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

该提案的主要目的是进行一项新的免疫疗法的II期临床试验 联合程序性死亡蛋白1（PD-1）阻断、冷冻消融和肿瘤内注射 树突状细胞疫苗（DC）在非霍奇金淋巴瘤（NHL）。NHL是第七种最常见的癌症 也是美国十大癌症死亡原因之一。侵袭性NHL患者继续 在复发或难治性疾病时接受挽救治疗的生存率很低。惰性NHL仍然存在 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，免疫疗法是近年来最令人兴奋的进展之一。 我们已经完成了一项I期研究，通过冷冻消融和肿瘤内注射 自体DC注入冷冻消融的肿瘤中。该治疗耐受性良好，无重大不良反应 事件更重要的是，这种无毒的局部免疫疗法可观察到远位全身反应 approach. 10名接受治疗的患者中有5名部分缓解，平均进展时间为64周 （范围51 - 80周）。在这种有希望的方法的基础上，我们发现了两个可以改进的不足之处。 靶向PD-1阻断：1. DC具有增加的PD-L1（程序性死亡配体-1）表达， 削弱其引发CD8 T细胞抗原特异性应答的能力; 2.增加小说的存在感 淋巴瘤患者血液和肿瘤中的肿瘤反应性CD8 T细胞群， 功能和能力分化成记忆细胞。我们假设PD-1和 单克隆抗体Pembrolizumab（默克公司提供）阻断、冷冻消融和肿瘤内DC 治疗将通过改善抗淋巴瘤免疫力来提高临床疗效， 增加的抗原应答、增加的效应子功能和/或降低的免疫抑制表型。 我们设计了一项I/II期研究，并为研究的I期部分获得了资金，其中MTD 这个组合将被确定。在这项拟议研究中，我们的目标是完成 确定这种新型组合的临床疗效并检查免疫力变化的研究 NHL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.