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

• 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
• 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

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 缺乏针对胶质母细胞瘤（GBM）患者的有效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。免疫疗法是一种吸引人的策略 免疫细胞流动和破坏大脑中浸润的肿瘤细胞的潜在能力。过去15 几年，我们的小组和其他人一直在测试主动疫苗策略，例如树突状细胞（DC） 与肿瘤裂解物一起诱导胶质母细胞瘤患者的抗肿瘤免疫学。从临床的临时结果 我们在当前的孢子资金期间启动的试验还发现，除了诱导T细胞浸润外 脑肿瘤，直流疫苗 +抗PD1封锁也可能在 诱导免疫抑制髓样细胞的肿瘤（TIM）。这些细胞在表型上是 类似于主要减弱T细胞对慢性病毒感染的T细胞反应的类似 抵消肿瘤内直流疫苗诱导的有效抗肿瘤T细胞反应 微环境。靶向肿瘤微环境内髓样细胞的疗法代表了 新策略。因此，使用CSF-1R抑制剂抑制这些髓样细胞，并结合自体 肿瘤裂解物脉冲DC疫苗接种（ATL-DC）和PD-1 MAB阻滞，导致显着延长 具有较大的颅内（I.C.）神经胶质瘤的肿瘤动物的存活。我们的假设是 髓样细胞培养培养基自适应免疫抗药性，以响应由T细胞激活引起的T细胞激活 免疫疗法。在这个孢子项目更新中，我们计划了一系列新的临床前研究，以重新进行 极化髓样细胞，以优化免疫疗法的时间和序列如何影响蚂蚁肿瘤 免疫力和一项新的临床试验，以测试新的大脑渗透率CSF-1R抑制剂的首次人类组合 （CSF-1RI; PLX3397，daiichi-sankyo）与直流疫苗接种和PD-1 MAB封锁（Pembrolizumab，Merck） 新诊断为GBM的患者。更好地了解这些细胞相互作用的生物学 提供对这种致命类型的治疗性抗肿瘤免疫反应的更有效方法的见解 脑肿瘤。这些研究跨越了脑肿瘤免疫疗法中转化研究的连续性， 可能会为开发新的，理性的免疫策略提供信息的新见解 脑肿瘤患者。