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.

与卵巢癌相关的高死亡率是由于肿瘤定向治疗失败的 产生持久的治疗反应。最近患有其他实体瘤患者的耐用生存率 使用免疫检查点抗体实现了，但是女性尚未观察到相似的结果 患有卵巢癌。我们实验室发表的工作表明，结合了poly（腺苷 具有免疫检查点封闭的聚合酶（PARP）抑制剂的二磷酸 - 核糖）可以实现长期 卵巢癌模型中的术语生存。正在进行的临床试验的早期结果现已证明 该方案在复发性卵巢癌的女性中的显着临床功效。在这里我们建议 解剖导致该组合观察到的治疗协同作用的机制，以实现 免疫治疗与细胞毒性方案的最佳整合，以使其长期利益 卵巢癌。这项研究的科学前提是积累了动态的证据 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 和疾病结果。我们的工作还表明，TME与肿瘤直接相互作用 靶向剂以增强肿瘤清除率。联合PARP抑制和CTLA4封锁导致 TME中产生IFNγ的T细胞的比例显着增加，这种作用持续了很长 完成治疗后。我们发现，IFNγ响应于PARP的肿瘤细胞毒性增强了 通过体外细胞中的机制抑制，生存益处需要IFNγ 在体内观察到。肿瘤环境中的条件显着调节治疗的证据 PARP抑制剂的功效称为“上下文合成致死性”，为最大化的机会提供了机会 患者的结果和目标治疗对TME的影响。在这里，我们建议剖析细胞中的细胞 和 - 负责观察到的PARP抑制剂治疗协同作用的脱位机制和 CTLA4封锁并开发一种与临床机制相关的治疗预测生物标志物 翻译。随着免疫检查点抗体和PARP抑制剂的快速采用 对于卵巢癌和其他肿瘤类型，该建议有可能通过 当前和计划的临床试验。