PARP (poly (ADP-ribose) polymerase) is a core DNA damage sensor that plays an important role in repairing frequently occurring single-strand breaks (“nicks”) in the DNA which occur in the cell cycle. In cancers with defects in the tumor suppressor gene, the cancer cells can only be repaired with PARP. PARP inhibitors aim to inhibit the DNA repairing in cancer cells and promote cancer cell death. Some PARP inhibitors have been approved by the FDA and considered as first-line maintenance therapies for multiple cancers.
Immune checkpoint inhibitors (ICIs) block checkpoint proteins from binding with their partner proteins and reactivate anti-tumor signal of cancer-killing immune cells. Combining PARP inhibitors with ICIs provides a synergistic anti-tumor effect, which improves the anti-tumor responses, increases duration of response, extends survival, and overcomes resistance. PARP inhibitors have been shown to increase the efficacy of ICIs via promoting cross-presentation and modifying immune microenvironment. PARP inhibitors and ionizing radiation could enhance the infiltration of cytotoxic T lymphocytes into the tumor bed, enhancing anti-tumor immune responses. Furthermore, PARP inhibitors are also involved in the regulation of tumor immune microenvironment by increasing genomic instability and immune pathway activation, thereby promote responsiveness to ICIs.
Fig.1 The potential synergy between PARP inhibition and immune checkpoint blockade. (Vikas, 2020)
Scientists employed two genetically engineered mouse models bearing high-grade serous ovarian cancer to investigate the treatment outcome of the combination of anti-PD-1 antibody and PARP inhibitor. Compared to anti-PD-1 or PARP inhibitor monotherapy, the combination therapy inhibited tumor growth and prolonged survival time of mice. Besides, CD8+ T cells possessed the greater capability to produce IFN-γ and TNF-α in the peripheral blood of mice after PARP inhibitor treatment.
Currently, several clinical trials have examined or are investigating the synergistic effects of PARP inhibition and ICI in ovarian cancer, and results showed a promising outcome. In the phase II basket study, the combination of anti-PD-L1 antibody and PARP inhibitor had an overall response rate of 63% and a 12-week disease control rate of 81% in 32 patients with platinum-sensitive relapsed ovarian cancer.
PARP inhibitors have been shown to significantly increased the expression of PD-L1 in breast cancer cell lines and xenograft models. In vivo studies have reported that the combination of anti-PD-L1 blockade and PARP inhibitor shows more potent anti-cancer activity and increases the abundance of tumor-infiltrating lymphocytes (TILs) compared with an anti-PD-L1 blockade or PARP inhibitor monotherapies.
Furthermore, several clinical trials are also ongoing to evaluate the safety and efficacy of the combination of ICIs and PARP inhibitors in breast cancer. In a phase I/II trial of 32 breast cancer patients with germline BRCA mutations, the combination of PD-L1 blockade and PARP inhibitor showed an overall response rate of 53% and a 12-weeks disease control rate of 47% with minimal adverse events.
PARP inhibitor monotherapy has been shown significant anti-tumor activity in prostate cancer with HRR gene mutations. Now the proposal of the combination of PARP inhibitor and ICI opens a new landscape for the treatment of prostate cancer. Most research is ongoing conducted to address the safety and efficacy of combination therapy for prostate cancer.
In a study of a cohort of 41 patients with mCRPC (metastatic castrate-resistant prostate cancer) and HRR (homologous recombination repair) wild-type, the combination of anti-PD-1 antibody and PARP inhibitor showed a partial response of 7% and disease control rate of 29%. However, some adverse events such as anemia, fatigue, and nausea were also found in these cases.
The combination of ICIs and PARP inhibitors provides a promising orientation for cancer treatment. Several clinical trials are ongoing to explore the efficacy of various targeted therapies and checkpoint blockade immunotherapy in advanced and metastatic solid tumors. As an expert in the field of immune checkpoint therapy, Creative Biolabs is confident in providing a series of immune checkpoint therapy services, including but not limited to:
If you are interested in our services, please contact us to discuss your project.
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