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

基本信息

批准号：
10574567
负责人：
Diwakar Davar
金额：
$ 53.45万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10574567
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 Immunologics Immunotherapy Impairment In complete remission Interferon Type I Interferon alpha Interferons Interleukin-10 Mediating Melanoma Cell 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 infiltration T cell receptor repertoire sequencing T cell response T-Lymphocyte TLR9 gene Testing Therapeutic Therapeutic Agents Toxic effect Translations Tumor Antigens Tumor Expansion Tumor Promotion Vaccines anti-PD-1 anti-PD1 antibodies antigen-specific T cells cancer infiltrating T cells 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 relapse risk response single-cell RNA sequencing spectrograph tumor tumor microenvironment

项目摘要

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.

项目概要摘要临床可检测到的 III 期高风险可切除黑色素瘤患者（MP），无论是否在途使用抗 PD1 单克隆抗体对黑色素瘤进行新辅助免疫治疗具有高风险复发。单独使用抗体在 25-30% 的 MP 中显示出免疫学、病理学和临床反应的证据 Neoajduvant PD1/CTLA4 阻断进一步改善了病理和临床反应，同时毒性最小。 73-90% 接受治疗的黑色素瘤患者出现 3 级不良事件。新辅助免疫治疗是一种早期评估疗效和治疗效果的有吸引力的方法。在本申请中，我们提出了黑色素瘤的新型组合免疫疗法的毒性。评估 CMP-001 (CMP)，这是一种 A 型 CpG，它具有多种独特的特性，支持其在与临床上测试的其他 CpG 相比，CMP 似乎增加了抗原呈递和 T 细胞启动。有效诱导浆细胞样树突状细胞 (pDC) 产生 IFNα，但不产生 IL10，因此这是一种非常有效的方法。治疗剂以避免在“冷”肿瘤中观察到的 IFNα 产生的有希望的缺乏，这些肿瘤是 T 细胞浸润不良且无法对免疫检查点封锁做出反应以评估疗效和针对 CMP 对黑色素瘤的毒性，我们实施了首个 CMP 人体新辅助临床试验瘤内注射和纳武单抗 (CMP/Nivolumab) 用于 PD1 初治高风险可切除黑色素瘤患者。该研究的主要终点是主要病理反应率，包括病理完全反应和使用共识标准评估的接近完成在本应用程序中，我们将确定以下机制：根据我们的初步发现，我们调查是否对 CMP/Nivolumab 产生反应或耐药。 CMP/Nivolumab :1) 增加肿瘤微环境中的 pDC 活化和成熟，以促进 CD8+TIL 扩增和功能；2) 诱导黑色素瘤细胞死亡并启动有效的新表位特异性 CD8+T 细胞；3) 由于黑色素瘤细胞外源性或黑色素瘤而无法诱导有效的 T 细胞反应总的来说，本申请的发现将增进我们对细胞内在机制的理解。他们将进一步支持黑色素瘤对 CMP/Nivolumab 的反应和耐药机制。组合免疫疗法进一步增强 CMP/Nivolumab 的免疫原性和临床活性在黑色素瘤中。