With only a 46 percent 5-year survival rate, ovarian cancer is the most lethal of all gynecological malignancies. High grade serous ovarian cancers (HGSOC) are the most common type of ovarian cancer. Nearly half of all HGSOC have a mutation in one of the genes related to homologous recombination, which is the mechanism for non-error prone double stranded DNA break repair. Two genes that are often mutated in in ovarian cancer and are important to this pathway are BRCA1 and BRCA2. Poly (ADP-ribose) polymerase (PARP) plays an important role in this DNA repair processes, thus inhibition of PARP is particularly sensitive to cancers with BRCA1/2 mutations. PARP inhibitors (PARPis) have been the first big breakthrough in the treatment of ovarian cancer since the introduction of paclitaxel more than 20 years ago. Three PARPis have been approved for third-line or maintenance therapy for ovarian cancer. Despite the promising short-term clinical response to PARPis, most of these patients will result in drug resistance and release. Due to the broadening uses of PARPis in ovarian cancer, understanding of the mechanisms of PARPi resistance and further treatment options are of increasing importance.
Autologous tumor infiltrating lymphocyte (TIL) therapy uses a patient’s own tumor reactive T-cells to fight the cancer cells. These cells have already been “educated” to recognize and kill tumor cells. Autologous TIL therapy has shown promising results in clinical trials of ovarian cancer, however it is expected that blocking inhibitory signals on T-cells would increase T-cell activity, thereby increasing the effectiveness of TIL therapy. One inhibitory signal on T-cells is the interaction of cell surface marker PD-1 with tumor surface marker PD-L1. Preliminary data shows that PARPi resistance BRCA1 mutant tumors have increased PD-L1 expression and TILs co-cultured with autologous tumor cells increased T-cell PD-1 expression. These results provide rationale for studying inhibition of the PD-1/PD-L1 interaction in this context. By blocking this interaction, it is expected that T-cells will be able to maintain their tumor killing activity and thus this combination therapy needs to be studied in PARPi resistant ovarian cancer.
The purpose of this study is to develop a model for PARPi resistant BRCA1/2 mutant ovarian cancer to test TIL therapy. The model that we will develop is a patient derived model of ovarian cancer that better recapitulates the clinical disease manifestations than historically used models. This will ensure that the results will be more indicative of results that would be seen in patient populations. Using this preclinical platform, we will test the effectiveness of autologous TIL therapy and inhibition of PD-L/PD-L1 interaction. Moreover, this study is designed to determine how PARPis impact TILs by studying patient samples that have been exposed to PARPis compared to those that are PARPi naive. Overall, this study aims to create a clinically relevant model in which autologous TIL therapy will be studied in the context of PARPi resistant BRCA1/2 mutant ovarian cancer, while providing new insights into PARPi resistance.
This grant is made possible by generous donations from Joseph and Angela Campolo, in memory of Phebe Aubry, and family and friends in loving memory of Sandra Gralnick.
Dr. Sarah Gitto is a postdoctoral researcher at the Ovarian Cancer Research Center at the University of Pennsylvania in Philadelphia. Dr. Gitto earned her Ph.D. from the University of Central Florida in 2017, where she was awarded numerous honors including induction into the Order of Pegasus, the most prestigious award at her alma mater. Her graduate studies focused on developing autologous NK cell therapy for ovarian cancer, delineating the role that chronic inflammation has on the development of pancreatic cancer, and testing novel molecular therapeutics to treat pancreatic cancer.
Dr. Gitto is currently working on a collaborative project under the mentorship of Dr. Daniel J Powell and Dr. Fiona Simpkins to develop novel orthotropically implanted patient-derived xenograph models of mutant ovarian cancer that are also reconstituted with patient-matched autologous tumor infiltrating lymphocytes (TILs). The ultimate goal of this study is to develop BRCA1/2 mutant PAPR inhibitor resistant tumor/TILs models and to use these models to test the efficacy of immune modulating therapies, including checkpoint inhibitors. PARP inhibitors are clinically approved for ovarian cancer maintenance therapy and are effective for use in BRCA mutant ovarian cancer. However, the majority of patients develop PARP inhibitor resistance and ultimately tumor recurrence. The support from the OCRA will equip her with the tools to discover new effective therapeutic strategies for this patient population.