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

项目摘要 前列腺癌是一个重要的全球性健康问题，需要新的治疗方法。目标 在过去的二十年里，我们的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，并将最近的研究重点放在 在雄激素受体（AR LBD）的配体结合域上的努力作为靶点。我们证明， 编码AR LBD的DNA疫苗（pTVG-AR）可在HLA-A2中诱导表位特异性溶细胞性CD 8 + T细胞 转基因小鼠和前列腺荷瘤小鼠的免疫引起抗肿瘤反应， 延长了他们的总体生存期。基于这些结果，我们最近完成了一项多中心I期临床试验， 一项使用pTVG-AR疫苗治疗转移性前列腺癌患者的试验证明， 安全且具有免疫活性。与我们的临床前研究一致，T细胞免疫的发展 对AR LBD的反应与去势抵抗时间延长相关。 在临床前研究中，我们发现雄激素剥夺（AD）导致AR过度表达， 前列腺癌细胞中的蛋白质，这反过来又使它们更容易被AR激活的CD 8 + T细胞识别。 有针对性的疫苗接种。我们随后证明，AD因此可以战略性地与 次免疫在其他临床前研究中，我们进一步发现，通过接种疫苗激活的CD 8 + T细胞 表达多种免疫检查点受体（ICR），并且用疫苗接种阻断某些ICR导致 更大的抗肿瘤作用。 总之，这些发现导致了本提案中要测试的假设，即将AD与 AR靶向疫苗接种和T细胞检查点阻断，将导致肿瘤特异性CD 8 + T细胞增加 浸润、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， 癌症进行机制评估的影响，AD与疫苗接种和ICR封锁， T细胞记忆和抗原扩散的发展。这种方法也将在研究者中进行评估- 在前列腺切除术前的高危前列腺癌患者中启动临床试验，设计符合 根据临床前研究的结果修改研究组。因此，这项建议， 利用目前已完成I期临床试验评估的新型抗肿瘤疫苗的开发， 并探索了在临床前模型和生物标志物驱动的临床研究中提高其治疗效果的方法。 审判该提案的结果将确定进一步临床研究的最佳策略和临床场景。 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.