Project 2: Immunotherapy with CMP-001 intratumoral and nivolumab in melanoma

项目 2：使用 CMP-001 瘤内注射和纳武单抗治疗黑色素瘤的免疫疗法

基本信息

批准号：
10683757
负责人：
HASSANE M ZAROUR
金额：
$ 36.97万
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：
2021-08-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683757
关键词：
Adjuvant Adverse event Agonist Antibodies Antigen Presentation B-Lymphocytes Binding Biological CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 blockade Cancer Vaccines Cell Death Cell Maturation Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Combination immunotherapy Cytosine Defect Dendritic Cells Dendritic cell activation Epitope spreading Epitopes Evaluable Disease Experimental Models Flow Cytometry Frequencies Guanosine Human Immune response Immunotherapy Interferon Type I Interferon alpha Interferons Mediating Melanoma Cell Metastatic Melanoma Methylation Monoclonal Antibodies Mus Necrosis Neoadjuvant Therapy Nivolumab PD-1 blockade Pathologic Patients Peptide Vaccines Phase II/III Clinical Trial Positron-Emission Tomography Production Progression-Free Survivals Property RIPK3 gene Randomized Refractory Resectable Resistance Serious Adverse Event Signal Transduction Skin Cancer Solid Neoplasm Survival Rate T cell receptor repertoire sequencing T cell response T-Lymphocyte TLR9 gene Therapeutic Toxic effect Tumor Antigens Tumor Expansion Tumor Immunity Tumor Promotion Vaccines anti-CTLA4 anti-PD-1 anti-PD1 antibodies antigen-specific T cells beta-2 Microglobulin cancer infiltrating T cells clinical efficacy combinatorial digital exhaust first-in-human high risk immune checkpoint blockade immunogenicity improved in vivo melanoma melanoma-associated antigen neoantigens novel programmed cell death protein 1 programs recruit resistance mechanism response spectrograph transcriptomics tumor tumor microenvironment

项目摘要

PROJECT SUMMARY ABSTRACT: Project 2 Immunotherapy with anti-PD1 monoclonal antibodies (mAbs) is associated with improved response and survival rates in multiple solid tumors, including melanoma1. Anti-PD1 mAbs (anti-PD1) produces durable clinical responses in 33-40% of melanoma patients with minimal toxicity. While dual anti-PD1/anti-CTLA4 blockade produces higher response rates (58%) and 5-year PFS (36%), this is associated with 55% grade 3/4 adverse events. Therefore, there is a critical need for novel combinatorial immunotherapy to improve the efficacy of anti-PD1 while mitigating the rate of serious adverse events in advanced melanoma. One major barrier limiting the efficacy of anti-PD1 is the lack of spontaneous tumor-infiltrating T cells (TILs) and defective IFNa production in tumor microenvironment (TME) in so-called “cold” or non-inflamed tumors. One promising therapeutic approach to overcome this hurdle is via toll-like receptor 9 (TLR9) agonists. TLR9 is predominantly expressed by plasmacytoid dendritic cells (pDCs) and B cells and binds to agonists including unmethylated cytosine guanosine oligodinucleotides (CpG). We have recently performed the first-in-human trial of neoadjuvant intratumoral CMP, a novel type A CpG, and Nivolumab in PD1-naïve high-risk resectable melanoma (NCT03618641). In 30 evaluable melanoma patients, we have observed 60% major pathologic responses with increased CD8+ TILs and peritumoral CD303+ pDCs in injected tumors, and higher frequency circulating PD1+Ki67+CD8+ T cells in responders. Therapy with intratumoral CMP and Nivolumab (CMP/Nivolumab) has also shown clinical efficacy in PD1 refractory melanoma with responses in non-injected tumors, supporting the occurrence of systemic antitumor immunity beyond the injected tumors. To further our understanding of the mechanisms of responses or resistance to CMP/Nivolumab in injected and non-injected tumors, we will take advantage of a substudy of 60 melanoma patients included in the randomized phase II/III clinical trial evaluating CMP/nivolumab vs. nivolumab in PD1 naïve metastatic melanoma with accessible tumors for intratumoral CMP. Based on our preliminary findings, we will investigate whether CMP/Nivolumab :1) increases pDC activation and recruitment into injected tumors to promote CD8+TIL expansion and functions in injected and non-injected tumors; 2) induces melanoma cell death, primes potent neoepitope-specific CD8+T cells in injected tumors, and epitope spreading to melanoma-associated antigens; 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 injected and non-injected tumors of advanced melanoma.

项目摘要摘要：项目2 抗PD1单克隆抗体（mAb）的免疫疗法与改善的反应和包括黑色素瘤在内的多种实体瘤中的存活率。抗PD1 mAb（抗PD1）产生耐用 33-40％的黑色素瘤患者的临床反应最少。而双抗PD1/抗CTLA4 g圈产生较高的响应率（58％）和5年PFS（36％），这与55％的3/4级有关不利事件。因此，新型组合免疫疗法的迫切需要抗PD1的疗效，同时减轻晚期黑色素瘤严重不良事件的速度。一个主要限制抗PD1效率的障碍是缺乏自发性肿瘤渗透T细胞（TIL）和缺陷肿瘤微环境（TME）中的IFNA产生在所谓的“冷”或非炎症肿瘤中。一个诺言克服这一障碍的治疗方法是通过Toll样受体9（TLR9）激动剂。 TLR9主要是由浆细胞样树突状细胞（PDC）和B细胞表达，并与激动剂结合，包括未甲基化的胞嘧啶鸟嘌呤寡核苷酸（CPG）。我们最近进行了人类的第一次试验 NeoAdjuvant肿瘤内CMP，一种新型的A型CpG和Nivolumab，pd1-Nothe-Ne无高风险可切除黑色素瘤（NCT03618641）。在30名可评估的黑色素瘤患者中，我们观察到60％的主要病理学 CD8+ TIL和周围CD303+ PDC注入肿瘤的反应，并且频率更高在响应中循环PD1+Ki67+CD8+T细胞。用肿瘤内CMP和Nivolumab治疗（CMP/Nivolumab）还显示了PD1难治性黑色素瘤的临床效率，未注射的反应肿瘤，支持注射肿瘤以外的全身抗肿瘤免疫。进一步理解注射和未注射的反应机制或对CMP/Nivolumab的抗性肿瘤，我们将利用随机II/III的60例黑色素瘤患者的质量评估CMP/Nivolumab vs. Nivolumab的临床试验，可及可访问的转移性黑色素瘤肿瘤内CMP的肿瘤。根据我们的初步发现，我们将研究CMP/Nivolumab是否：1）将PDC激活和募集到注入的肿瘤中，以促进CD8+TIL扩张和功能注射和未注射的肿瘤； 2）诱导黑色素瘤细胞死亡，素数有效的neoeppitope特异性CD8+T 细胞注射肿瘤，表位扩散到黑色素瘤相关的抗原。 3）无法诱导有效 T细胞反应是由于黑色素瘤细胞 - 超支或黑色素瘤细胞中性机制。集体，该应用程序中的发现将提高我们对响应机制和抵抗的理解黑色素瘤中的CMP/Nivolumab。他们将进一步支持新型组合免疫疗法以进一步增强CMP/Nivolumab注射和未注射的肿瘤的免疫原性和临床活性晚期黑色素瘤。