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期临床试验测试新的免疫疗法 结合程序性死亡蛋白1（PD-1）阻滞，冷冻和肿瘤内注射 非霍奇金淋巴瘤（NHL）中的树突状细胞疫苗（DC）。 NHL是第七种最常见的癌症类型 这是美国癌症死亡的十大原因之一。具有侵略性NHL的患者继续 复发或难治性疾病时的救助治疗生存率差。保留了懒惰的NHL 无法治愈，使毒性较小但有效的治疗是治疗选择考虑的重要部分。为了 这两种考虑因素，免疫疗法一直是近年来最令人兴奋的进步之一。 我们已经完成了I期研究，以治疗NHL患者的冷冻和注射肿瘤内注射 自体DC进入冷冻肿瘤。这种治疗的耐受性很好，没有重大不良 事件。更重要的是，使用这种无毒的局部免疫疗法可以看到潜线的全身反应 方法。 10例治疗患者中有5个具有部分反应，平均进展为64周 （范围为51-80周）。在这种有前途的方法的基础上，我们确定了两种缺陷 针对PD-1封锁：1。DCS已增加PD-L1（编程死亡配体1）表达式表达 损害其为抗原特异性反应的CD8 T细胞启用的能力； 2。小说的存在增加 淋巴瘤患者的血液和肿瘤中肿瘤反应性CD8 T细胞的种群患者的肿瘤降低 分化为记忆单元的功能和能力。我们假设PD-1的组合 用单克隆抗体Pembrolizumab（由默克提供），冷冻和肿瘤内DC的封锁 治疗将通过改善抗淋巴瘤免疫力通过结合的抗淋巴瘤免疫来提高临床功效 抗原反应增加，效应子功能的增加和或免疫抑制表型降低。 我们设计了一项I/II期研究并获得了MTD的研究的第一阶段部分的资金 将确定这种组合。在这项拟议的研究中，我们旨在完成该研究的第二阶段部分 研究以确定临床功效并检查这种新型组合的免疫力变化 NHL的免疫疗法。