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

瘤内 CPG 和 PD-1 阻断的新辅助免疫治疗黑色素瘤

• 批准号: 10352418
• 负责人: Diwakar Davar
• 金额: $ 53.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352418
• 关键词: Adjuvant; Adjuvant Study; Adverse event; Affect; Agonist; Antibodies; Antigen Presentation; B cell differentiation; B-Lymphocytes; Binding; Biological; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 blockade; Cancer Vaccines; Cell Death; Cell Maturation; Clinic; Clinical; Clinical Trials; Combination immunotherapy; Consensus; Cytosine; Defect; Dendritic Cells; Dendritic cell activation; Disease; Evaluation; Exhibits; Experimental Models; Exposure to; Flow Cytometry; Guanosine; Human; Image; Immunologics; Immunotherapy; Impairment; Interferon-alpha; Interferons; Interleukin-10; Mediating; Melanoma Cell; Monoclonal Antibodies; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; Nivolumab; PD-1 blockade; Pathologic; Patients; Peptide Vaccines; Plasma Cells; Production; Property; RIPK3 gene; Refractory; Relapse; Resectable; Resected; Resistance; Signal Transduction; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; TLR9 gene; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Translations; Tumor Antigens; Vaccines; anti-PD1 antibodies; base; cancer therapy; clinical development; clinical efficacy; combinatorial; efficacy evaluation; exhaust; first-in-human; high risk; immune checkpoint blockade; immunogenicity; immunotherapy trials; improved; melanoma; neoantigens; novel; phase III trial; primary endpoint; programmed cell death protein 1; randomized trial; recruit; response; single-cell RNA sequencing; tumor; tumor microenvironment

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.

项目摘要 具有临床可检测III期的高风险可切除黑色素瘤患者（MP），有或无过境 转移有高风险复发1.抗PD 1单克隆抗体新辅助免疫治疗黑色素瘤 单独的抗体在25-30%的MP中显示出免疫学、病理学和临床应答的证据， 毒性极小。Neoajduvant PD 1/CTLA 4阻断进一步改善了病理学和临床反应， 在73-90%的治疗的黑素瘤患者中引起3级不良事件。这些观察提示 新辅助免疫治疗代表了一种用于早期评估疗效和治疗效果的有吸引力的方法。 黑色素瘤的新型组合免疫疗法的毒性。在本申请中，我们提出 评估CMP-001（CMP），一种A型CpG，具有几种独特的特性，支持其在 增加抗原呈递和T细胞引发。与临床上测试的其他CpG相比，CMP似乎 有效诱导浆细胞样树突状细胞（pDC）产生IFNα，但不产生IL 10。因此，这是一个非常 有前途的治疗剂，以规避缺乏干扰素α生产观察“冷”肿瘤，这是 T细胞浸润不良，并且不能对免疫检查点阻断做出反应。评定疗效和 CMP在黑色素瘤中的毒性，我们已经实施了第一次在人类新辅助临床试验与CMP 肿瘤内注射和Nivolumab（CMP/Nivolumab）治疗PD 1初治的高风险可切除黑色素瘤患者。的 研究的主要终点是主要病理学反应的发生率，包括病理学完全反应和 使用共识标准评估接近完成。在本申请中，我们将确定 对CMP/Nivolumab的反应或抗性。根据我们的初步调查结果，我们调查是否 CMP/纳武单抗：1）增加肿瘤微环境中的pDC活化和成熟，以促进肿瘤微环境中的细胞分化。 CD 8 +TIL扩增和功能; 2）诱导黑色素瘤细胞死亡并引发有效的新表位特异性免疫应答。 CD 8 +T细胞;和3）由于黑色素瘤细胞外源性或黑色素瘤， 细胞内在机制总的来说，本申请中的发现将提高我们对 在黑素瘤中对CMP/Nivolumab的应答和抗性机制。他们将进一步支持小说 进一步增强CMP/Nivolumab的免疫原性和临床活性的组合免疫疗法 黑色素瘤