2022 Recipient Veethika Pandey, PhD

Veethika Pandey, PhD

Overcoming T Cell Exhaustion in Ovarian Cancer Tumor Microenvironment

Project Summary

Immunotherapy for cancer treatment presents tremendous opportunity for curing diseases such as ovarian cancer. However, there are various challenges that need to be addressed to see an effective increase in patient survival using immunotherapy. Current focus in the field is geared towards empowering patients’ own T cells to kill tumors. T cells are a natural defense mechanism of the immune system, but are rendered weak (exhausted) by the growing tumors. In this proposal, we aim to empower T cells present in ovarian tumors and genetically modify them such that they exhibit all characteristics of robust T cells, capable of fighting off tumor cells. We will modify them by introducing a CoCAR molecule onto the T cell surface that can bind to a specific molecule expressed on the tumor cell and internally, sends a signal to the T cell to get activated. This internal signaling is carried out by the CD28 domain, which is crucial for a robust activation of a T cell. Therefore, in a tumor environment, where the growing cancer doesn’t allow for the stimulation of critical CD28 signals, the engineered T cells with the CoCAR will bypass that requirement by binding to the tumor cells through the engineered receptor and receive an activation signal through the CD28 domain. In a separate aim of the proposal, we will also attempt to target a known T cell inhibitory molecule, PD-1. We will incorporate the CoCAR molecule within the locus of the gene for PD-1, causing disruption of PD-1 synthesis and incorporation of the CoCAR at the same time. Modified T cells will then be robustly tested against tumor cells in vitro as well as in a mouse model that has an established tumor, generated from the same patient whose tumor was used to isolate T cells for genetic modification. Experiments proposed here provide a promising strategy of genetically modifying patients’ own immune cells to treat their tumors.

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