Targeting B7-H3 in ovarian cancer

靶向 B7-H3 治疗卵巢癌

• 批准号: 10320055
• 负责人: Gianpietro Dotti
• 金额: $ 61.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320055
• 关键词: Adoptive Immunotherapy; Aftercare; Antigen Targeting; Antigens; Apoptotic; Ascites; Autologous; B lymphoid malignancy; B-Lymphocytes; Biopsy; CD19 Antigens; CD19 gene; CD276 gene; Cancer Model; Cell Shape; Cell physiology; Cells; Clinical; Clinical Research; Complex; Cyclophosphamide; Data; Development; Dose; Electroporation; Enrollment; 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; 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; 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-associated macrophages; Tumor-infiltrating immune cells; 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 checkpoint blockade; in vivo; inhibitor; innate immune function; intraperitoneal; leukemia; macrophage; malignant breast neoplasm; melanoma; mouse model; neoplastic cell; novel; pancreatic cancer model; peripheral blood; pre-clinical; preclinical study; prevent; receptor; response; small molecule inhibitor; success; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions; tumorigenesis; tumorigenic

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.

摘要 在B细胞恶性肿瘤中，通过过继性T细胞转移已报告了显著的临床应答 用对CD 19抗原特异性的嵌合抗原受体（CAR）重定向。然而，开发CAR-T 用于治疗包括卵巢癌（OC）在内的实体瘤是具有挑战性的，因为：（1）OC相关的 可被CAR-T靶向的抗原是有限的，通常不排他地由OC表达，并且充当 乘客，而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） 是高度免疫抑制的。在本提案中，我们旨在解决这些关键问题。我们已经确认了B7-H3 在OC中，CD 276作为嵌合抗原受体（CAR）T细胞的合适靶标。B7-H3是一种促肿瘤细胞 跨膜蛋白在60%至93%的胰腺癌、黑色素瘤、白血病 乳腺、前列腺和OC，而在正常健康组织中观察到有限的表达。我们已经开发并 在异种和免疫活性肿瘤模型中测试的B7-H3.CAR-Ts显示抗肿瘤活性， 几种肿瘤模型，包括OC和安全性。因此，在目标1中，我们建议进行I期临床研究， 评估自体B7-H3的安全性和抗肿瘤活性。CAR-Ts接种 腹腔注射本研究的IND（IND 19641）已在北卡罗来纳州大学获得， 用于制造B7-H3的临床级试剂。CAR-T已在手。在目标2中，我们建议进行 对从参加研究的患者中收集的肿瘤活检和腹水进行全面的免疫学分析， 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 目的3：对肿瘤相关巨噬细胞和髓源性抑制细胞进行重编程 通过使用有效的和口服生物可利用的TAM RTK， 北卡罗来纳州大学开发的小分子抑制剂（IND 128236）。因此我们将执行 临床前研究，以评估巨噬细胞和MDSC中的TAM RTK信号传导抑制是否有利于 B7-H3.CAR-Ts在OC同基因模型中的抗肿瘤活性。如果成功，这一战略将包括 进入B7-H3.CAR-Ts的拟议I期临床研究的第二阶段。