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: 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
• 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

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