Project 1: Targeting immunotherapy-induced resistance with DC vaccination and PD-1/CSF-1R inhibition

项目 1：通过 DC 疫苗接种和 PD-1/CSF-1R 抑制来针对免疫治疗引起的耐药性

基本信息

批准号：
10673749
负责人：
Robert M Prins
金额：
$ 37.84万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-11 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673749
关键词：
Active Immunotherapy Animal Model Animals Ants Attenuated Autologous Blood Brain Brain Neoplasms CD8B1 gene CSF1R gene Cancer Vaccines Cell physiology Cells Cellular biology Chronic Clinical Clinical Trials Data Dendritic Cell Vaccine Dendritic Cells Development Funding Gene Expression Genes Glioblastoma Glioma Health Imaging technology Immigration Immune Immune Evasion Immune response ImmunoPET Immunologic Markers Immunologic Monitoring Immunotherapy Infiltration Magnetic Resonance Imaging Malignant neoplasm of brain Mediating Modeling Monoclonal Antibodies Mus Myeloid Cells Myeloid-derived suppressor cells Neoadjuvant Therapy Newly Diagnosed PD-1 blockade Patients Phase I Clinical Trials Phenotype Physiologic pulse Positron-Emission Tomography Recurrence Resistance Series T cell infiltration T cell response T-Cell Activation T-Lymphocyte Testing Therapeutic Toxic effect Translational Research Treatment outcome Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Vaccination Vaccines Virus Diseases anti-PD-1 anti-tumor immune response checkpoint inhibition clinically relevant dendritic cell vaccination design effective therapy first-in-human imaging biomarker imaging modality immune checkpoint blockade immune resistance immunogenicity improved outcome inflammatory milieu inhibitor innovation insight mouse model neoplasm immunotherapy neoplastic cell novel pembrolizumab pre-clinical preclinical study programmed cell death protein 1 resistance mechanism response response biomarker targeted treatment tumor tumor microenvironment vaccination strategy

项目摘要

PROJECT SUMMARY/ABSTRACT – Project 1 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. For the past 15 years, our group and others have been testing active vaccination strategies, such as dendritic cells (DC) pulsed with tumor lysate, to induce antitumor immunity in glioblastoma patients. From the interim results of the clinical trial we initiated in our current SPORE funding period, we found that in addition to inducing T-cell infiltration into brain tumors, DC vaccination + anti-PD1 blockade may also create a pro-inflammatory environment within the tumor that induces the immigration of immunosuppressive myeloid cells (TIM). These cells are phenotypically similar to the myeloid cells that dominantly attenuate the T-cell response to chronic viral infections, and may counteract the effective anti-tumor T-cell responses induced by DC vaccination within the tumor microenvironment. Therapies that target myeloid cells within the tumor microenvironment represent a promising new strategy. As such, inhibition of these myeloid cells using a CSF-1R inhibitor, in conjunction with autologous tumor lysate-pulsed DC vaccination (ATL-DC) and PD-1 mAb blockade, resulted in significantly prolonged survival in tumor-bearing animals with large, well-established intracranial (i.c.) gliomas. Our hypothesis is that myeloid cells mediate adaptive immune resistance in response to T cell activation induced by immunotherapy. In this SPORE Project renewal, we have planned a series of novel pre-clinical studies to re- polarize myeloid cells, to optimize how the timing and sequence of immunotherapy can influence ant-tumor immunity, and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM. 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. 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.

项目摘要/摘要 – 项目 1 胶质母细胞瘤 (GBM) 患者缺乏有效的治疗方法仍然是一个重大的健康问题强调了对新颖和创新方法的需求，因为免疫疗法是一种有吸引力的策略。在过去的 15 年里，免疫细胞运输并摧毁大脑中浸润性肿瘤细胞的潜在能力。多年来，我们的团队和其他人一直在测试主动疫苗接种策略，例如树突状细胞 (DC) 脉冲根据临床的中期结果，用肿瘤裂解物诱导胶质母细胞瘤患者的抗肿瘤免疫。我们在当前的 SPORE 资助期间启动了试验，我们发现除了诱导 T 细胞渗透到脑肿瘤、DC疫苗接种+抗PD1阻断也可能在脑内创造促炎环境诱导免疫抑制性骨髓细胞 (TIM) 迁移的肿瘤这些细胞具有表型特征。与主要减弱 T 细胞对慢性病毒感染反应的骨髓细胞相似，并且可能抵消肿瘤内 DC 疫苗接种诱导的有效抗肿瘤 T 细胞反应针对肿瘤微环境中的骨髓细胞的治疗代表了一种有前途的治疗方法。因此，使用 CSF-1R 抑制剂结合自体细胞抑制这些骨髓细胞。肿瘤裂解物脉冲 DC 疫苗接种 (ATL-DC) 和 PD-1 mAb 阻断，导致显着延长患有大型、成熟的颅内（i.c）神经胶质瘤的荷瘤动物的存活率我们的假设是：骨髓细胞介导适应性免疫抵抗，以响应 T 细胞激活在这个 SPORE 项目更新中，我们计划了一系列新颖的临床前研究来重新治疗。极化骨髓细胞，优化免疫治疗的时间和顺序如何影响抗肿瘤免疫，以及一项新的临床试验，以测试新型脑渗透性 CSF-1R 抑制剂的首次人体组合（CSF-1Ri；PLX3397，Daiichi-Sankyo）联合 DC 疫苗接种和 PD-1 mAb 阻断（Pembrolizumab，Merck）新诊断的 GBM 患者对这些细胞相互作用的生物学会有更好的了解。提供更有效的方法来诱导针对这种致命类型的治疗性抗肿瘤免疫反应这些研究涵盖了脑肿瘤免疫治疗的连续转化研究，以及可能会为开发新的、合理的基于免疫的策略提供信息丰富的新见解脑肿瘤患者。