Project 4: Combined targeting of DNA repair and macrophage-mediated immunosuppression in BRCA1/2-associated breast cancer

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT Inhibitors of poly (ADP-Ribose) polymerase (PARP) are now part of the standard armamentarium for patients with BRCA-associated breast cancer. Mechanistically, these agents not only induce synthetic lethality in homologous recombination (HR) repair-deficient tumor cells but also induce cGAS-STING-mediated immune responses that result in CD8+ T-cell infiltration and activation. Although these immunomodulatory effects are critical for maximal efficacy of PARP inhibition, to date, the addition of PD-1/L1 blockade has not improved PARP inhibitor efficacy in preclinical models or in clinical trials. Our recent preclinical work has demonstrated that PARP inhibition also results in infiltration of CSF-1R+ tumor-associated macrophages (TAMs) that carry a highly immunosuppressive phenotype. CSF-1R blockade depletes these TAMs and significantly augments PARP inhibitor efficacy in BRCA-deficient models in a CD8+ T-cell-dependent manner. In the first Specific Aim, these preclinical findings will be validated in biopsies procured from patients with BRCA-associated breast cancer who have received PARP inhibitor-based treatment on clinical trials. In the TALAVE trial, patients received one month of talazoparib alone, followed by cycles of talazoparib/avelumab, with biopsies obtained pre-treatment, after talazoparib alone and after the combination. A neoadjuvant trial combining niraparib and dostarlimab will also be leveraged, in which pre-treatment, on-treatment and surgical specimens will be available for analysis. RNA sequencing and single-cell, multiplex cyclic immunofluorescence (CyCIF) will be used to deeply characterize both the T-cell and TAM components of the tumor microenvironment (TME) in response to PARP inhibition. TAM diversity before and on-treatment will be explored based on transcriptionally defined unique subsets. The topology and spatial relationships of TAMs with T-cells will also be explored. In Aim 2, a Phase 1 clinical trial combining the anti-CSF-1R antibody axatilimab and olaparib will be conducted in patients with PARP inhibitor- naïve or sensitive metastatic BRCA-associated breast cancer. Tumor biopsies will be obtained pre-treatment, after a 2-week lead-in of olaparib alone, and after combination treatment to perform proof-of-mechanism pharmacodynamics to document depletion of CD163+CSF-1R+ immunosuppressive TAMs. Finally, in Aim 3, combined CSF-1R blockade and PARP inhibition will be studied in preclinical immunocompetent models of BRCA1-deficient breast cancer with acquired PARP inhibitor resistance. Because the efficacy of this strategy is dependent on activation of CD8+ T-cells, and based on a greater degree of TAM infiltration and immune checkpoint protein expression in PARP inhibitor-resistant tumors, combined anti-CSF-1R and olaparib will also be studied with immune checkpoint blockade, including anti-PD-1 and anti-TIM-3, the latter shown to activate dendritic cells in a cGAS/STING-dependent manner. Taken together, these studies will define the T-cell and TAM components of the TME in response to PARP inhibition in patient samples and develop the strategy of combined CSF-1R blockade and PARP inhibition in PARP inhibitor-sensitive and resistant tumors.