CTIM-29. CLINICAL EVALUATION OF CHLOROTOXIN-DIRECTED CAR T CELLS FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
| Autor: | Jana Portnow, Chetan Raj Lingaraju, Massimo D'Apuzzo, Jonathan Hibbard, Maryam Aftabizadeh, M. Suzette Blanchard, Paige McNamara, Stephen J. Forman, Jamie Wagner, Christine E. Brown, Julie Kilpatrick, Dongrui Wang, Michael E. Barish, Julie A. Ressler, Tracey Stiller, Ramsinh Dodia, Renate Starr, Behnam Badie, Baishakhi Barva |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty business.industry medicine.medical_treatment Recurrent glioblastoma Phases of clinical research Tissue membrane 26th Annual Meeting & Education Day of the Society for Neuro-Oncology chemistry.chemical_compound Cytokine Chlorotoxin chemistry Internal medicine Medicine Neurology (clinical) Car t cells Liquid biopsy business Clinical evaluation |
| Zdroj: | Neuro Oncol |
| Popis: | Chlorotoxin (CLTX), a peptide component of scorpion venom, exhibits selective and broad binding to glioblastoma (GBM) and other tumors with minimal activity against non-malignant cells. We have developed a novel CAR that utilizes CLTX as the tumor targeting domain. Preclinical studies established that CLTX-CAR T cells target GBM through recognition of a receptor complex incorporating membrane-bound matrix metalloprotease-2 (MMP-2). Here, we report initial clinical findings for our phase I trial evaluating safety and bioactivity of CLTX-CAR T cells in patients with MMP2+ recurrent GBM (NCT04214392). Weekly infusions of CLTX-CAR T cells are delivered locoregionally, either directly into the tumor cavity (ICT; Arm 1), or in combination with intracerebroventricular (ICV) delivery (dual ICT/ICV; Arm 2). At this interim analysis, four participants have received at least three cycles of CLTX-CAR T cells ICT (Arm 1; 3-8 cycles) at dose level 1 (DL1; 4M, 20M, 20M CAR T cells per cycle). None of the participants experienced dose limiting toxicity (DLT) during the DLT evaluation period of 28-days, although one participant experienced a serious adverse event of grade 3 cerebral edema, possibly attributed to CAR T cells. Overall, Arm 1-DL1 was well-tolerated, and the next patient cohort will be treated on Arm 2-DL1 (dual ICT/ICV; 8M, 40M, 40M CAR T cells per cycle), as per protocol design. Disease response was assessed by RANO, overall survival, and time to progression; three of four participants achieved a best response of stable disease. Liquid biopsy detected persistent CAR T cells in the tumor cavity throughout treatment, suggesting that the therapeutic cells are not immunogenic. Ongoing studies are evaluating biomarkers of response and resistance, including CAR T cell activation and inflammatory cytokines. This clinical study provides first-in-human evidence for the safety and feasibility of CLTX-CAR T cells as a new class of toxin-based CARs for treatment of GBM. |
| Databáze: | OpenAIRE |
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