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Pooled screening for CAR function identifies novel IL-13Rα2-targeted CARs for treatment of glioblastoma
Khloe S Gordon1,2,3, Caleb R Perez1,2,3, Andrea Garmilla2,4
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Background:
Chimeric antigen receptor (CAR) therapies have demonstrated potent efficacy in treating B-cell malignancies, but have yet to meaningfully translate to solid tumors. Nonetheless, they are of particular interest for the treatment of glioblastoma, which is an aggressive form of brain cancer with few effective therapeutic options, due to their ability to cross the highly selective blood-brain barrier.
Methods:
Here, we use our pooled screening platform, CARPOOL, to expedite the discovery of CARs with antitumor functions necessary for solid tumor efficacy. We performed selections in primary human T cells expressing a library of 1.3×106 third generation CARs targeting IL-13Rα2, a cancer testis antigen commonly expressed in glioblastoma. Selections were performed for cytotoxicity, proliferation, memory formation, and persistence on repeated antigen challenge.
Results:
Each enriched CAR robustly produced the phenotype for which it was selected, and one enriched CAR triggered potent cytotoxicity and long-term proliferation on in vitro tumor rechallenge. It also showed significantly improved persistence and comparable tumor control in a microphysiological human in vitro model and a xenograft model of human glioblastoma, but also demonstrated increased off-target recognition of IL-13Rα1.
Conclusion:
Taken together, this work demonstrates the utility of extending CARPOOL to diseases beyond hematological malignancies and represents the largest exploration of signaling combinations in human primary cells to date.
Insights
Chimeric antigen receptor (CAR) therapies show promise for glioblastoma treatment. A new screening platform identified a CAR with potent anti-tumor activity, though off-target effects require further study.
Area of Science:
- Immunotherapy
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is effective against B-cell cancers but limited in solid tumors.
- Glioblastoma, an aggressive brain cancer, has few treatment options, making CAR T-cell therapy a potential avenue due to blood-brain barrier penetration.
Purpose of the Study:
- To discover CARs with anti-tumor functions for solid tumors using a pooled screening platform.
- To identify CARs targeting IL-13Rα2, a glioblastoma-specific antigen, for improved glioblastoma treatment.
Main Methods:
- Utilized the CARPOOL pooled screening platform to select CARs from a library of 1.3x10^6 third-generation CARs.
- Performed selections based on cytotoxicity, proliferation, memory formation, and persistence in primary human T cells targeting IL-13Rα2.
Main Results:
- Enriched CARs demonstrated the desired anti-tumor phenotypes.
- One CAR exhibited potent cytotoxicity, long-term proliferation, enhanced persistence, and tumor control in vitro and in vivo models.
- This CAR also showed cross-reactivity with IL-13Rα1, indicating a potential off-target effect.
Conclusions:
- The CARPOOL platform is effective for discovering CARs for solid tumors beyond hematological malignancies.
- This study represents a large-scale investigation of CAR signaling combinations in human primary cells.
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