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.