Hematopoietic stem cells overcome treatment resistance to adoptive cellular therapy against malignant gliomas

造血干细胞克服了恶性胶质瘤过继性细胞疗法的治疗耐药性

• 批准号: 10241491
• 负责人: Catherine T Flores
• 金额: $ 33.36万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241491
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Adult; Antigens; Bone Marrow; Brain Neoplasms; Brain Stem Glioma; Bypass; Cell Therapy; Cells; Child; Clinical Research; Communication; Cross-Priming; Data; Dendritic Cells; Disease; Feedback; Future; Glioblastoma; Glioma; Goals; Hematopoietic System; Hematopoietic stem cells; Hour; Human; Immune; Immune system; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; Infusion procedures; Institution; Interferon Type II; Intracranial Neoplasms; Knowledge; Maintenance; Malignant Glioma; Malignant neoplasm of brain; Modeling; Mus; Nature; Pathway interactions; Pharmacology; Physiologic pulse; Pre-Clinical Model; Primary Neoplasm; Publishing; RNA; Recurrence; Regulatory Pathway; Regulatory T-Lymphocyte; Role; Sampling; Solid Neoplasm; Suppressor-Effector T-Lymphocytes; System; T cell therapy; T-Cell Activation; T-Lymphocyte; Therapeutic; Toxic effect; Transforming Growth Factor beta; Treatment Failure; Tumor Antigens; Tumor Escape; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; anti-tumor immune response; checkpoint inhibition; combinatorial; draining lymph node; hematopoietic stem cell differentiation; immunoregulation; innovation; medulloblastoma; monocyte; mouse model; novel; novel strategies; pre-clinical; recruit; resistance mechanism; therapy resistant; transcriptome; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY AND ABSTRACT High grade gliomas including recurrent glioblastoma in adults and brain stem gliomas in children are invariably fatal. Harnessing the immune system using immunotherapy has made significant strides towards treatment against solid tumors in both murine and human systems, however, in the setting of malignant gliomas, the majority of hosts still succumb to disease. Two major contributors to treatment resistance in immunotherapy against malignant gliomas are 1) tumor heterogeneity, and 2) immunosuppression within both the tumor microenvironment and the hosts' hematopoietic system. Our group has recently demonstrated that concomitant transfer of hematopoietic stem cells (HSC) with immunotherapy leads to overcoming of treatment failure to both adoptive cellular therapy and checkpoint inhibition by directly addressing these two challenges (Flores et al. Nature Communications. In press). A novel and innovative way to address tumor heterogeneity is by leveraging HSC co-transfer with adoptive cellular therapy. Transferred HSCs migrate to intracranial tumor within hours and differentiate into dendritic cells that capture tumor antigens in situ and present to both adoptively transferred and host tumor infiltrating lymphocytes, demonstrably perpetuating T cell activation within the otherwise immunosuppressive tumor microenvironment. In addition, our recently published data demonstrates a novel approach of concomitant transfer of HSCs with immunotherapy shuts down multiple key immunoregulatory pathways within the tumor microenvironment simultaneously including PD-L-1, TGFβ, iNOS, and IDO-1. HSCs also supplant endogenous host MDSCs and TAMs within malignant glioma decreasing overall regulatory cells. We suspect that the HSC transfer impacts either the proliferation or recruitment of endogenous suppressive cells to tumor. This reduction in suppressive pathways is likely a major contributor to the maintenance of T cell activation. This proposal will focus on the mechanisms by which HSCs supplant endogenous immunoregulatory cells within the tumor and increase activation of adoptively transferred tumor-reactive T cells within the tumor microenvironment. As HSCs turn off immunosuppressive regulatory pathways, they concurrently increase tumor- reactive T cell activation. If successful, ongoing and near future clinical studies at our institution can increase efficacy of adoptive cellular therapy in children with malignant gliomas. Our HYPOTHESIS is that HSCs overcome treatment resistance to adoptive cellular therapy by continual cross-priming of T lymphocytes while shutting down regulatory pathways both within the tumor microenvironment. The AIMS of this project are to:AIM 1. Determine if HSC-derived dendritic cells have the capacity to present antigens from escaped tumor after adoptive cellular therapy; AIM 2. Evaluate the mechanisms by which HSCs simultaneously target multiple modulatory pathways within the tumor microenvironment; AIM 3. Understand resistance mechanisms to HSC + adoptive cellular therapy in subjects with non-curative treatment.

项目总结和摘要 高级别胶质瘤，包括成人复发性胶质母细胞瘤和儿童脑干胶质瘤， 总是致命的利用免疫疗法来利用免疫系统已经取得了重大进展， 然而，在鼠和人系统中针对实体瘤的治疗，在恶性神经胶质瘤的情况下， 大多数宿主仍然死于疾病。免疫治疗中治疗耐药性的两个主要因素 针对恶性胶质瘤的免疫抑制是1）肿瘤异质性，和2）肿瘤内的免疫抑制， 微环境和宿主的造血系统。我们的团队最近证明， 用免疫疗法转移造血干细胞（HSC）导致克服对两种疾病的治疗失败， 过继细胞疗法和检查点抑制通过直接解决这两个挑战（弗洛雷斯等人， Nature Communications.待印）。解决肿瘤异质性的一种新颖和创新的方法是利用 HSC与过继性细胞治疗的共转移。转移的HSC在数小时内迁移到颅内肿瘤， 分化成树突状细胞，其原位捕获肿瘤抗原并呈递给过继转移和 宿主肿瘤浸润淋巴细胞，证明在其他组织中持续T细胞活化， 免疫抑制肿瘤微环境。此外，我们最近公布的数据表明， HSC与免疫疗法的伴随转移的方法关闭了多个关键的免疫调节因子， 肿瘤微环境内的信号通路，同时包括PD-L-1、TGFβ、iNOS和IDO-1。HSCs 还取代了恶性胶质瘤内的内源性宿主MDSC和TAM，减少了整体调节细胞。 我们怀疑HSC转移影响内源性抑制细胞的增殖或募集 肿瘤。这种抑制途径的减少可能是维持T细胞增殖的主要因素。 activation.这项建议将集中在HSC取代内源性免疫调节的机制， 肿瘤内过继转移的肿瘤反应性T细胞的活化 微环境当HSC关闭免疫抑制调节通路时，它们同时增加了肿瘤的生长。 反应性T细胞活化。如果成功，我们机构正在进行的和不久的将来的临床研究可以增加 过继细胞治疗儿童恶性胶质瘤的疗效我们的假设是HSC 通过T淋巴细胞的持续交叉致敏克服对过继细胞疗法的治疗抗性， 关闭肿瘤微环境中的调节途径。本项目的目标是： 1.确定HSC衍生的树突状细胞是否具有呈递来自逃逸肿瘤的抗原的能力， 过继性细胞疗法; AIM 2。评估HSC同时靶向多个 肿瘤微环境内的调节途径; AIM 3.了解HSC +的耐药机制 在接受非治愈性治疗的受试者中进行过继性细胞治疗。