Determinants of prostate cancer sensitivity to PD-1 blockade

项目总结/摘要 虽然免疫疗法已经改变了许多恶性肿瘤的治疗，但这种影响尚未完全消除。 前列腺癌（PCa）是最常见的癌症之一。根据第1阶段的结果，PCa是 目前认为对抗PD-1单药治疗的检查点抑制无反应。然而，新兴数据 表明10-30%的转移性PCa可以对抗PD-1应答。鉴于之前的研究表明 具有微卫星不稳定性的癌症对抗PD-1反应良好，值得注意的是，错配修复或 其他DNA修复途径涉及约20%的PCa，并且可以通过增加抗PD-1应答来调节抗PD-1应答。 新抗原产生。总之，这些发现提出了几个挑战：证明特定的DNA损伤 修复缺陷（DRD）与PCa中的PD-1反应有关，并且在PD-1无反应的患者中激发反应。 PCa，特别是那些缺乏与反应相关的遗传特征的PCa。我们的假设是 PCa患者缺乏足够的预先存在的抗肿瘤免疫应答，其可以通过抗PD-1扩增， 介导临床反应。我们建议通过选择以下患者来提高应答率： 特异性DRD，或将PD-1阻断与化疗相结合。我们正在启动一项2期研究， 转移性去势抵抗性前列腺癌（CRPC）患者，评价抗PD-1的临床疗效 治疗重要的是，我们将选择具有或缺乏DNA修复缺陷的患者，这些患者最近 在CRPC中描述。我们假设有这些缺陷的患者不仅会有更高的 突变负荷导致新抗原产生增加，但也会导致先天DNA的激活， 感测免疫途径，这两者都将导致免疫刺激环境。肿瘤和血液样本 将使用本临床试验得出的数据来检验这些假设。在目标1中，我们将确定肿瘤- 反应的内在分子决定因素，重点是MSI状态，DRD的存在，包括定义的 与DRD相关的体细胞或生殖系改变、新抗原负荷和表达特征。相反 由于仅由新抗原负荷驱动，我们预计应答将与特异性 DRD与免疫激活的分级水平相关，这可以通过我们对 配对样本中的免疫激活。在目标2中，我们将测试具有这些DRD的肿瘤是否具有 肿瘤内免疫浸润和PD-L1表达增加，以及循环免疫增强 治疗前或治疗期间。这种增强的免疫激活也将反映在更高频率的 肿瘤反应性T细胞，我们可以通过血液和肿瘤的T细胞受体测序来追踪。在目标3中， 将研究抗PD-1治疗是否会诱导免疫选择压力，从而导致克隆进化 在肿瘤中。总的来说，这项工作不仅会促进我们对肿瘤反应的理解， 免疫检查点阻断，而且还加速了预测反应的生物标志物的开发， 将为CRPC患者获益的临床相关联合治疗提供依据。

PROJECT SUMMARY/ABSTRACT While immunotherapy has transformed treatment for numerous malignancies, this impact has not yet been fully realized in prostate cancer (PCa), one of the most common cancers. Based on Phase 1 results, PCa is currently felt to be unresponsive to checkpoint inhibition with anti-PD-1 monotherapy. However, emerging data indicates that 10-30% of metastatic PCa can respond to anti-PD-1. Given previous studies suggesting that cancers with microsatellite instability respond well to anti-PD-1, it is notable that defects in mismatch repair or other DNA repair pathways involve ~20% of PCa and could modulate anti-PD-1 response by increasing neoantigen production. Together, these findings pose several challenges: proving that specific DNA damage repair defects (DRDs) are linked to PD-1 responses in PCa, and inciting responses in PD-1-nonresponsive PCa, particularly those that lack the genetic signatures associated with response. Our hypothesis is that most PCa patients lack sufficient pre-existing anti-tumor immune responses that can be amplified by anti-PD-1 to mediate clinical responses. We propose that response rates can be increased by selecting patients with specific DRDs, or by combining PD-1 blockade with chemotherapy. We are initiating a phase 2 study in patients with metastatic castration resistant prostate cancer (CRPC) evaluating the clinical efficacy of anti-PD-1 treatment. Importantly, we will select patients that either possess or lack DNA repair defects that have recently been described in CRPC. We hypothesize that patients with these defects will not only have a higher mutational burden leading to increased neoantigen production, but will also lead to activation of innate DNA- sensing immune pathways, both of which will lead to an immuno-stimulatory milieu. Tumor and blood samples derived from this clinical trial will be used to test these hypotheses. In Aim 1, we will determine the tumor- intrinsic molecular determinants of response with a focus on MSI status, presence of DRDs including defined somatic or germline alterations, neoantigen burden, and expression signatures associated with DRD. Instead of being driven solely by neoantigen burden, we anticipate that responses will be associated with specific DRDs that correlate with graded levels of immune activation, which can be corroborated by our assessment of immune activation in paired samples. In Aim 2, we will test whether tumors with these DRDs possess increased intratumoral immune infiltration and PD-L1 expression, as well as heightened circulating immunity before or during treatment. This enhanced immune activation will also be reflected in a higher frequency of tumor-reactive T cells that we can track with T cell receptor sequencing of both blood and tumor. In Aim 3, we will examine whether anti-PD-1 treatment induces immuno-selective pressure that can lead to clonal evolution in the tumor. Collectively this work will not only advance our understanding of what makes a tumor responsive to immune checkpoint blockade, but also accelerate the development of biomarkers predictive of response and will provide the rationale for clinically relevant treatment combination therapies to benefit patients with CRPC.