Clinical Evaluation of Chlorotoxin-redirected Chimeric Antigen Receptor (CAR) T cells for Treatment of Glioblastoma

项目总结 尽管越来越积极的护理标准治疗，胶质母细胞瘤(GBM)患者的 几十年来一直没有改变的预后，这是一个基本的未得到满足的医疗需求。 广泛肿瘤类型的免疫治疗的进展为免疫学方法提供了希望， 包括CAR T细胞治疗，可能会改善GBM患者的预后。这得到了以下能力的支持 以CD19为靶点的CAR T细胞，以消除中枢神经系统(CNS)中的B细胞恶性肿瘤 早期临床经验表明CAR T细胞在GBM中具有安全性和疾病修饰活性。一大专业 GBM免疫治疗面临的挑战是GBM肿瘤的表型异质性和稀缺性。 靶向肿瘤相关抗原。作为应对这一挑战的一种方法，我们开发了一部小说 利用氯毒素(CLTX)选择性和广泛的GBM结合特性的CAR。CLTX是一种36个氨基酸 蝎子毒液的酸性多肽成分，与基底膜和其他肿瘤特异性结合，交叉作用最小. 对非恶性细胞的反应性。以前的早期临床试验已经确定了CLTX在使用时的安全性 作为一种用于成像和放射治疗的GBM靶向肽。我们的临床前研究表明，CLTX-CAR T细胞在体外和体内都有很强的抗肿瘤活性，但对正常人没有明显的效应活性。 或者当过继转移到交叉反应小鼠模型时。在这项提案中，我们现在的目标是 临床验证CLTX-CAR T细胞在以下情况下将是安全的并介导抗肿瘤作用的假设 GBM患者局部地区性传递至中枢神经系统。目标1将评估可行性、安全性和响应 在一期临床试验中复发的GBM患者的CLTX-CAR T细胞比率。CLTX-CAR T细胞将被 通过肿瘤内[ICT]和脑室内[ICV]导管局部注射。目标2将评估 CAR介导的免疫学变化与应答和耐药相关。利用我们的 基于导管的局部区域给药策略，允许在整个治疗过程中对脑脊液进行采样，我们将 监测CAR T细胞活性的替代标志物，包括CAR T细胞持久性和炎症性变化 细胞因子和内源性免疫亚群。我们还将比较不同版本的内部特性 具有临床反应的自体CAR T细胞产品。AIM 3将研究GBM肿瘤耐药的途径 和CAR诱导的肿瘤在治疗前后的演变，研究抗原逃逸途径和适应性 CAR-T治疗的免疫抑制机制。蝎子来源的CLTX在肿瘤治疗中的创新应用 靶向将是基于天然多肽−的汽车在临床上的第一个例子，有可能扩大汽车 超越基于抗体和配体的靶向域的设计。CLTX-CAR T细胞靶向广泛 单个肿瘤中的GBM细胞具有重要意义，因为它将扩大我们的医疗设备，并潜在地帮助 限制抗原逃逸，加强肿瘤根除，从而改善GBM患者的预后。

PROJECT SUMMARY Despite increasingly aggressive standard of care treatments, patients with glioblastoma (GBM) have a poor prognosis that has remained unchanged for decades, and this represents a fundamental unmet medical need. Progress in immunotherapy across a broad range of tumor types provides hope that immunological approaches, including CAR T cell therapy, may improve outcomes for patients with GBM. This is supported by the ability of CD19-targeted CAR T cells to eliminate B cell malignancies in the central nervous system (CNS), as well as early clinical experiences showing safety and disease-modifying activity of CAR T cells in GBM. One major challenge for GBM immunotherapies is the phenotypic heterogeneity of GBM tumors coupled with the scarcity of targetable tumor-associated antigens. As an approach to address this challenge we have developed a novel CAR that exploits the selective and broad GBM-binding properties of chlorotoxin (CLTX). CLTX is a 36-amino acid peptide component of scorpion venom that binds specifically to GBM and other tumors with minimal cross- reactivity to non-malignant cells. Previous early phase clinical trials have established safety of CLTX when used as a GBM-targeting peptide for imaging and radiotherapy. Our preclinical studies demonstrate that CLTX-CAR T cells mediate potent antitumor activity in vitro and in vivo, with no observable effector activity against normal human cells or when adoptively transferred into cross-reactive mouse models. We now aim, in this proposal, to clinically test the hypothesis that CLTX-CAR T cells will be safe and mediate antitumor effects when locoregionally delivered to the CNS in patients with GBM. Aim 1 will evaluate the feasibility, safety and response rates of CLTX-CAR T cells in patients with recurrent GBM in a phase 1 clinical trial. CLTX-CAR T cells will be delivered locoregionally via intratumoral [ICT] and intracerebroventricular [ICV] catheters. Aim 2 will assess CAR-mediated immunological changes associated with response and resistance. Taking advantage of our catheter-based locoregional delivery strategy that allows sampling of the CSF throughout treatment, we will monitor surrogate markers of CAR T cell activity, including CAR T cell persistence and changes in inflammatory cytokines and endogenous immune subsets. We will also compare the intrinsic characteristics across different autologous CAR T cell products with clinical response. Aim 3 will investigate pathways of GBM tumor resistance and CAR-induced tumor evolution pre- and post-therapy, investigating antigen escape pathways and adaptive immunosuppressive mechanisms to CAR T treatment. The innovative use of scorpion-derived CLTX for tumor targeting would be the first example of a natural peptide−based CAR in the clinic, potentially expanding CAR designs beyond antibody- and ligand-based targeting domains. CLTX-CAR T cell targeting of a wide range of GBM cells within individual tumors is significant in that it will expand our armamentarium and potentially help to limit antigen escape and enhance tumor eradication, thereby improving outcomes for patients with GBM.