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Human mast cells as a platform for new cancer immunotherapy strategies

人类肥大细胞作为新癌症免疫治疗策略的平台

基本信息

批准号：
10729728
负责人：
Chris L KEPLEY
金额：
$ 37.28万
依托单位：
LIBERTY UNIVERSITY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729728
关键词：
3-Dimensional Adipose tissue Adoptive Cell Transfers Affect Affinity Antibodies Antigens Antitumor Response Autologous Binding Cancer Biology Cancer cell line Cell Count Cell Death Cell Degranulation Cell Therapy Cells Cellular Immunology Clinic Clinical Trials Complement Complex Correlative Study Cryopreservation Dimensions ERBB2 gene Engraftment Epitopes Equus caballus FDA approved Fluorescence Folic Acid Antagonists Foundations Future Genetic Goals Good Manufacturing Process Hematologic Neoplasms Histamine Human Human Activities IgE Immune Immune response Immunocompetent Immunocompromised Host Immunotherapy In Vitro In complete remission Incubated Infiltration Infusion procedures Intravenous Investigational New Drug Application Knock-out Learning Lentivirus Vector Lymphoma MS4A1 gene Malignant Neoplasms Mediating Mediator Medicine Modeling Monitor Mus Pathology Patient-Focused Outcomes Patients Production Proteins Protocols documentation Role Signal Transduction Solid Solid Neoplasm Survival Rate Techniques Testing Therapeutic Time Tissues Toxic effect Toxicology Tumor Volume Work adaptive immune response adipose derived stem cell antitumor effect cancer cell cancer immunotherapy cancer therapy cancer type chimeric antigen receptor T cells comparison control efficacy study efficacy testing engineered T cells folate-binding protein good laboratory practice graduate student human tissue in vivo intravenous administration loss of function mRNA Expression malignant breast neoplasm mast cell mouse model neoplastic cell novel novel strategies peripheral blood progenitor safety study translational study treatment planning tumor tumor microenvironment tumor progression tumor xenograft undergraduate student

项目摘要

ABSTRACT The role of human tissue mast cells (MC) in the pathology of many cancers is not known. Correlative studies in humans have found high MC numbers in the tumor microenvironment have pro- and anti-tumor effects and contrasting patient outcomes depending on the cancer types. We discovered that human MC, are activated by, and promote killing of, cancer cells in vitro and in vivo, infiltrate solid cell tumor masses, bind to tumors in vivo, can be obtained in quantities necessary for patient infusion, cryopreserved without loss of function, and display no overt toxic effects when injected intravenously into mice with engrafted human tumors. To develop this novel, cell-based cancer immunotherapy we will utilize FDA approved humanized IgE (which bind MC FcεRI with extremely high affinity) to target MC to cancer cells. This new approach is premised on efficient, autologous production of MC, tumor targeting, and effective tumor specific killing. This strategy has not been feasible heretofore as these cells reside in tissue and cannot be obtained for autologous use. Our overall hypothesis is tumor targeted MC will bind to cancer cells in vitro and in vivo after intratumoral or intravenous administration and elicit significant anti-tumor activity. Here we will determine the in vitro and in vivo activity of human MC against several cancer types. These studies could lead to new adoptive cell therapies for diverse cancers ranging from lymphoma to breast cancer.

抽象的人体组织肥大细胞 (MC) 在许多癌症病理学中的作用尚不清楚。相关研究人类发现肿瘤微环境中的高 MC 数量具有促肿瘤和抗肿瘤作用，并且根据癌症类型对比患者的结果。我们发现人类 MC 被激活，并促进体外和体内癌细胞的杀伤，浸润实体细胞肿瘤块，与体内肿瘤结合，可以获得患者输液所需的数量，冷冻保存而不丧失功能，并进行展示当静脉注射到移植有人类肿瘤的小鼠体内时，没有明显的毒性作用。为了发展这部小说，基于细胞的癌症免疫疗法，我们将利用 FDA 批准的人源化 IgE（将 MC FcεRI 与极高的亲和力）将 MC 靶向癌细胞。这种新方法的前提是高效、自体 MC的产生、肿瘤靶向和有效的肿瘤特异性杀伤。这个策略并不可行迄今为止，由于这些细胞驻留在组织中并且无法获得用于自体使用。我们的总体假设是瘤内或静脉注射后，肿瘤靶向MC将在体外和体内与癌细胞结合并引发显着的抗肿瘤活性。在这里我们将测定人类MC的体外和体内活性对抗多种癌症类型。这些研究可能会为多种癌症带来新的过继细胞疗法从淋巴瘤到乳腺癌。