Enhancing cell therapy for brain tumors

增强脑肿瘤的细胞治疗

• 批准号: 9788348
• 负责人: Catherine M. Bollard
• 金额: $ 63.68万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788348
• 关键词: Adoptive Cell Transfers; Adverse effects; Adverse event; Allogeneic Bone Marrow Transplantation; Allogenic; Antigens; Autologous; Blood - brain barrier anatomy; Brain; Brain Neoplasms; CCL2 gene; CD19 gene; CD276 gene; Cell Therapy; Cells; Child; Clinical Treatment; Clinical Trials; Cytolysis; Cytotoxic T-Lymphocytes; Data; Development; Dominant-Negative Mutation; Donor person; Effector Cell; Environment; Enzyme-Linked Immunosorbent Assay; Epitope spreading; Exhibits; Failure; Flow Cytometry; Frequencies; Glioblastoma; Hematologic Neoplasms; Heterogeneity; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunity; Immunocompetent; Immunotherapy; Implant; Inflammatory; Kinetics; Lipids; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modification; Mus; Natural Immunity; Natural Killer Cells; North Carolina; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Population; Property; Radiation therapy; Recurrent disease; Refractory; Relapse; Resistance; Safety; Sampling; Signal Transduction; Site; Stress; T cell therapy; T-Lymphocyte; Testing; Therapeutic Uses; Tissues; Transforming Growth Factor beta; Transplantation; Tumor Antigens; Tumor Immunity; Tumor-associated macrophages; Universities; Vaccines; Work; adaptive immune response; base; cancer cell; cellular transduction; chemokine; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; cross reactivity; cytokine; design; experience; in vivo; interest; leukemia/lymphoma; macrophage; melanoma; mind control; monocyte; mouse model; neoplastic cell; next generation; novel; patient population; receptor; response; standard care; synergism; trafficking; transcriptome; tumor; tumor microenvironment; tumor progression

ABSTRACT Glioblastoma multiforme (GBM) is the most lethal primary brain cancer, with standard treatments based on surgery, radiotherapy, and chemotherapy promoting an overall survival of approximately 15 months. This has led to a resurgence of interest in immune-based approaches. While augmenting immunity has been successful in other malignancies like melanoma and leukemia/lymphoma, their efficacy in treatment of brain tumors has been very limited. Tumor antigen heterogeneity, limited number of infiltrating lymphocytes at the tumor site, and failure of checkpoint inhibitor drugs to cross the blood brain barrier all represent major obstacles to effective immune-therapies in GBM. Altered immunity in patients with GBM further contributes to the poor prognoses of these tumors and their relative resistance to vaccine and checkpoint inhibitors. Utilizing healthy donor immune cells in the form of adoptive cell therapy may offer a more effective alternative. However, limited information is available on the properties of effector populations that would exert effective anti-tumor activity in the brain. Pioneering work by Dr. Rick Jones at Johns Hopkins University utilizing haploidentical donor transplant (haplo-BMT) for brain tumors offers an opportunity to test kinetics of infused healthy donor immune cells in this patient population, providing a glimpse of what donor immune cells can do against brain tumors. Previous experiences with haplo-BMT suggest that effector cells of the innate immunity – natural killer cells (NKs) and invariant natural killer T cells (iNKTs) – mediate anti-tumor activity with decreased frequency of relapse. Innate immune cells are also potentially advantageous in the brain tumor setting, which affords very little tolerance for the adverse events associated with (for example) CD19-CAR T cell based-therapies. Finally, both iNKT and NK cells can actively migrate to the site of GBM following the CCL2 gradient, the chemokine released by tumor cells and the surrounding tumor associated macrophages (TAM). Dr. Savoldo at University of North Carolina has unique expertise in the development of chimeric antigen receptor (CAR) transduced T cells and iNKT cells and Dr. Bollard at Children's National has extensive experience with the genetically modified T cells and NK cells. Hence, in this collaborative proposal we hypothesize that nontolerized innate immune cells (NKs and iNKTs) derived from healthy donors will promote anti- tumor immunity in patients GBM, and may be developed as effective cellular therapies. This overarching hypothesis will be tested in 3 Specific Aims where Dr. Jones (Aim 1) will compare the cellular signatures of iNKTs and NK cells isolated from healthy donors versus patients with GBM. In Aim 2, Dr. Savoldo and the UNC team will evaluate the anti-tumor efficacy of healthy donor iNKT and NK cells modified to express an anti- B7H3 chimeric antigen receptor (CAR) and in Aim 3, Drs. Bollard and Cruz at CNMC overcome the inhibitory tumor microenvironment in GBM by targeting immune suppressive tumor associated macrophages (TAMs) and TGFβ.

抽象的 多形性胶质母细胞瘤 (GBM) 是最致命的原发性脑癌，标准治疗基于 手术、放疗和化疗可促进约 15 个月的总生存期。这有 导致人们对基于免疫的方法重新产生兴趣。虽然增强免疫力已取得成功 在黑色素瘤和白血病/淋巴瘤等其他恶性肿瘤中，它们治疗脑肿瘤的功效已得到证实 非常有限。肿瘤抗原异质性，肿瘤部位浸润淋巴细胞数量有限， 检查点抑制剂药物未能穿过血脑屏障都是主要障碍 GBM 的有效免疫疗法。 GBM 患者免疫力的改变进一步导致贫困 这些肿瘤的预后及其对疫苗和检查点抑制剂的相对抵抗力。使用健康 过继细胞疗法形式的供体免疫细胞可能提供更有效的替代方案。然而，有限 有关效应群体特性的信息可在以下方面发挥有效的抗肿瘤活性： 大脑。约翰·霍普金斯大学的 Rick Jones 博士利用半相合供体进行了开创性工作 脑肿瘤移植（单倍体 BMT）提供了测试输注健康供体免疫动力学的机会 该患者群体中的细胞，让我们了解供体免疫细胞对脑肿瘤的作用。 之前的单倍体 BMT 经验表明，先天免疫的效应细胞——自然杀伤细胞 (NK) 和不变的自然杀伤 T 细胞 (iNKT) – 介导抗肿瘤活性，且频率降低 复发。先天免疫细胞在脑肿瘤环境中也具有潜在的优势，这提供了非常好的治疗效果。 对与（例如）基于 CD19-CAR T 细胞的疗法相关的不良事件的耐受性极低。最后， iNKT 和 NK 细胞都可以按照趋化因子 CCL2 梯度主动迁移到 GBM 部位 由肿瘤细胞和周围肿瘤相关巨噬细胞（TAM）释放。萨沃尔多博士在 北卡罗来纳大学在嵌合抗原受体（CAR）开发方面拥有独特的专业知识 转导的 T 细胞和 iNKT 细胞，国家儿童医院的 Bollard 博士在这方面拥有丰富的经验 转基因T细胞和NK细胞。因此，在这个合作提案中，我们假设 来自健康捐赠者的非耐受先天免疫细胞（NK 和 iNKT）将促进抗- GBM 患者的肿瘤免疫，并可能被开发为有效的细胞疗法。这个总体 假设将在 3 个具体目标中进行检验，琼斯博士（目标 1）将比较以下细胞的细胞特征： 从健康捐赠者与 GBM 患者中分离出的 iNKT 和 NK 细胞。在目标 2 中，萨沃尔多博士和 UNC 团队将评估健康供体 iNKT 和经过修饰以表达抗肿瘤药物的 NK 细胞的抗肿瘤功效。 B7H3 嵌合抗原受体 (CAR) 和目标 3，博士。 CNMC 的 Bollard 和 Cruz 克服了抑制 GBM 中的肿瘤微环境通过靶向免疫抑制性肿瘤相关巨噬细胞 (TAM) 和 转化生长因子β。