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

这项建议的主要目的是进行第二阶段临床试验，测试一种新的免疫疗法。 联合PD-1阻断、冷冻消融和肿瘤内注射 树突状细胞疫苗(DC)治疗非霍奇金淋巴瘤(NHL)非霍奇金淋巴瘤是第七种最常见的癌症 也是美国十大癌症致死原因之一。侵袭性非霍奇金淋巴瘤患者继续 在复发或难治性疾病时接受抢救治疗的存活率较低。惰性NHL残留 不可治愈，使毒性较小但有效的治疗成为治疗选择考虑的重要部分。为 考虑到这两点，免疫治疗是近年来最令人兴奋的进展之一。 我们已经完成了一项治疗NHL患者的I期研究，采用冷冻消融和肿瘤内注射 自体树突状细胞植入冷冻消融的肿瘤。这种疗法耐受性很好，没有重大不良反应。 事件。更重要的是，这种无毒、局部的免疫疗法出现了非局部性的全身反应。 接近。10例接受治疗的患者中有5例部分缓解，平均进展时间为周 (范围51-80周)。在这个有希望的方法的基础上，我们已经确定了两个可以 以PD-1阻断为靶点：1.DC增加PD-L1(程序性死亡配体-1)的表达， 削弱他们启动CD8 T细胞进行抗原特异性反应的能力；2.一种新的 效应性降低的淋巴瘤患者血液和肿瘤中肿瘤反应性CD8 T细胞的数量 分化为存储单元的功能和能力。我们假设PD-1的结合 用单抗pembrolizumab(由默克公司提供)阻断、冷冻消融和肿瘤内DC 治疗将通过联合使用以下药物提高抗淋巴瘤免疫力来提高临床疗效 抗原反应增强，效应器功能增强和/或免疫抑制表型减少。 我们已经设计了一项第一阶段/第二阶段的研究，并为研究的第一阶段部分获得了资金，在该部分中，MTD 这一组合的结果将会被确定。在这项拟议的研究中，我们的目标是完成 联合用药的临床疗效及免疫功能变化的研究 非霍奇金淋巴瘤的免疫治疗。

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.