Integrating Ipilimumab Immunotherapy with Approved Treatment Strategies in CRPC

将 Ipilimumab 免疫疗法与已批准的 CRPC 治疗策略相结合

• 批准号: 8999528
• 负责人: JAMES P ALLISON
• 金额: $ 32.23万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-02 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999528
• 关键词: Acetates; Aftercare; Androgen Receptor; Antitumor Response; Biological; Blood specimen; Cancer Center; Cancer Patient; Cells; Characteristics; Clinical; Clinical Trials; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Disease; Disease Progression; Drug Targeting; Effectiveness; Evaluation; Exhibits; Flow Cytometry; Future; Gene Expression; Goals; Image; Imaging Techniques; Immune; Immune Targeting; Immune response; Immune system; Immunocompetent; Immunofluorescence Immunologic; Immunohistochemistry; Immunologics; Immunotherapy; Infiltration; Knowledge; Lead; Life; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Memory; Metastatic Neoplasm to the Bone; Molecular; Monoclonal Antibodies; Neoplasm Metastasis; Outcome; Pathway interactions; Patient Selection; Patients; Performance; Phase III Clinical Trials; Placebos; Radiation therapy; Radioimmunoconjugate; Radiolabeled; Radiopharmaceuticals; Receptor Signaling; Research Personnel; Resistance; Resources; Signal Pathway; Signal Transduction; Solid Neoplasm; Specific qualifier value; Specimen; Study of serum; T cell response; T-Lymphocyte; Toxic effect; University of Texas M D Anderson Cancer Center; VTCN1 gene; Vaccines; Visceral; abiraterone; base; bone; cancer cell; cancer imaging; castration resistant prostate cancer; chemotherapy; cytokine; effective therapy; experience; improved; melanoma; men; mouse model; novel; patient subsets; peripheral blood; radiotracer; response; targeted agent; targeted treatment; treatment strategy; tumor; tumor growth

PROJECT SUMMARY (Project 1) The mainstay therapy for castration-resistant prostate cancer (CRPC) consists of agents targeting the androgen receptor (AR) signaling pathway and chemotherapies, which induce antitumor responses, and in select men a vaccine and a radiopharmaceutical bone-targeting therapy. The responses with all of these therapies tend to be short-lived. Conversely, treatment with the cytotoxic T-lymphocyte antigen 4 (CTLA-4)– targeting drug, ipilimumab, which promotes enhanced T-cell responses and generates memory immune responses, has led to durable regression of metastatic disease and an overall survival benefit. A recent phase 3 trial of ipilimumab in patients with CRPC demonstrated dramatic responses in a subset of them and improved survival in those with favorable clinical characteristics, who also tend to have good responses to therapies targeting the AR signaling pathway. Previous studies demonstrated that inhibition of AR signaling has positive effects on the immune system. We hypothesize that patients with cancers that regress with therapies targeting AR signaling will benefit from the addition of anti-CTLA-4 (ipilimumab) immunotherapy. In addition, given the lack of imaging capabilities to differentiate between tumor growth and tumor infiltration by immune cells as a result of immunotherapy, we propose to develop radiolabeled antibody imaging to evaluate tumor responses to immunotherapy. We aim to rationally integrate anti-CTLA-4 (ipilimumab) immunotherapy with agents targeting the AR signaling pathway to provide durable clinical benefit with improved survival in patients with prostate cancer, and utilize novel imaging techniques to accurately identify tumor responses. In this project, we will identify molecular changes associated with clinical outcomes of anti-CTLA-4 (ipilimumab) immunotherapy for prostate cancer by examining matched tumor and peripheral blood specimens obtained in recently completed clinical trials. We will perform in-depth examination of the specimens using immunohistochemistry, immunofluorescence, flow cytometry, gene expression studies, and serum cytokine analyses. We will prospectively evaluate the most promising molecular determinants in our novel clinical trial with the aim of linking the interactions between the immune system and the AR signaling pathway. Finally, because our group has identified other immunologic molecules that may be targeted with radiolabeled antibodies for imaging, we propose to evaluate this possibility in murine models to provide data for future clinical trials. Our proposed studies will provide data to enable integration of anti-CTLA-4 (ipilimumab) immunotherapy into a treatment strategy for prostate cancer that induces durable responses and improves overall survival, with the goal of curing the disease.

项目概要（项目1） 去势抵抗性前列腺癌（CRPC）的主要治疗方法包括靶向靶向前列腺癌的药物。 雄激素受体（AR）信号通路和化学疗法，其诱导抗肿瘤反应，以及 选择男性进行疫苗和放射性药物骨靶向治疗。所有这些反应 治疗往往是短暂的。相反，用细胞毒性T淋巴细胞抗原4（CTLA-4）治疗- 靶向药物ipilimumab，促进增强T细胞反应并产生记忆免疫 缓解，导致转移性疾病的持久消退和总体生存益处。最近的一个阶段 在CRPC患者中进行的3项伊匹单抗试验在其中一个亚组中显示出显著的反应 并提高了具有良好临床特征的患者的生存率，这些患者也倾向于对 靶向AR信号通路的治疗。先前的研究表明，抑制AR信号传导， 对免疫系统有积极作用。我们假设，癌症患者的癌症消退， 靶向AR信号传导的治疗将受益于抗CTLA-4（ipilimumab）免疫治疗的加入。在 此外，由于缺乏成像能力来区分肿瘤生长和肿瘤浸润， 免疫细胞作为免疫治疗的结果，我们建议开发放射性标记抗体成像，以评估 肿瘤对免疫疗法的反应。我们的目标是合理整合抗CTLA-4（易普利姆玛）免疫治疗 与靶向AR信号通路的药物一起提供持久的临床益处， 前列腺癌患者，并利用新的成像技术，以准确地确定肿瘤的反应。 在这个项目中，我们将确定与抗CTLA-4（ipilimumab）临床结局相关的分子变化。 前列腺癌的免疫治疗，通过检查匹配的肿瘤和外周血标本， 最近完成的临床试验。我们将使用以下方法对样本进行深入检查： 免疫组织化学、免疫荧光、流式细胞术、基因表达研究和血清细胞因子 分析。我们将在我们的新的临床试验中前瞻性地评估最有希望的分子决定因素 目的是连接免疫系统和AR信号通路之间的相互作用。最后， 因为我们的小组已经鉴定出其他免疫分子， 我们建议在小鼠模型中评估这种可能性，为将来的研究提供数据。 临床试验我们拟定的研究将提供数据，使抗CTLA-4（易普利姆玛） 将免疫疗法引入前列腺癌的治疗策略中， 总生存率，以治愈疾病为目标。