing cancer cells from other melanoma patients. If so, we will begin to build a library of TCR-T that can be rapidly employed in the clinic for subsets of melanoma patients. This innovative strategy offers both a personalized engineering approach and the ability to rapidly generate high numbers of tumor-specific immune cells for clinical administration to patients. Thus, we believe that these studies will lead to a novel immunotherapy treatment option for melanoma patients that will offer durable, long-lasting survival.