# Mechanisms of selective therapeutic synergy of PARP-inhibition and CTLA4 blockade engaged by interferon-gamma in the ovarian tumor microenvironment

> **NIH NIH R37** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $348,832

## Abstract

The high mortality rate associated with ovarian cancer results from the failure of tumor-directed therapy to
produce lasting treatment responses. Durable survival in patients with other solid tumors has recently been
achieved using immune checkpoint antibodies, however similar results have not been observed in women
with ovarian cancer. Published work from our lab demonstrates that combining poly(adenosine
diphosphate-ribose) polymerase (PARP) inhibitors with immune checkpoint blockade can achieve long-
term survival in ovarian cancer models. Early results from an ongoing clinical trial have now demonstrated
significant clinical efficacy of this regimen in women with recurrent ovarian cancer. Here we propose to
dissect the mechanisms responsible for the observed therapeutic synergy of this combination to enable
the optimal integration of immune therapy with cytotoxic regimens for long-term benefit in women with
ovarian cancer. The scientific premise for this study is based accumulating evidence of a dynamic
interaction between tumor cells and the tumor microenvironment (TME) that regulates treatment response
and disease outcomes. Our work additionally demonstrates that the TME interacts directly with tumor-
targeted agents to enhance tumor clearance. Combined PARP-inhibition and CTLA4 blockade resulted in
a significant increase in the proportion of T cells producing IFNγ in the TME, an effect which persisted long
after completion of therapy. We found that IFNγ enhanced tumor cytotoxicity in response to PARP-
inhibition through a cell-intrinsic mechanism in vitro, and that IFNγ was required for the survival benefit
observed in vivo. Evidence that conditions in the tumor environment significantly modulate the therapeutic
efficacy of PARP-inhibitors, termed “contextual synthetic lethality”, presents an opportunity to maximize
patient outcomes and target treatment effects to the TME. Here we propose to dissect the cell-intrinsic
and –extrinsic mechanisms responsible for the observed therapeutic synergy of PARP inhibitors and
CTLA4 blockade and to develop a treatment predictive biomarker linked to these mechanisms for clinical
translation. With the rapid adoption of immune checkpoint antibodies and PARP-inhibitors for the treatment
of ovarian cancer and other tumor types, this proposal has potential for immediate clinical impact through
current and planned clinical trials.

## Key facts

- **NIH application ID:** 9875445
- **Project number:** 5R37CA229221-02
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Sarah Foster Adams
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,832
- **Award type:** 5
- **Project period:** 2019-02-18 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875445

## Citation

> US National Institutes of Health, RePORTER application 9875445, Mechanisms of selective therapeutic synergy of PARP-inhibition and CTLA4 blockade engaged by interferon-gamma in the ovarian tumor microenvironment (5R37CA229221-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9875445. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*