Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models

Abstract

PARP inhibitors have been proven clinically efficacious in platinum-responsive ovarian cancer regardless of BRCA1/2 status and in breast cancers with germline BRCA1/2 mutation. However, resistance to PARP inhibitors may preexist or evolve during treatment in many cancer types and may be overcome by combining PARP inhibitors with other therapies, such as immune checkpoint inhibitors, which confer durable responses and are rapidly becoming the standard of care for multiple tumor types. This study investigated the therapeutic potential of combining niraparib, a highly selective PARP1/2 inhibitor, with anti-PD-1 immune checkpoint inhibitors in preclinical tumor models. Our results indicate that niraparib treatment increases the activity of the type I (alpha) and type II (gamma) interferon pathways and enhances the infiltration of CD8+ cells and CD4+ cells in tumors. When coadministered in immunocompetent models, the combination of niraparib and anti-PD-1 demonstrated synergistic antitumor activities in both BRCA-proficient and BRCA-deficient tumors. Interestingly, mice with tumors cured by niraparib monotherapy completely rejected tumor growth upon rechallenge with the same tumor cell line, suggesting the potential establishment of immune memory in animals treated with niraparib monotherapy. Taken together, our findings uncovered immunomodulatory effects of niraparib that may sensitize tumors to immune checkpoint blockade therapies.

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

“…Although the result of an early phase II clinical trial combining Durvalumab with Olaparib in patients with relapsed small cell lung cancer did not meet the preset bar for efficacy [93], we are awaiting the results of ongoing clinical trials to better judge their effectiveness. Moreover, the PARP inhibitor Niraparib has been shown to enhance type I interferon signaling and T cell infiltration in the tumor and improve the therapeutic effect of anti-PD-1 [94]. NK cells can kill cancer cells by inducing death receptor-mediated apoptosis through the expression of FasL or TRAIL [71].…”

Poly(ADP-Ribose) Polymerase Inhibitors in Pancreatic Cancer: A New Treatment Paradigms and Future Implications

“…Interestingly, synergistic anti-tumor activity of niraparib and PD-1 blockade was seen in both BRCA-deficient and BRCA-proficient immunocompetent tumor models indicating that this combination may be active regardless of BRCA status. Furthermore, mice in complete remission after treatment rejected implanted tumor cells indicating the generation of memory T-cells [94]. Preclinical studies have shown that DSBs leads to upregulation of PD-L1 expression through ATM/ATR/Chk-1.…”

PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma

“…However, there is hope for increased response rates through patient selection and combination of therapies. For example, there is emerging preclinical data suggesting that the patient population that responds to PARP inhibition and PD-1/PD-L1 antibodies may significantly overlap [9], and it is hypothesized that increased DNA damage by PARP inhibition will increase the number of tumor neoantigens, creating a more antigenic environment in which to stimulate the immune microenvironment [10]. Thus, development of predictive biomarkers is needed to identify the subset of patients who will benefit from treatment and to minimize the risk of toxicities.…”