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：
10270232
负责人：
HASSANE M ZAROUR
金额：
$ 36.39万
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/10270232
关键词：
Adjuvant Adverse event Agonist 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 Cutaneous Melanoma Cytosine Defect Dendritic Cells Dendritic cell activation Epitope spreading Epitopes Evaluable Disease Experimental Models Flow Cytometry Frequencies Guanosine Human Image Immune response Immunotherapy 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 Immunity Vaccines anti-PD-1 anti-PD1 antibodies base beta-2 Microglobulin clinical efficacy combinatorial digital exhaust first-in-human high risk immune checkpoint blockade immunogenicity improved in vivo melanoma melanoma-associated antigen neoantigens neoplastic cell novel programmed cell death protein 1 programs recruit resistance mechanism response 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 使用抗 PD1 单克隆抗体 (mAb) 的免疫疗法与改善反应有关，并且多种实体瘤（包括黑色素瘤）的存活率可产生持久的效果。 33-40% 的黑色素瘤患者有临床反应，而双抗 PD1/抗 CTLA4 的毒性最小。封锁产生更高的响应率 (58%) 和 5 年 PFS (36%)，这与 55% 的 3/4 级相关因此，迫切需要新型组合免疫疗法来改善不良事件。抗 PD1 的疗效，同时降低晚期黑色素瘤严重不良事件的发生率。限制抗 PD1 疗效的屏障是缺乏自发性肿瘤浸润 T 细胞 (TIL) 和缺陷在所谓的“冷”或非炎症肿瘤的肿瘤微环境（TME）中产生 IFNa 是一种有希望的方法。克服这一障碍的治疗方法主要是通过 Toll 样受体 9 (TLR9) 激动剂。由浆细胞样树突状细胞 (pDC) 和 B 细胞表达，并与包括未甲基化在内的激动剂结合我们最近进行了胞嘧啶鸟苷寡二核苷酸（CpG）的首次人体试验。新辅助瘤内 CMP（一种新型 A 型 CpG）和纳武单抗在 PD1 初治高危可切除患者中的应用黑色素瘤 (NCT03618641) 在 30 名可评估的黑色素瘤患者中，我们观察到 60% 为主要病理学。注射肿瘤中 CD8+ TIL 和瘤周 CD303+ pDC 增加的反应，且频率更高使用瘤内 CMP 和 Nivolumab 治疗应答者中的循环 PD1+Ki67+CD8+ T 细胞。 (CMP/Nivolumab) 还显示出对 PD1 难治性黑色素瘤的临床疗效，在非注射治疗中也有反应肿瘤，支持注射肿瘤之外的全身抗肿瘤免疫的发生。了解注射和非注射对 CMP/Nivolumab 的反应或耐药机制肿瘤，我们将利用随机 II/III 期纳入的 60 名黑色素瘤患者的亚组研究评估 CMP/nivolumab 与 nivolumab 治疗 PD1 初治转移性黑色素瘤的临床试验根据我们的初步研究结果，我们将研究 CMP/Nivolumab 是否适用于肿瘤。 :1) 增加 pDC 激活和招募到注射肿瘤中，以促进 CD8+TIL 扩增和功能在注射和非注射肿瘤中；2) 诱导黑色素瘤细胞死亡，引发有效的新表位特异性 CD8+T 注射肿瘤中的细胞，以及扩散至黑色素瘤相关抗原的表位；3) 未能诱导有效；由于黑色素瘤细胞外在或黑色素瘤细胞内在机制而产生的 T 细胞反应。该应用中的发现将提高我们对响应和抵抗机制的理解他们将进一步支持新型组合免疫疗法以进一步治疗黑色素瘤。增强 CMP/Nivolumab 在注射和非注射肿瘤中的免疫原性和临床活性晚期黑色素瘤。