Immunotherapy using personalized T cell receptor engineered T cells
Colt Egelston, PhD
Mentor | Peter Lee, MD |
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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.