Trends in Cancer
ReviewDevelopment of poly(ADP-ribose) polymerase inhibitor and immunotherapy combinations: progress, pitfalls, and promises
Introduction
The field of oncology drug development has seen substantial progress in the treatment of different cancers over the past decade. Inhibitors of key DDR mechanisms, specifically against PARP, have proven to be effective and are now approved as single-agent therapies in breast, ovarian, pancreatic, and castration-resistant prostate cancers (CRPC) [1]. ICB agents targeting cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) have also emerged as effective strategies to improve survival outcomes in various solid tumors [2]. However, clinical benefit for both classes of drugs is limited by innate and acquired resistance and/or drug-related toxicities. Preclinical studies have supported the mechanistic rationale for the combination of PARPi and ICB as a therapeutic strategy for patients with different solid tumors [3].
In this review, we discuss the preclinical, translational, and clinical studies supporting the combination of PARPi and ICB therapies as well as consider important questions to be addressed with future research.
Section snippets
PARP and synthetic lethality
The PARP family of enzymes consists of 17 proteins that play important roles in the DDR pathways for base excision repair (BER) and single-strand break repair (SSB) [4., 5., 6.]. PARP1, the most widely studied protein of this family, is composed of a common catalytic domain, which generates poly(ADP-ribose) chains upon binding to SSB through a process known as auto-PARylation [4,7,8]. These PARP complexes promote the downstream recruitment of SSB repair proteins and lead to the chromatin
Clinical activity of PARPi
Four randomized Phase III trials – SOLO-1 (NCT01844986i), PAOLA-1/ENGOT-OV25 (NCT02477644ii), PRIMA/ENGOT-OV26 (NCT02655016iii), and VELIA/GOG-3005 (NCT02470585iv) – have demonstrated clinically significant progression-free survival (PFS) in newly diagnosed ovarian cancer patients undergoing PARPi treatment. Olaparib and rucaparib have already received FDA approval for the treatment of BRCA1/2 mutated recurrent, platinum-sensitive ovarian cancer. Olaparib, niraparib, and rucaparib have been
Immuno-oncology and ICB
Immuno-oncology (IO) therapy targets the complex adaptive changes in the tumor microenvironment upon antigen recognition [33]. An interesting IO target is CTLA-4, a co-inhibitory molecule found on the cell surface of regulatory T cells that interacts with antigen-presenting cells (APC) [34]. In conjunction with the downregulation of co-stimulatory CD80 and CD86 cells, CTLA-4 suppresses T cell function and mitigates the amplitude of the cytotoxic T cell response [33,34]. Murine models have
Combining PARP inhibition and immunotherapy: a rational approach
Despite the approval of different PD-1/PD-L1 agents for the treatment of multiple cancer types, only a minority of patients will benefit from a monotherapeutic approach [36,41]. This is exemplified in gynecological cancers, where the use of PD-1/PD-L1 agents has demonstrated modest 10–15% response rates in ovarian, cervical, and endometrial cancers [44,45]. Recently, we have observed a shift towards developing rational combinatorial strategies to enhance the efficacy of ICB, including
Patient selection
To maximize the number of patients who may benefit from combined PARP and immune checkpoint inhibition, we must optimize patient selection through the use of response and resistance predictive biomarkers [9]. While tumors with other known mechanisms of HR deficiency or ‘BRCAness’ may also benefit from exploiting the synthetic lethality relationship with PARPi beyond BRCA1/2 mutations, empirically targeting other HRR alterations has yet to show a comparable level of clinical benefit [1]. What
Concluding remarks
Despite FDA approval for use of PARPi in HR-deficient CRPC and BRCA1/2-mutated ovarian, breast, and pancreatic tumors, the efficacy of single agent use and combination therapy has been limited by drug resistance and toxicity. Similarly, durable responses with ICB single therapy have been limited to a minority of patients and tumor types. Robust preclinical data have suggested activation of the cGAS-STING pathway by PARP inhibition, shifting the tumor immune microenvironment from one of
Acknowledgments
M.M.P. is supported by the National Institutes of Health (T32 CA101642/CA/NCI NIH HHS/United States). N.Y.L.N. is supported by the National Medical Research Council, Singapore (MOH-FLWSHP19may-0006). D.S.P. T. is supported by the National Medical Research Council, Singapore (CSAINV16may008), and has received charitable research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund. G.P. is supported by MD Anderson Cancer Center Support grant (NCI CA016672), the
Declaration of interests
N.Y.L.N. received honoraria from AstraZeneca and Janssen. D.S.P.T. received research funding from AstraZeneca, Bayer, and Karyopharm and honoraria from AstraZeneca, MSD, Tessa Therapeutics, Novartis, Bayer, and Genmab. T.A.Y. received research funding (paid to his institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon
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