PD-1 blockade with cryoablation and dendritic vaccine to treat lymphoma

通过冷冻消融和树突状疫苗阻断 PD-1 来治疗淋巴瘤

• 批准号: 10453752
• 负责人: Yi Lin
• 金额: $ 48.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-02 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453752
• 关键词: Adopted; Adverse event; Animals; Antibodies; Antigens; Autologous Dendritic Cells; B-Cell NonHodgkins Lymphoma; Biological Assay; Biopsy; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Etiology; Cells; Cessation of life; Clinical; Clinical Trials; Combination immunotherapy; Cryosurgery; Cytotoxic Chemotherapy; Dendritic Cell Vaccine; Dendritic Cells; Disease; Dose; Effector Cell; Funding; Future; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunosuppression; Immunotherapy; Impairment; Indolent; Injections; Lymphoma; Measures; Mediator of activation protein; Memory; Methods; Modality; Monoclonal Antibodies; Non-Hodgkin' s Lymphoma; Pathogenesis; Patients; Phase; Phase I/II Trial; Phase II Clinical Trials; Phenotype; Pilot Projects; Population; Prediction of Response to Therapy; Property; Proteins; Recurrent disease; Refractory Disease; Regimen; Schedule; Secure; Selection for Treatments; Signal Transduction; T-Lymphocyte; Testing; Time; Toxic effect; Tumor Antigens; United States; Vaccine Therapy; Vaccines; anti-PD1 antibodies; anti-tumor immune response; antigen-specific T cells; cancer type; clinical efficacy; clinical predictors; cytotoxic; design; effective therapy; effector T cell; efficacy evaluation; fighting; immune function; improved; innovation; melanoma; monocyte; non-Hodgkin' s lymphoma patients; novel; novel marker; partial response; pembrolizumab; peripheral blood; phase 1 study; programmed cell death ligand 1; responders and non-responders; response; therapeutic vaccine; treatment response; tumor; tumor microenvironment

The primary object of this proposal is to conduct a Phase II clinical trial testing a novel immunotherapy combination with programmed death protein 1 (PD-1) blockade, cryoablation, and intra-tumor injection of dendritic cell vaccines (DC) in non-Hodgkin lymphoma (NHL). NHL is the seventh most common type of cancer and one of the top ten causes of cancer deaths in United States. Patients with aggressive NHL continue to have poor survival with salvage treatments at the time of relapsed or refractory disease. Indolent NHL remains incurable, making less toxic but effective treatment an important part of therapy selection consideration. For both these considerations, immunotherapy has been one of the most exciting advances in the recent years. We have completed a Phase I study treating NHL patients with cryoablation and intra-tumor injections of autologous DC into the cryoablated tumors. This treatment was very well tolerated with no major adverse events. More importantly, abscopal systemic response was seen with this non-toxic, localized immunotherapy approach. Five of the 10 treated patients had partial response with an average time to progression of 64 weeks (range 51-80 weeks). Building on this promising approach, we have identified two deficiencies that can be targeted with PD-1 blockade: 1. DCs have increased PD-L1 (programmed death ligand-1) expressions that impairs their ability to prime CD8 T cell for antigen-specific responses; 2. Increased presence of a novel population of tumor-reactive CD8 T cells in the blood and tumors of lymphoma patients with decreased effector functions and capacity to differentiate into memory cells. We hypothesize that the combination of PD-1 blockade with monoclonal antibody Pembrolizumab (supplied by Merck), cryoablation and intra-tumor DC therapy will improve clinical efficacy through improved anti-lymphoma immunity through a combination of increased antigenic response, increased effector function and or decreased immunosuppressive phenotype. We have designed a Phase I/II study and secured funding for the Phase I portion of the study where the MTD of this combination will be determined. In this proposed study, we aim to complete the phase II portion of the study to determine the clinical efficacy and examine the immunity changes with this novel combination immunotherapy in NHL.

该提案的主要目的是进行 II 期临床试验，测试一种新型免疫疗法 结合程序性死亡蛋白 1 (PD-1) 阻断、冷冻消融和肿瘤内注射 非霍奇金淋巴瘤 (NHL) 的树突状细胞疫苗 (DC)。 NHL 是第七种最常见的癌症 也是美国十大癌症死因之一。侵袭性 NHL 患者继续 在复发或难治性疾病时，通过抢救治疗生存率较差。惰性 NHL 依然存在 无法治愈，因此毒性较小但有效的治疗成为治疗选择考虑的重要组成部分。为了 考虑到这些因素，免疫疗法一直是近年来最令人兴奋的进展之一。 我们已经完成了一项通过冷冻消融和肿瘤内注射治疗 NHL 患者的 I 期研究 将自体 DC 注入冷冻消融的肿瘤中。这种治疗的耐受性非常好，没有出现重大不良反应 事件。更重要的是，这种无毒的局部免疫疗法观察到了远隔系统反应 方法。 10 名接受治疗的患者中有 5 名出现部分缓解，平均进展时间为 64 周 （范围 51-80 周）。基于这种有前途的方法，我们发现了两个可以弥补的缺陷 以 PD-1 阻断为目标： 1. DC 增加了 PD-L1（程序性死亡配体-1）表达， 损害其启动 CD8 T 细胞进行抗原特异性反应的能力； 2.增加小说的存在感 效应细胞减少的淋巴瘤患者血液和肿瘤中肿瘤反应性 CD8 T 细胞群 具有分化成记忆细胞的功能和能力。我们假设 PD-1 的组合 单克隆抗体 Pembrolizumab（Merck 提供）阻断、冷冻消融和肿瘤内 DC 治疗将通过结合以下方法改善抗淋巴瘤免疫力来提高临床疗效 增强的抗原反应、增强的效应器功能和/或降低的免疫抑制表型。 我们设计了一项 I/II 期研究，并为该研究的 I 期部分获得了资金，其中 MTD 该组合的值将被确定。在这项拟议的研究中，我们的目标是完成第二阶段部分 研究以确定这种新组合的临床疗效并检查免疫变化 NHL 中的免疫治疗。