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.
This grant was made possible in part by a generous donation from Angela and Joseph Campolo, in memory of Phebe Aubry.
Dr. Veethika Pandey is currently a postdoctoral researcher at the University of Pennsylvania, under the mentorship of Dr. Daniel J. Powell Jr. Her research interest lies in developing novel ways to overcome immunosuppression in solid tumor microenvironment to enhance immunotherapies. Currently, she is working on armoring ovarian tumor infiltrating lymphocytes with costimulatory signals to enhance their tumor-targeting potential in autologous PDX mouse models. Dr. Pandey obtained her PhD in biomedical sciences at the University of Central Florida, under the mentorship of Dr. Deborah Altomare. Her dissertation work focused on developing cytotoxic natural killer cell expansion methods to support in vivo persistence and better tumor targeting. She also worked on several other projects focused on developing transgenic mouse models of pancreatic cancer development and tested anti-metastatic compounds in orthotopic tumor models. After completing her graduate training, she worked as a Research Fellow at Mayo Clinic, in Dr. Peter Storz’s lab. She obtained grant funding from the pancreatic cancer SPORE program to study reprogramming of macrophage polarization in the tumor microenvironment. During this time, she acquired a wide skill-set for studying solid tumor microenvironment, utilizing multiple pre-clinical models. OCRA’s support at this stage of her career will help her utilize an extensive background in tumor immunology to develop novel approaches for personalized immunotherapies against ovarian cancer.