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: 10478821
• 负责人: JENNIFER D WU
• 金额: $ 33.48万
• 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/10478821
• 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; 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：摘要/摘要