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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
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High-Affinity Chimeric Antigen Receptor With Cross-Reactive scFv to Clinically Relevant EGFR Oncogenic Isoforms
Radhika Thokala1,2, Zev A Binder1,2, Yibo Yin1,2
1Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Frontiers in Oncology
|September 27, 2021
Summary
A new chimeric antigen receptor (CAR) T cell therapy targeting EGFR alterations shows promise against glioblastoma (GBM). This enhanced therapy effectively targets multiple tumor clones, overcoming resistance seen with previous EGFRvIII-specific CAR T cells.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Genomics
Background:
- Tumor heterogeneity in glioblastoma (GBM) contributes to treatment failure and recurrence.
- Existing chimeric antigen receptor (CAR) T cell therapies targeting EGFRvIII show limited efficacy against EGFRvIII-negative cells.
- GBM tumors can escape therapy through EGFR amplification and extracellular domain (ECD) mutations.
Purpose of the Study:
- To develop and evaluate a novel EGFR-specific CAR T cell therapy with broader specificity for glioblastoma.
- To compare the efficacy of the new 806 CAR T cells against existing 2173 CAR T cells in preclinical GBM models.
Main Methods:
- Generation of 806 CAR T cells by fusing the mAb 806 to a 4-1BB co-stimulatory domain.
- In vitro testing of CAR T cell specificity and cytotoxicity against various GBM cell lines and patient-derived organoids.
- In vivo efficacy studies comparing 806 CAR T cells and 2173 CAR T cells in GBM models.
Main Results:
- 806 CAR T cells demonstrated specific lysis of tumor cells and cytokine secretion in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations.
- 806 CAR T cells showed minimal toxicity against healthy cells like fetal brain astrocytes and keratinocytes.
- 806 CAR T cells exhibited superior in vivo antitumor activity compared to 2173 CAR T cells.
Conclusions:
- The 806 CAR T cell therapy offers a broader targeting strategy for glioblastoma by recognizing diverse EGFR alterations.
- This approach has the potential to overcome tumor escape mechanisms driven by antigen loss and target multiple tumor clones.
- 806 CAR T cells represent a promising advancement in CAR T cell therapy for glioblastoma.
