Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma

项目1：主动免疫疗法联合检查点调节治疗胶质母细胞瘤 总结/摘要 胶质母细胞瘤（GBM）患者缺乏有效的治疗仍然是一个重大的健康问题， 强调需要新颖和创新的方法。免疫疗法是一种有吸引力的策略，因为 免疫细胞运输并破坏脑中浸润的肿瘤细胞的潜在能力。临床前研究 树突状细胞（DC）疫苗接种GBM的临床试验已经显示出一些有希望的结果，但也有一些 治疗失败。该研究项目的总体目标是研究免疫机制， 主动免疫治疗后的逃避，并制定合理的免疫策略组合 以克服脑肿瘤微环境的免疫抑制环境。我们新的初步数据 这强烈表明，DC疫苗接种的主动免疫疗法可能会产生促炎性肿瘤， 微环境，诱导免疫抑制性抗原呈递细胞（iAPC）的迁移， 表达高水平的PD-L1和IL-10。我们发现，这些细胞在表型上与iAPC相似， 主要影响T细胞对慢性病毒感染的反应，并可能抵消有效的T细胞 DC疫苗接种通过涉及PDL 1/PD-1的机制诱导的免疫应答。此外，抑制iAPC 使用抗PD 1 mAb（Nivolumab，BMS）或CSF-1 R的CNS渗透抑制剂（PLX-3397，Plexxikon）， 与肿瘤裂解物推动的DC疫苗接种（DC-Vax-L）结合，导致在2011年12月至2012年12月期间， 具有良好建立的颅内（i.c.）神经胶质瘤因此，我们假设，临床上， 对胶质母细胞瘤（GBM）的相关抗肿瘤免疫必须具有两种细胞成分：1）显著的浸润 肿瘤特异性肿瘤浸润淋巴细胞（TIL）;和2）阻断免疫调节抗原呈递 细胞（iAPC）在肿瘤微环境中的功能。因此，我们的假设是， 脑肿瘤微环境中iAPC和T淋巴细胞之间的相互作用是一个关键因素， 影响胶质母细胞瘤患者免疫治疗的疗效。更好地了解生物学 这些细胞相互作用将提供更有效的方法来诱导治疗性抗肿瘤免疫， 对这种致命的脑瘤的反应。在目标1中，我们将研究iAPC限制胶质瘤的机制- 体外和体内特异性抗肿瘤免疫应答。在目标2中，我们将评估联合 具有免疫检查点抑制的肿瘤裂解物脉冲的DC疫苗接种（以诱导T细胞浸润到肿瘤中） 和其他新的免疫调节靶点（以阻断iAPC功能）， 胶质母细胞瘤，并探索使用一种新的PET示踪剂作为免疫的非侵入性成像生物标志物 反应最后，在目标3中，我们将开发和验证预测肿瘤，免疫学和成像 入组DCVax-L +/-II期临床试验的复发性胶质母细胞瘤患者的缓解生物标志物 纳武单抗这些研究跨越了脑肿瘤免疫治疗转化研究的连续体， 可能为开发新的，合理的基于免疫的大脑策略提供了信息丰富的新见解。 肿瘤患者。

Project 1: Active immunotherapy combined with checkpoint modulation for glioblastoma SUMMARY/ABSTRACT The lack of effective treatments for glioblastoma (GBM) patients remains a significant health problem and highlights the need for novel and innovative approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells in the brain. Pre-clinical studies and clinical trials of dendritic cell (DC) vaccination for GBM have shown some promising results, but also some treatment failures. The broad overall goals of this research project are to investigate mechanisms of immune evasion following active immunotherapy, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. Our new preliminary data strongly suggests that active immunotherapy with DC vaccination may create a pro-inflammatory tumor microenvironment that induces the immigration of immunosuppressive antigen presenting cells (iAPC), which express high levels of PD-L1 and IL-10. We show that these cells are phenotypically similar to the iAPC that dominantly influence the T-cell response to chronic viral infection, and may act to counteract effective T-cell responses induced by DC vaccination via a mechanism involving PDL1/PD-1. Furthermore, inhibition of iAPC using an anti-PD1 mAb (Nivolumab, BMS) or a CNS penetrant inhibitor of CSF-1R (PLX-3397, Plexxikon), in conjunction with tumor lysate-pusled DC vaccination (DC-Vax-L), resulted in significantly prolonged survival in tumor-bearing animals with well-established intracranial (i.c.) gliomas. We therefore postulate that clinically relevant anti-tumor immunity to glioblastoma (GBM) must have two cellular components: 1) significant infiltration of tumor-specific tumor-infiltrating lymphocytes (TIL); and 2) blockade of immune-regulatory antigen presenting cell (iAPC) function within the tumor microenvironment. As such, our hypothesis is that the local cellular interactions between iAPC and T lymphocytes within the brain tumor microenvironment is a critical factor influencing the efficacy of immunotherapies in glioblastoma patients. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor. In Aim 1, we will study the mechanisms by which iAPC limit glioma- specific anti-tumor immune responses in vitro and in vivo. In Aim 2, we will evaluate the efficacy of combining tumor lysate-pulsed DC vaccination (to induce T-cell infiltration into tumors) with immune checkpoint inhibition and other novel immunoregulatory targets (to block iAPC function) in pre-clinical syngeneic animal models of glioblastoma, and explore the use of a novel PET tracers as non-invasive imaging biomarkers of immune response. Finally, in Aim 3, we will develop and validate predictive tumor, immunological and imaging biomarkers of response in recurrent glioblastoma patients enrolled in a Phase II clinical trial of DCVax-L +/- Nivolumab. These studies span the continuum of translational research in brain tumor immunotherapy, and will likely provided informative new insights for the development of new, rational immune-based strategies for brain tumor patients.