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

干扰素-γ在卵巢肿瘤微环境中选择性抑制 PARP 和 CTLA4 阻断的协同治疗机制

• 批准号: 10098009
• 负责人: Sarah Foster Adams
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-18 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10098009
• 关键词: Address; Adoption; Antibodies; Antibody Therapy; Area; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; Biological Markers; Blood specimen; CD8-Positive T-Lymphocytes; CTLA4 blockade; CTLA4 gene; Cancer Biology; Cancer Model; Cell Cycle; Cell Death; Cells; Clinical; Clinical Data; Clinical Trials; Correlative Study; Cytotoxic agent; Data; Development; Disease; Disease Outcome; Environment; Failure; Gene Expression; Goals; Immune; Immunobiology; Immunotherapy; In Vitro; Interferon Type II; Interferons; Knowledge; Leukocytes; Link; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Mus; Patient-Focused Outcomes; Patients; Phase; Poly Adenosine Diphosphate Ribose; Polymerase; Production; Publishing; Recurrence; Recurrent disease; Regimen; Resistance; Sampling Studies; Signal Transduction; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Translations; Treatment Efficacy; Tumor Immunity; Woman; Work; base; blood treatment; cancer therapy; clinical efficacy; clinical translation; combinatorial; cytotoxic; cytotoxicity; genetic signature; immune checkpoint; immune checkpoint blockade; immunogenic; immunoregulation; in vivo; inhibitor/antagonist; melanoma; mortality; mutation carrier; neoplastic cell; novel; ovarian neoplasm; pre-clinical; predicting response; predictive marker; recruit; response; response biomarker; synergism; targeted agent; therapy resistant; treatment effect; treatment response; tumor; tumor microenvironment

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.

卵巢癌的高死亡率是由于肿瘤定向治疗失败造成的 最近已在其他实体瘤患者中产生持久的治疗反应。 使用免疫检查点抗体实现了这一目标，但在女性中尚未观察到类似的结果 我们实验室发表的研究表明，结合聚腺苷。 二磷酸核糖）聚合酶（PARP）抑制剂与免疫检查点阻断可以实现长期 一项正在进行的临床试验的早期结果现已证明卵巢癌模型的足月生存。 在此我们建议该方案对复发性卵巢癌女性具有显着的临床疗效。 剖析导致该组合观察到的治疗协同作用的机制，以实现 免疫疗法与细胞毒疗法的最佳整合，可以为女性患者带来长期益处 这项研究的科学前提是不断积累的动态证据。 肿瘤细胞与调节治疗反应的肿瘤微环境 (TME) 之间的相互作用 我们的工作还表明，TME 与肿瘤直接相互作用。 联合 PARP 抑制和 CTLA4 阻断产生了增强肿瘤清除的靶向药物。 TME 中产生 IFNγ 的 T 细胞比例显着增加，这种效应持续很长时间 治疗完成后，我们发现 IFNγ 增强了对 PARP- 的肿瘤细胞毒性。 体外通过细胞内在机制进行抑制，并且 IFNγ 是生存益处所必需的 体内观察到的证据表明肿瘤环境条件显着调节治疗。 PARP 抑制剂的功效，称为“背景合成致死率”，提供了一个机会来最大化 在这里，我们建议剖析细胞内在的患者结果和目标治疗效果。 – 导致观察到的 PARP 抑制剂治疗协同作用的外在机制 CTLA4 阻断并开发与这些临床机制相关的治疗预测生物标志物 随着免疫检查点抗体和 PARP 抑制剂的快速采用进行治疗。 对于卵巢癌和其他肿瘤类型，该提案有可能通过以下方式产生直接的临床影响： 当前和计划中的临床试验。