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

氯毒素重定向嵌合抗原受体 (CAR) T 细胞治疗胶质母细胞瘤的临床评价

基本信息

批准号：
10394391
负责人：
CHRISTINE BROWN
金额：
$ 73.42万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394391
关键词：
Address Adoptive Transfer Amino Acids Antibodies Antigens Autologous B lymphoid malignancy Binding Blood Brain Brain Neoplasms CAR T cell therapy CD19 gene Catheters Cells Cerebrospinal Fluid Characteristics Chlorotoxin Cities Clinic Clinical Clinical Research Clinical Trials Coupled Cyst Fluid Data Disease Disease remission Evolution Future Gene Expression Glioblastoma Goals Hematologic Neoplasms Heterogeneity Human Image Immune Immunologic Monitoring Immunologics Immunotherapy Individual Inflammatory Investigational New Drug Application Letters Ligands Maximum Tolerated Dose Mediating Medical Modality Monitor Nature Neuraxis Non-Malignant Normal tissue morphology Organ Outcome Participant Pathway interactions Patient-Focused Outcomes Patients Peptides Phase I Clinical Trials Phenotype Population Positioning Attribute Prognosis Property Radiation therapy Recurrence Research Resistance Safety Sampling Scorpion Venoms Scorpions Solid Neoplasm Surface Antigens Surrogate Markers T-Lymphocyte Testing Therapeutic Time Tumor Antigens antitumor effect base cancer cell chimeric antigen receptor chimeric antigen receptor T cells clinical translation cross reactivity cytokine design early phase clinical trial experience first-in-human improved improved outcome in vitro activity in vivo innovation mouse model neoplasm immunotherapy neoplastic cell novel novel therapeutics patient prognosis patient response phase I trial preclinical study pressure programs protein expression research clinical testing response standard of care success therapy resistant treatment response tumor tumor eradication

项目摘要

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.

项目摘要尽管护理标准越来越积极，但胶质母细胞瘤（GBM）的患者的患者较差几十年来一直保持不变的预后，这代表了基本的未满足医疗需求。各种肿瘤类型的免疫疗法的进展为免疫方法提供了希望，包括CAR T细胞疗法，可以改善GBM患者的预后。这是由靶向CD19的CAR T细胞以消除中枢神经系统（CNS）中的B细胞恶性肿瘤，以及早期的临床经验显示了GBM中CAR T细胞的安全性和疾病改良活性。一个主要 GBM免疫疗法的挑战是GBM肿瘤的表型异质性与短缺可靶向肿瘤相关的抗原的。作为解决这一挑战的方法，我们开发了一本小说利用氯毒素（CLTX）的选择性和宽GBM结合特性的汽车。 CLTX是一个36-Amino 蝎子毒液的酸性肽成分，该毒液专门与GBM和其他肿瘤结合对非恶性细胞的反应性。使用的早期临床试验已确定CLTX的安全性作为用于成像和放射疗法的GBM靶向肽。我们的临床前研究表明CLTX卡车 T细胞在体外和体内介导潜在的抗肿瘤活性，没有可观察到的效应子活性针对正常人类细胞或适当转移到交叉反应性小鼠模型中时。现在，在此提案中，我们的目标是临床检验以下假设：Cltx-Car T细胞将是安全的，并且介导的抗肿瘤作用 GBM患者的局部分配给中枢神经系统。 AIM 1将评估可行性，安全性和响应在1期临床试验中，复发性GBM患者的CLTX-CAR T细胞速率。 CLTX-CAR T细胞将是通过肿瘤内[ICT]和室内室内[ICV]导管局部传递。 AIM 2将评估 CAR介导的免疫学变化与反应和抗性有关。利用我们的基于导管的局部交付策略允许在整个治疗过程中对CSF取样，我们将监测CAR T细胞活性的替代标记，包括CAR T细胞持久性和炎症变化细胞因子和内源性免疫亚群。我们还将比较不同的不同的特征具有临床反应的自体汽车T细胞产物。 AIM 3将研究GBM肿瘤耐药性的途径以及疗法前后汽车诱导的肿瘤进化，研究抗原逃生途径和自适应对汽车治疗的免疫抑制机制。蝎子衍生的CLTX用于肿瘤的创新使用靶向将是诊所中天然肽汽车的第一个例子，可能会扩大汽车除了基于抗体和配体的靶向域之外的设计。 CLTX-CAR T细胞靶向广泛的范围单个肿瘤中的GBM细胞很重要，因为它将扩大我们的arammentarium，并有可能有助于限制抗原逃逸并增强肿瘤放射分配，从而改善了GBM患者的预后。