Assessing the role of the DNA repair landscape in immune checkpoint therapy

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Project Summary/Abstract: The success achieved with immunostimulatory therapies blocking the PD-1 axis has uncovered the power of modulating immune inhibitory signals in the tumor microenvironment. However, these therapies benefit only a fraction of patients. One of the major current challenges is the identification of mechanisms to treat the majority of patients with the so-called "non-inflammed" tumors lacking marked lymphocyte infiltration and PD-L1 expression. The immunogenicity of tumors is prominently influenced by the production of neoantigens. Neoantigens arise from somatic mutations and have the potential to be recognized as “non-self” by the immune system, leading to tumor cell killing upon immune reinvigoration using checkpoint blockade. Therefore, tumors with high mutation burden (a hypermutator phenotype) are more likely to harbor neoepitopes and to respond to immunotherapies. The Yale Comprehensive Cancer Center (YCCC) Early Therapeutics Program has recently received approval from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) to conduct a Phase I clinical trial of the poly-ADP-ribose polymerase (PARP) inhibitor ABT- 888 (veliparib), in combination MPDL3280A, which is a human monoclonal antibody containing a modified Fc domain that binds directly to PD-L1, thereby preventing binding to PD-1 and CD80 in patients with advanced (metastatic or unresectable) solid BRCA1 or BRCA2 mutant tumors for which standard curative or palliative measures do not exist or are no longer effective. The scientific premise of this trial is that treatment of BRCA1/2 defective tumors with veliparib will result in increased mutational load, enabling the tumor to respond to anti-PD-L1. The broad, long-term objectives of our proposed research are to determine if treatment with PARP inhibitors in combination with the DNA repair landscape increases the mutational load of cancer cells and to elucidate the underlying mechanism of mutagenesis by PARP inhibitors. Additional long-term objectives include increasing our understanding of the relationship between mutational signatures, DNA repair, and cancer therapies to treatment outcomes. The specific aims of this application are (1) To determine if treatment of BRCA 1/2 defective cells with PARP inhibitors leads to increased mutational load; and (2) To determine if treatment of patients harboring BRCA1/2 deficient breast cancer with veliparib results in an increased mutational load within their tumors. We will characterize in vitro cellular mutational responses of BRCA mutant cells to treatment with PARP inhibitors, focusing on mutational load. We will also determine whether treatment of tumors with veliparib as part of the clinical trial increases mutational load.Our studies are significant because they have the potential to provide important mechanistic insights regarding the relationship between PARP inhibitor treatment, the DNA repair landscape, and mutational load as they relate to outcomes.