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

项目2：摘要/摘要 治疗MPC的选择有限，MPC是一种致命的前列腺癌。免疫疗法已经显著地 改善各种实体肿瘤患者的存活率；然而，它对患有 转移性前列腺癌。对这种从头开始的潜在机制缺乏了解 抵抗。在我们的临床前研究中，我们已经确定了一种前列腺癌用来破坏 并逃避免疫系统。我们发现转移性前列腺癌细胞将应激诱导的 免疫刺激细胞表面分子，即MHC I链相关分子(MIC)，对一种高度免疫 抑制可溶性MIC(SMIC)，通过蛋白降解介导的脱落。重要的是，患有MPC的患者 循环中免疫抑制SMIC明显升高，免疫细胞功能严重受抑。 为了克服中芯国际的免疫抑制，我们研制了一种一流的中芯国际靶向单抗 单抗B10G5在消除前列腺癌转移中的显著效果 临床前模型中的代理。联合使用时，B10G5与免疫检查点阻断有协同作用 并减少免疫检查点治疗引起的结肠毒性。单抗B10G5已针对人类进行了优化 使用(称为huB10G5)，在试点毒性评估中被证明在非人类灵长类动物(NHP)中是安全的，并且是 目前正在进行支持IND的研究。这个孢子项目的目标是完成关键的临床前研究和 将B10G5疗法转化为治疗MPC的潜在疗法。最近，我们发现雄激素 受体(AR)活性通过上调颗粒酶抑制物保护PC细胞免受免疫细胞毒性 SerpinB9和B10G5治疗可激活Fas介导的杀伤。因此，我们假设 靶向抗体huB10G5可作为一种有效的免疫治疗剂用于治疗单一的MPC 或与免疫检查点阻断治疗和/或标准AR靶向治疗相结合。我们 提出三个具体目标：1)明确临床MPC患者的血清MIC水平 肿瘤免疫调节的特点及其与肿瘤免疫调节的关系；2)确定靶向治疗效果 中芯国际单独或联合免疫检查点阻断(ICB)和/或AR靶向治疗 同时进行内脏和骨骼MPC；3)在mCRPC中首次进行人huB10G5的I期临床研究 病人。这些研究将为未来的第一阶段扩展和第二阶段研究提供关键信息。

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.