Project 2: Androgen deprivation as an immune modulating therapy in combination with targeted immunotherapy of prostate cancer

项目总结 前列腺癌是一个重大的世界性健康问题，需要新的治疗方法。目标是 在过去的二十年里，我们实验室一直致力于开发前列腺癌的免疫疗法。 我们已经评估了多种癌症相关蛋白作为抗肿瘤疫苗的靶点，并在最近 努力将雄激素受体的配体结合域(AR LBD)作为靶点。我们展示了一个 编码AR LBD的DNA疫苗(pTVG-AR)可诱导人类白细胞抗原A2表位特异性的CD8+T细胞 转基因小鼠和前列腺癌荷瘤小鼠的免疫诱导抗肿瘤反应和显著 延长了它们的总体生存时间。基于这些结果，我们最近完成了一项多中心I期临床试验。 转移性前列腺癌患者使用pTVG-AR疫苗的试验证明，疫苗接种 是安全的，而且具有免疫活性。与我们的临床前研究一致，T细胞免疫的发展 对AR LBD的反应与对去势抵抗的时间延长有关。 在临床前研究中，我们发现雄激素剥夺会导致AR的过度表达 蛋白质，这反过来使它们更多地被AR-1激活的CD8+T细胞识别。 有针对性的接种疫苗。我们随后演示了AD因此可以战略性地用于 免疫接种。在其他临床前研究中，我们进一步发现，接种疫苗后CD8+T细胞被激活 表达多个免疫检查点受体(ICR)，用疫苗阻断某些ICR会导致 更强的抗肿瘤作用。 总而言之，这些发现导致了要在该提案中检验的假设，该方案将AD和 AR靶向接种和T细胞检查点阻断将导致肿瘤特异性CD8+T细胞增加 渗透、肿瘤根除和持久免疫记忆。我们将使用相关的小鼠前列腺模型 癌症将对接种疫苗和阻断ICR对AD的影响进行机械评估 T细胞记忆的发展和抗原的传播。这一方法也将在一名调查员身上进行评估- 在前列腺癌高危患者行前列腺癌切除术前启动临床试验，设计符合 根据临床前研究的结果修改研究臂。因此，这项提议， 利用一种新型抗肿瘤疫苗的开发，该疫苗现已完成第一阶段临床试验评估， 并探索在临床前模型和生物标记物驱动的临床中提高其治疗效果的方法 审判。这项提案的结果将确定进一步临床应用的最佳策略和临床方案 这种治疗方法的发展。

PROJECT SUMMARY Prostate cancer is a significant worldwide health problem for which new treatments are needed. The goal of our laboratory for the past twenty years has been to develop immunotherapy treatments for prostate cancer. We have evaluated multiple cancer-associated proteins as anti-tumor vaccine targets and have focused recent efforts on the ligand-binding domain of the androgen receptor (AR LBD) as a target. We demonstrated that a DNA vaccine encoding the AR LBD (pTVG-AR) can elicit epitope-specific cytolytic CD8+ T cells in HLA-A2 transgenic mice, and immunization of prostate tumor-bearing mice elicited anti-tumor responses and significantly prolonged their overall survival. Based on these results, we recently completed a multi-center phase I clinical trial using the pTVG-AR vaccine for patients with metastatic prostate cancer and demonstrated that vaccination is safe and immunologically active. Consistent with our preclinical studies, the development of T-cell immune response to the AR LBD was associated with a prolonged time to castration resistance. In preclinical studies, we have found that androgen deprivation (AD) leads to overexpression of the AR protein in prostate cancer cells, and this in turn makes them more recognized by CD8+ T cells activated by AR- targeted vaccination. We have subsequently demonstrated that AD can thus be used strategically with immunization. In other preclinical studies, we have further found that CD8+ T cells activated by vaccination express multiple immune checkpoint receptors (ICR), and that blockade of certain ICR with vaccination leads to greater anti-tumor effects. Together, these findings have led to the hypothesis to be tested in this proposal that combined AD, with AR-targeted vaccination and T-cell checkpoint blockade, will lead to increased tumor-specific CD8+ T cell infiltration, tumor eradication, and persistent immune memory. We will use relevant murine models of prostate cancer to conduct a mechanistic evaluation of the effects of AD with vaccination and ICR blockade on the development of T cell memory and antigen spread. This approach will also be evaluated in an investigator- initiated clinical trial in patients with high-risk prostate cancer prior to prostatectomy, with a design amenable to modification of study arms depending on the outcomes from the preclinical studies. This proposal, consequently, capitalizes on development of a novel anti-tumor vaccine that has now completed phase I clinical trial evaluation, and explores methods to increase its therapeutic effect in preclinical models and in a biomarker-driven clinical trial. Results from this proposal will identify optimal strategies and clinical scenarios for further clinical development of this treatment approach.