Targeting B7-H3 in ovarian cancer

靶向 B7-H3 治疗卵巢癌

基本信息

批准号：
10543762
负责人：
Gianpietro Dotti
金额：
$ 10.92万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10543762
关键词：
Adoptive Immunotherapy Aftercare Antigen Targeting Antigens Apoptotic Ascites Autologous B lymphoid malignancy B-Lymphocytes Binding Biological Availability Biopsy CD19 Antigens CD19 gene CD276 gene Cancer Model Cells Clinical Clinical Research Complex Cross Reactions Cyclophosphamide Data Development Dose Electroporation FOLR1 gene Family Goals Greater sac of peritoneum Growth Hand Hematologic Neoplasms Human Immune Immunocompetent Immunologic Monitoring Immunologics Immunotherapy Infusion procedures Integral Membrane Protein Link Macrophage Malignant lymphoid neoplasm Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Messenger RNA Modeling Modification Monitor Monoclonal Antibodies Mus Myeloid-derived suppressor cells Normal tissue morphology North Carolina Oral Organ PD-1 blockade Patients Peritoneal Fluid Phase Phase I Clinical Trials Positioning Attribute Procedures Prognosis Publishing Reagent Receptor Protein-Tyrosine Kinases Recurrence Refractory Regulatory T-Lymphocyte Relapse Reporting Safety Sampling Serine Shapes Signal Transduction Solid Neoplasm Specificity T cell therapy Testing Therapeutic Tissues Toxic effect Tumor Escape Tumor Promotion Tumor-associated macrophages Universities Woman Xenograft procedure angiogenesis base cancer cell chimeric antigen receptor chimeric antigen receptor T cells clinical application clinical development cross reactivity effector T cell exosome fludarabine immune cell infiltrate immune checkpoint blockade in vivo inhibitor innate immune function intraperitoneal leukemia malignant breast neoplasm manufacture melanoma mouse model neoplastic cell novel pancreatic cancer model participant enrollment peripheral blood pre-clinical preclinical study prevent programs receptor response safety assessment small molecule inhibitor success tumor tumor heterogeneity tumor microenvironment tumor-immune system interactions tumorigenesis tumorigenic

项目摘要

ABSTRACT Remarkable clinical responses have been reported in B-cell malignancies by adoptive transfer of T cells redirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen. However, developing CAR-Ts for the treatment of solid tumors including ovarian cancer (OC) is challenging because: (1) OC-associated antigens that are targetable by CAR-Ts are limited, generally not exclusively expressed by OC, and act as passengers, not as drivers of tumorigenesis, allowing for antigenic drift; (2) OC tumor microenvironment (TME) is highly immunosuppressive. In this proposal we aim at solving these critical issues. We have identified B7-H3 (CD276) as a suitable target for chimeric antigen receptor (CAR) T cells in OC. B7-H3 is a tumor-promoting transmembrane protein aberrantly expressed in 60% to 93% of pancreatic cancer, melanoma, leukemia, breast, prostate and OC, while limited expression is seen on normal healthy tissues. We have developed and tested B7-H3.CAR-Ts in xenogeneic and immunocompetent tumor models showing antitumor activity is several tumor models including OC and safety. Thus in Aim 1 we propose to conduct a phase I clinical study in patients with OC to assess safety and antitumor activity of autologous B7-H3.CAR-Ts inoculated intraperitoneally. An IND (IND19641) for this study has been obtained at University of North Carolina, and clinical grade reagents to manufacture B7-H3.CAR-Ts are in hands. In Aim 2 we propose to conduct a comprehensive immunologic analysis of tumor biopsies and ascites collected from patients enrolled in the study before and after treatment to assess antigen loss and immunologic perturbation of the TME in OC. In Aim 3, we propose to reprogram tumor-associated macrophages (TAMs) and myeloid derived suppressor cells (MDSC) of the OC TME to a non-immunosuppressive state by using potent and orally bioavailable TAM RTK small molecule inhibitors developed at University of North Carolina (IND128236). We will thus perform preclinical studies to evaluate whether TAM RTK signaling inhibition in macrophages and MDSC would favor the antitumor activity of B7-H3.CAR-Ts in a syngeneic model of OC. If successful, this strategy will be included into a second phase of the proposed Phase I clinical study with B7-H3.CAR-Ts.

抽象的 B细胞恶性肿瘤已通过T细胞的过继转移报告了显着的临床反应用针对CD19抗原的嵌合抗原受体（CAR）重定向。但是，开发汽车-TS 对于包括卵巢癌（OC）在内的实体瘤的治疗是具有挑战性的，因为：（1）OC相关由CAR-TS靶向的抗原受到限制，通常不仅限OC表达，并充当乘客，不是肿瘤发生的驱动因素，允许抗原漂移；（2）OC肿瘤微环境（TME）高度免疫抑制。在此提案中，我们旨在解决这些关键问题。我们已经确定了B7-H3 （CD276）作为OC中的嵌合抗原受体（CAR）T细胞的合适靶标。 B7-H3是肿瘤的跨膜蛋白异常表达在60％至93％的胰腺癌，黑色素瘤，白血病，乳房，前列腺和OC，而在正常健康组织上表达有限。我们已经开发了在异构和免疫功能抗体活性的异质和免疫能力肿瘤模型中测试的B7-H3.CAR-TS是几种肿瘤模型，包括OC和安全性。因此，在目标1中，我们建议在 OC的患者评估接种自体B7-H3.CAR-TS的安全性和抗肿瘤活性腹膜内。这项研究的IND（IND19641）已在北卡罗来纳州大学获得生产B7-H3.CAR-TS的临床级试剂掌握在手中。在AIM 2中，我们建议进行从入学的患者中收集的肿瘤活检和腹水的全面免疫学分析在治疗前后的研究，以评估OC中TME的抗原丢失和免疫学扰动。在 AIM 3，我们建议重新编程肿瘤相关的巨噬细胞（TAM）和髓样衍生的抑制细胞（MDSC）通过使用有效和口服生物可利用的tam rtk，将OC TME到非免疫抑制状态在北卡罗来纳大学（IND128236）开发的小分子抑制剂。因此，我们将执行临床前研究评估巨噬细胞和MDSC中的TAM RTK信号抑制是否会有利于 OC的合成模型中B7-H3.CAR-TS的抗肿瘤活性。如果成功，将包括此策略使用B7-H3.CAR-TS进入拟议I期临床研究的第二阶段。