Enhancing cell therapy for brain tumors

增强脑肿瘤的细胞治疗

• 批准号: 10246936
• 负责人: Catherine M. Bollard
• 金额: $ 63.65万
• 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/10246936
• 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; Immunotherapeutic agent; 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 胶质母细胞瘤多形（GBM）是最致命的原发性脑癌，标准治疗基于 手术，放疗和化学疗法促进了大约15个月的总生存率。这就是 导致对基于免疫的方法的兴趣重新出现。增强免疫力已经成功 在其他恶性肿瘤（如黑色素瘤和白血病/淋巴瘤）中，它们在治疗脑肿瘤方面的效率具有 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， 检查点抑制剂药物越过血脑屏障的失败都代表着主要障碍 GBM中有效的免疫治疗。 GBM患者的免疫支持改变进一步导致了较差 这些肿瘤的预后及其对疫苗和检查点抑制剂的相对耐药性。利用健康 以适应性细胞疗法形式的供体免疫细胞可能会提供更有效的选择。但是，有限 有关效应人群的特性，可以在有效的抗肿瘤活动中获得信息 大脑。约翰·霍普金斯大学（Johns Hopkins University）的里克·琼斯（Rick Jones）博士利用单倍体供体 用于脑肿瘤的移植（Haplo-BMT）提供了测试注入健康供体免疫动力学的机会 该患者人群中的细胞，可瞥见供体免疫细胞可以针对脑肿瘤所做的事情。 Haplo-BMT的先前经验表明，先天免疫的效应细胞 - 天然杀伤细胞 （NKS）和不变的天然杀手T细胞（INKTS） - 介导抗肿瘤活性，频率降低 复发。先天免疫细胞在脑肿瘤环境中也有可能有利，这提供了非常有利的 与（例如）基于CD19-CAR T细胞膜相关的不良事件的耐受性很小。最后， CCL2梯度趋化因子，Inkt和​​NK细胞都可以主动迁移到GBM的位置 由肿瘤细胞和周围肿瘤相关的巨噬细胞（TAM）释放。 Savoldo博士 北卡罗来纳大学在开发嵌合抗原受体（CAR）方面具有独特的专业知识 转导T细胞和Inkt细胞和儿童国家的Bollard博士具有丰富的经验 转基因T细胞和NK细胞。因此，在这个合作提议中，我们假设 从健康供体衍生的非固化先天免疫细胞（NK和INKT）将促进抗抗 患者GBM的肿瘤免疫力，可以作为有效的细胞疗法发展。这个总体 假设将以3个特定目的进行检验，其中琼斯博士（AIM 1）将比较 与GBM患者相比，从健康供体中分离出的INKT和NK细胞。在AIM 2中，Savoldo博士和 UNC团队将评估健康供体Inkt和​​NK细胞的抗肿瘤效率，以表达抗肿瘤 B7H3嵌合抗原受体（CAR）和AIM 3，Drs。 CNMC的Bollard和Cruz克服了抑制 通过靶向免疫抑制性肿瘤相关巨噬细胞（TAM）和 TGFβ。