Project 2: Re-directing the Sensitivity of Metastatic Castration-Resistant Prostate Cancer to Immunotherapy

项目 2：重新调整转移性去势抵抗性前列腺癌对免疫治疗的敏感性

• 批准号: 10089064
• 负责人: JENNIFER D WU
• 金额: $ 32.4万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10089064
• 关键词: Address; Androgen Receptor; Antibodies; Antigen-Antibody Complex; Antigens; Archives; Binding; Biological; Blood Circulation; CD34 gene; CD8-Positive T-Lymphocytes; Cancer Patient; Cell physiology; Cell surface; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Colon; Combined Modality Therapy; Data; Disease; Disease Resistance; Dose; Drug Kinetics; Epithelial; Event; Fostering; Future; Genomics; Goals; Granzyme; Hormones; Human; Immune; Immune system; Immunologic Cytotoxicity; Immunologic Surveillance; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; Knowledge; Malignant neoplasm of prostate; Mediating; Membrane; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Monoclonal Antibodies; Myeloid-derived suppressor cells; Neoplasm Metastasis; Oxidative Stress; Patient Selection; Patients; Pharmacodynamics; Phase; Phase I Clinical Trials; Pre-Clinical Model; Prostate; Prostatic Neoplasms; Resistance; Safety; Sampling; Serum; Signal Transduction; Solid Neoplasm; Stress; Surface; System; Target Populations; Testing; Time; Tissue Sample; Toxic effect; Translating; Treatment Efficacy; Tumor Tissue; Tumor-associated macrophages; Vaccines; Variant; Visceral; Visceral metastasis; bone; castration resistant prostate cancer; checkpoint therapy; cohort; first-in-human; immune checkpoint blockade; immunoregulation; improved; inhibitor/antagonist; nonhuman primate; novel; patient population; phase 2 study; pre-clinical; preclinical study; prostate cancer cell; prostate cancer model; receptor; resistance mechanism; response; targeted treatment; tumor

PROJECT 2: SUMMARY/ABSTRACT Limited options are available for the treatment of mPC, a lethal prostate cancer. Immunotherapy has significantly improved survival in patients with a variety of solid tumors; however, it has had limited efficacy in patients with metastatic prostate cancer (mPC). There is a lack of understanding of underlying mechanisms for this de novo resistance. In our pre-clinical studies, we have identified a novel mechanism that prostate tumors use to subvert and evade the immune system. We have found that metastatic prostate tumor cells convert the stress-induced immune stimulatory cell surface molecule, the MHC I Chain related molecule (MIC), to a highly immune suppressive soluble MIC (sMIC), through proteolytic-mediated shedding. Importantly, patients with mPC have significantly elevated immune suppressive sMIC in the circulation and severely suppressed immune cell function. To overcome the immune suppression of sMIC, we have developed a first-in-class sMIC-targeting monoclonal antibody (mAb) B10G5 that has demonstrated remarkable efficacy in eliminating prostate metastasis as a single agent in preclinical models. When used in combination, B10G5 synergizes with immune checkpoint blockade and reduces immune checkpoint therapy-induced colon toxicity. The mAb B10G5 has been optimized for human use (termed as huB10G5), proven to be safe in non-human primates (NHP) in pilot toxicity assessments, and is currently under IND-enabling studies. The goal of this SPORE project is to fulfill critical pre-clinical studies and to translate the B10G5 therapy into a potential therapy for treating mPC. Very recently, we found that androgen receptor (AR) activity could protect PC cells from immune cytotoxicity by upregulating the granzyme inhibitor serpinB9 and that B10G5 therapy could activate FAS-mediated killing. Thus, we hypothesize that the sMICtargeting antibody huB10G5 can be an effective immunotherapeutic agent for treating mPC as a single agent or in combination with immune checkpoint blockade therapy and/or standard AR-targeted therapy. We propose three Specific Aims: 1) to define the landscape of serum MIC levels in mPC patients with clinical characteristics and association with tumor immune modulation; 2) to determine therapeutic efficacy of targeting sMIC alone or in combination with immune checkpoint blockade (ICB) and/or AR-targeting for treatment of concurrent visceral and bone mPC; 3) To conduct a first-in-human Phase I clinical study of huB10G5 in mCRPC patients. These studies will provide us critical information for future Phase I expansion and Phase II study.

项目2：总结/摘要 有限的选择可用于治疗mPC，一种致命的前列腺癌。免疫疗法具有显著的 改善了各种实体瘤患者的生存率;然而，它在患有 转移性前列腺癌（mPC）。对于这种重新发生的潜在机制缺乏了解 阻力在我们的临床前研究中，我们已经确定了前列腺肿瘤用来颠覆 避开免疫系统我们已经发现，转移性前列腺肿瘤细胞将应激诱导的 免疫刺激细胞表面分子，MHC I链相关分子（MIC），对高度免疫的 抑制性可溶性MIC（sMIC），通过蛋白水解介导的脱落。重要的是，mPC患者 在循环中显著升高的免疫抑制性sMIC和严重抑制的免疫细胞功能。 为了克服sMIC的免疫抑制，我们已经开发了一流的sMIC靶向单克隆抗体， 抗体（mAb）B10 G5，其作为单一的抗前列腺癌单克隆抗体，在消除前列腺转移中表现出显著的功效， 临床前模型中的药剂。当联合使用时，B10 G5与免疫检查点阻断协同作用 并降低免疫检查点疗法诱导的结肠毒性。mAb B10 G5已针对人 使用（称为huB 10 G5），在初步毒性评估中证明在非人灵长类动物（NHP）中是安全的， 目前正在进行国家发展研究。该SPORE项目的目标是完成关键的临床前研究， 将B10 G5疗法转化为治疗mPC的潜在疗法。最近，我们发现雄性激素 受体（AR）活性可通过上调颗粒酶抑制剂来保护PC细胞免受免疫细胞毒作用 serpinB 9和B10 G5治疗可以激活Fas介导的杀伤。因此，我们假设 靶向sMIC的抗体huB 10 G5可以作为一种有效的免疫抑制剂用于治疗mPC作为单一的 在一些实施方案中，本发明的组合物可与免疫检查点阻断剂或与免疫检查点阻断疗法和/或标准AR靶向疗法组合使用。我们 提出了三个具体目的：1）确定具有临床症状的mPC患者的血清MIC水平 特征和与肿瘤免疫调节的关联; 2）确定靶向免疫调节的治疗功效。 sMIC单独或与免疫检查点阻断（ICB）和/或AR靶向组合用于治疗 并行内脏和骨mPC; 3）在mCRPC中进行huB 10 G5的首次人体I期临床研究 患者这些研究将为我们未来的I期扩展和II期研究提供关键信息。