Cellular Immunotherapy of Ovarian Cancer

卵巢癌的细胞免疫治疗

基本信息

批准号：
10686345
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/10686345
关键词：
Adoptive Immunotherapy Adoptive Transfer Antigen Targeting Antigens B lymphoid malignancy CD19 gene CD276 gene Cancer Model Cells Cellular immunotherapy Clinical Cross Reactions Cytotoxic T-Lymphocytes Data Development 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 Predisposition Property Publications Publishing Recurrence Recurrent disease 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.

项目摘要大多数接力和晚期卵巢癌（OC）的女性的治疗非常有限选项。检查点封锁显示患者不到15％的客观反应。因此，开发更多潜在的免疫疗法方法，例如嵌合抗原受体（CAR）T细胞（CAR-TS）在这些患者中至关重要。我们已经将B7-H3确定为OC中CAR-TS的有效目标。我们有生成的B7-H3.CAR-TS并在包括OC模型在内的实体瘤模型中成功测试了它们。此外，自B7-H3.CAR以来，我们已经与MB7-H3进行了交叉反应，我们进行了效率和安全研究在免疫能力的小鼠中，没有毒性的抗肿瘤活性。已经确定并验证了B7-H3 OC的一个目标，在此应用中，我们旨在克服肿瘤微环境（TME） OC中的免疫抑制以充分探索汽车技术的潜力。 OC中的TME的特征是通过促进血管生成并塑造免疫抑制细胞的细胞网络。特别是肿瘤相关的巨噬细胞（TAM）和髓样衍生的抑制细胞（MDSC）在TME中丰富 OC，并抑制效应T细胞。与T细胞相比，NKT具有与生俱来的特性，可以与 TAM并通过其不变TCR（ITCR）以CD1D依赖性方式对TAM进行裂解作用。我们已经发布并生成了其他初步数据，表明表达汽车的人NKT是双重的特异性通过天然ITCR通过汽车和TAM靶向肿瘤细胞。此外，我们已经产生了初步数据表明，人类NKT也可以设计为释放IL-12，这是一种已知的细胞因子重编程MDSC。我们假设NKTS设计用于表达B7-H3.CAR和IL-12的NKTS将克服实体瘤免疫疗法的关键挑战：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和MDSC通过IL-12重编程。我们的新初步数据还表明，IL-12有可能通过新型机制（与独特的机制相关），增强了NKT中与CD62L相关的茎状程序 “维生素D签名”。因此，我们假设人NKT可能具有固有的可塑性值得赞赏的，并且IL-12可以通过维生素D途径对NKT进行重新编程为更不成熟的表型。三提出了具体目标：目标1：评估NKTS和本地ITCR合作的B7-H3.CAR和IL-12 OC细胞并在免疫能力的鼠模型中塑造TME。目标2：机械评估NKTS表达的IL-12如何促进NKT，持久性更长收养转移。目标3：评估人类免疫性肿瘤（HIT）小鼠中工程人NKT的抗肿瘤活性。