Targeting B7-H3 in ovarian cancer

摘要 过继转移T细胞治疗B细胞恶性肿瘤有显著的临床反应 重定向为针对CD19抗原的嵌合抗原受体(CAR)。然而，发展汽车-- 对于包括卵巢癌(OC)在内的实体肿瘤的治疗是具有挑战性的，因为：(1)OC相关 以CAR-T为靶点的抗原是有限的，通常不是由OC独占表达的，并且作为 乘客，不是肿瘤发生的驱动力，允许抗原漂移；(2)OC肿瘤微环境(TME) 具有高度的免疫抑制作用。在这项提案中，我们的目标是解决这些关键问题。我们已经确认了B7-H3 (CD276)作为卵巢癌嵌合抗原受体(CAR)T细胞的合适靶点。B7-H3是一种促癌物质 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表达有限。我们已经开发出了 在异种和免疫活性肿瘤模型中测试B7-H3CAR-ts显示抗肿瘤活性 包括OC和安全性在内的几种肿瘤模型。因此，在目标1中，我们建议在#年进行一项I期临床研究。 评估自体B7-H3CAR-ts接种对OC患者的安全性和抗肿瘤活性 在腹膜内。这项研究的IND(IND19641)已经在北卡罗来纳大学获得，并且 生产B7-H3CAR-TS的临床级试剂在手中。在目标2中，我们建议进行一项 肿瘤活检和腹水的综合免疫学分析 观察治疗前后OC患者TME的抗原丢失和免疫紊乱情况。在……里面 目的3，我们建议对肿瘤相关巨噬细胞(TAMs)和髓系来源的抑制细胞进行重新编程 口服有效的RTK将OC-TME转化为非免疫抑制状态 北卡罗来纳大学开发的小分子抑制剂(IND128236)。因此，我们将表演 抑制巨噬细胞和骨髓间充质干细胞中逆转录酶信号的临床前研究 B7-H3.CAR-ts的抗癌活性研究如果成功，这一战略将被包括在内 进入拟议的B7-H3CAR-ts第一阶段临床研究的第二阶段。

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.