Neoadjuvant Immunotherapy with Intratumoral CPG and PD-1 Blockade in Melanoma

项目总结摘要 临床可检测到III期的高危可切除黑色素瘤患者(MPS) 转移瘤复发的风险很高。抗PD1单抗新辅助免疫治疗黑色素瘤 在25-30%的MPS中，仅抗体就显示出免疫、病理和临床反应的证据 毒性最小。Neoajduvant PD1/CTLA4阻断进一步改善病理和临床反应 导致73-90%接受治疗的黑色素瘤患者发生3级不良事件。这些观察结果表明 新辅助免疫疗法是一种吸引人的方法，可用于早期评估疗效和 黑色素瘤新型联合免疫疗法的毒性。在本申请中，我们建议 评价CMP-001(CMP)，一种A型CpG，具有几个独特的属性，支持其在 增加抗原呈递和T细胞启动。与临床上检测的其他CPGS不同的是，CMP出现了 能有效诱导浆细胞样树突状细胞(PDCs)产生干扰素α，但不产生IL10。因此，它是一种非常 有希望的治疗药物，以避免缺乏干扰素α的“冷”肿瘤观察到，这是 T细胞渗透不良，对免疫检查点阻断无反应。为了评估疗效和 化学发光蛋白在黑色素瘤中的毒性，我们已经实施了人类第一次使用化学发光蛋白进行新辅助临床试验 PD1单纯高危可切除黑色素瘤患者的瘤内和尼伏卢单抗(CMP/Nivolumab)。这个 研究的主要终点是主要病理应答率，包括病理完全和 使用协商一致标准进行评估，接近完成。在本应用程序中，我们将确定 对CMP/Nivolumab的反应或耐药性。基于我们的初步发现，我们调查了 CMP/Nivolumab：1)促进肿瘤微环境中PDC的激活和成熟，以促进 CD8+TIL的扩增和功能；2)诱导黑色素瘤细胞死亡和启动新表位特异性 CD8+T细胞；以及3)由于黑色素瘤细胞-外源性或黑色素瘤-未能诱导强大的T细胞反应 细胞内在机制。总的来说，本申请中的发现将提高我们对 黑色素瘤对CMP/Nivolumab的反应和耐药机制。他们将进一步支持小说 联合免疫疗法进一步提高CMP/Nivolumab的免疫原性和临床活性 死于黑色素瘤。

PROJECT SUMMARY ABSTRACT High-risk resectable melanoma patients (MPs) with clinically detectable stage III with or without in-transit metastases have high-risk relapse1. Neoadjuvant immunotherapy of melanoma with anti-PD1 monoclonal antibodies alone showed evidence of immunological, pathological and clinical responses in 25-30% MPs with minimal toxicity. Neoajduvant PD1/CTLA4 blockade further improved pathological and clinical responses while causing grade 3 adverse events in 73-90% treated melanoma patients. These observations suggest that Neoadjuvant immunotherapy represents an appealing approach for the early assessment of the efficacy and toxicity of novel combinatorial immunotherapies of melanoma. In the present application, we propose to evaluate CMP-001 (CMP), a type A CpG which has several unique properties supporting its potency in increasing antigen presentation and T cell priming. In contrast to other CpGs tested in the clinic, CMP appears to potently induce IFNα but no IL10 production by plasmacytoid dendritic cells (pDCs). It is therefore a very promising therapeutic agent to circumvent the lack of IFNα production observed in “cold” tumors, which are poorly T cell-infiltrated and fail to response to immune checkpoint blockade. To evaluate the efficacy and toxicity of CMP in melanoma, we have implemented the first-in-human neoadjuvant clinical trial with CMP intratumoral and Nivolumab (CMP/Nivolumab) in PD1 naïve high-risk resectable melanoma patients. The primary end-point of the study is the rate of major pathologic response, comprising pathological complete and near-complete as assessed using consensus criteria. In this application, we will determine the mechanisms of responses or resistance to CMP/Nivolumab. Based on our preliminary findings, we investigate whether CMP/Nivolumab :1) increases pDC activation and maturation in the tumor microenvironment to promote CD8+TIL expansion and functions; 2) induces melanoma cell death and primes potent neoepitope-specific CD8+T cells; and 3) fails to induce potent T cell responses because of melanoma cell-extrinsic or melanoma cell-intrinsic mechanisms. Collectively, the findings in this application will improve our understanding of the mechanisms of response and resistance to CMP/Nivolumab in melanoma. They will further support novel combinatorial immunotherapies to further enhance the immunogenicity and clinical activity of CMP/Nivolumab in melanoma.