Cellular Immunotherapy of Ovarian Cancer

卵巢癌的细胞免疫治疗

基本信息

批准号：
10468715
负责人：
Gianpietro Dotti
金额：
$ 38.72万
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：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468715
关键词：
Adoptive Immunotherapy Adoptive Transfer Antigen Targeting Antigens B lymphoid malignancy CD19 gene CD276 gene Cancer Model Cell Shape Cells Cellular immunotherapy Clinical Cytotoxic T-Lymphocytes Data Development Disease Effector Cell Engineering Family Genetic Goals Human Human Engineering Immune Immunocompetent Immunosuppression Immunotherapy Integral Membrane Protein Interleukin-12 Letters Link Lytic Malignant neoplasm of ovary Mediating Modeling Modification Monoclonal Antibodies Mus Myeloid-derived suppressor cells Normal tissue morphology Organ Pathway interactions Patients Phenotype Pre-Clinical Model Property Publishing Recurrence Refractory Relapse Reporting SELL gene Shapes Signal Transduction Site Solid Neoplasm Specificity T-Lymphocyte Technology Testing Therapeutic Toxic effect Tumor Escape Tumor-associated macrophages Up-Regulation Vitamin D Woman Xenograft procedure angiogenesis cancer cell chimeric antigen receptor chimeric antigen receptor T cells clinical application cross reactivity cytokine effector T cell efficacy study engineered T cells experimental study immune checkpoint blockade mouse model neoplastic cell novel prevent programs receptor response safety study stem tumor tumor heterogeneity tumor microenvironment tumor-immune system interactions

项目摘要

Project Abstract The majority of women with relapsed and advanced ovarian cancer (OC) have then very limited therapeutic options. Checkpoint blockade has shown objective responses in less than 15% in patients. Therefore, the development of more potent immunotherapy approaches such as chimeric antigen receptor (CAR) T cells (CAR-Ts) is critical in these patients. We have identified B7-H3 as a valid target for CAR-Ts in OC. We have generated B7-H3.CAR-Ts and successfully tested them in solid tumor models including OC models. In addition, since the B7-H3.CAR we have developed cross-reacts with mB7-H3, we conducted efficacy and safety studies in immunocompetent mice showing antitumor activity without toxicity. Having identified and validated B7-H3 as a target for OC, in this application we aim at overcoming the tumor microenvironment (TME) immunosuppression in OC to fully exploit the potential of the CAR technology. The TME in OC is characterized by a cellular network that promotes angiogenesis and shapes immunosuppressive cells. In particular, tumor associated macrophages (TAMs) and myeloid-derived suppressive cells (MDSCs) are abundant in the TME of OC, and inhibit effector T cells. As compared to T cells, NKTs possess the innate property to co-localize with TAMs and to exploit lytic effects on TAMs in a CD1d-dependent manner via their invariant TCR (iTCR). We have published and generated additional preliminary data showing that CAR-expressing human NKTs are dual specific targeting both tumor cells via CAR and TAMs via native iTCR. Furthermore, we have generated preliminary data showing that human NKTs can also be engineered to release IL-12, a cytokine known to reprogram MDSCs. We hypothesize that NKTs engineered to express the B7-H3.CAR and IL-12 will overcome critical challenges of adoptive immunotherapy of solid tumors: effector cell localization to the tumor site, selective killing of tumor cells via B7-H3.CAR, elimination of tumor-protective TAMs via CD1d engagement by the iTCR, and reprogramming of MDSCs via IL-12. Our new preliminary data also revealed that IL-12 potently enhances CD62L-associated stem-like program in NKTs likely via a novel mechanism, associated with unique “vitamin D signature”. We thus hypothesize that human NKTs may have an intrinsic plasticity not previously appreciated, and that IL-12 may reprogram NKTs to a more immature phenotype via vitamin D pathway. Three specific Aims are proposed: Aim 1: To evaluate whether B7-H3.CAR and IL-12 engineering of NKTs and native iTCR cooperate in targeting OC cells and shaping the TME in an immunocompetent murine model. Aim 2: To mechanistically assess how IL-12 expressed by NKTs promotes NKTs with longer persistence upon adoptive transfer. Aim 3: To evaluate the antitumor activity of engineered human NKTs in Human-Immune Tumor (HIT) mice.

项目摘要大多数患有复发和晚期卵巢癌 (OC) 的女性的治疗方法非常有限检查点封锁在不到 15% 的患者中显示出客观反应。开发更有效的免疫治疗方法，例如嵌合抗原受体 (CAR) T 细胞 (CAR-T) 对于这些患者至关重要。我们已确定 B7-H3 作为 OC 中 CAR-T 的有效靶点。生成了 B7-H3.CAR-T，并在包括 OC 模型在内的实体瘤模型中成功进行了测试。自从 B7-H3.CAR 与 mB7-H3 发生交叉反应以来，我们进行了功效和安全性研究在免疫功能正常的小鼠中显示出抗肿瘤活性且无毒性。 OC 的目标，在此应用中，我们的目标是克服肿瘤微环境 (TME) OC 中的免疫抑制，以充分发挥 CAR 技术的潜力 OC 中的 TME 具有特征。通过促进血管生成和塑造免疫抑制细胞（特别是肿瘤）的细胞网络。相关巨噬细胞 (TAM) 和骨髓源性抑制细胞 (MDSC) 在 TME 中含量丰富 OC，并抑制效应 T 细胞与 T 细胞相比，NKT 具有与 T 细胞共定位的先天特性。 TAM 并通过其不变的 TCR (iTCR) 以 CD1d 依赖性方式利用 TAM 的裂解作用。已发表并生成了额外的初步数据，表明表达 CAR 的人类 NKT 是双重的通过 CAR 和 TAM 通过天然 iTCR 特异性靶向肿瘤细胞此外，我们还生成了。初步数据表明，人类 NKT 也可以被改造为释放 IL-12，这是一种已知的细胞因子我们勇敢地表示，经过改造的 NKT 能够表达 B7-H3.CAR 和 IL-12。实体瘤过继免疫治疗的关键挑战：效应细胞定位到肿瘤部位，通过 B7-H3.CAR 选择性杀死肿瘤细胞，通过 CD1d 参与消除肿瘤保护性 TAM iTCR 以及通过 IL-12 对 MDSC 进行重编程我们的新初步数据还表明 IL-12 具有强大的功效。可能通过一种新机制增强 NKT 中与 CD62L 相关的干细胞样程序，该机制与独特的因此，我们得出结论，人类 NKT 可能具有前所未有的内在可塑性。值得赞赏的是，IL-12 可以通过维生素 D 途径将 NKT 重编程为更不成熟的表型。提出了具体目标：目标 1：评估 NKT 和天然 iTCR 的 B7-H3.CAR 和 IL-12 工程是否协同靶向 OC 细胞并在免疫活性小鼠模型中塑造 TME。目标 2：从机制上评估 NKT 表达的 IL-12 如何促进 NKT 具有更长的持久性收养转移。目标 3：评估工程化人类 NKT 在人类免疫肿瘤 (HIT) 小鼠中的抗肿瘤活性。