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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.

项目总结