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Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
PTPRZ1-Targeting RNA CAR T Cells Exert Antigen-Specific and Bystander Antitumor Activity in Glioblastoma
Darel Martinez Bedoya1,2,3, Eliana Marinari1,2,3, Suzel Davanture1,2,3
1Brain Tumor and Immune Cell Engineering Laboratory, Agora Cancer Research Center, Lausanne, Switzerland.
Abstract:
The great success of chimeric antigen receptor (CAR) T-cell therapy in the treatment of patients with B-cell malignancies has prompted its translation to solid tumors. In the case of glioblastoma (GBM), clinical trials have shown modest efficacy, but efforts to develop more effective anti-GBM CAR T cells are ongoing. In this study, we selected protein tyrosine phosphatase receptor type Z (PTPRZ1) as a target for GBM treatment. We isolated six anti-human PTPRZ1 single-chain variable fragments from a human phage display library and produced second-generation CAR T cells in an RNA format. Patient-derived GBM PTPRZ1-knockin cell lines were used to select the CAR construct that showed high cytotoxicity while consistently displaying high CAR expression (471_28z). CAR T cells incorporating 471_28z were able to release IFNγ, IL2, TNFα, granzyme B, IL17A, IL6, and soluble FasL and displayed low tonic signaling. Additionally, they maintained an effector memory phenotype after in vitro killing. In addition, 471_28z CAR T cells displayed strong bystander killing against PTPRZ1-negative cell lines after preactivation by PTPRZ1-positive tumor cells but did not kill antigen-negative nontumor cells. In an orthotopic xenograft tumor model using NOD/SCIDγ mice, a single dose of anti-PTPRZ1 CAR T cells significantly delayed tumor growth. Taken together, these results validate PTPRZ1 as a GBM target and prompt the clinical translation of anti-PTPRZ1 CAR T cells.
Insights
Researchers developed new chimeric antigen receptor (CAR) T-cell therapy targeting protein tyrosine phosphatase receptor type Z (PTPRZ1) for glioblastoma (GBM). This PTPRZ1-targeting CAR T-cell therapy showed significant tumor growth delay in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy has succeeded in B-cell malignancies.
- Translating CAR T-cell therapy to solid tumors like glioblastoma (GBM) faces challenges, with current trials showing modest efficacy.
- Developing more effective anti-GBM CAR T cells is an active area of research.
Purpose of the Study:
- To identify and validate a novel target for GBM treatment.
- To develop and characterize novel anti-GBM CAR T cells.
- To assess the efficacy of PTPRZ1-targeting CAR T cells in preclinical models.
Main Methods:
- Selected protein tyrosine phosphatase receptor type Z (PTPRZ1) as a target for GBM.
- Isolated anti-PTPRZ1 single-chain variable fragments and produced second-generation CAR T cells in RNA format.
- Evaluated CAR T-cell cytotoxicity, phenotype, bystander killing, and in vivo efficacy in a GBM xenograft model.
Main Results:
- Identified a CAR construct (471_28z) with high cytotoxicity and CAR expression.
- Demonstrated that 471_28z CAR T cells release key effector molecules and maintain an effector memory phenotype.
- Observed significant tumor growth delay in an orthotopic xenograft model following a single dose of anti-PTPRZ1 CAR T cells.
Conclusions:
- PTPRZ1 is validated as a promising target for GBM treatment.
- Anti-PTPRZ1 CAR T cells exhibit potent anti-tumor activity and favorable characteristics for clinical translation.
- These findings support the advancement of anti-PTPRZ1 CAR T cells into clinical trials for GBM.
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