Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity against Glioblastoma
Meister H, Look T, Roth P, Pascolo S, Sahin U, Lee S, Hale BD, Snijder B, Regli L, Ravi VM, Heiland DH, Sentman CL, Weller M, Weiss T (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 28
Pages Range: 4747-4756
Journal Issue: 21
DOI: 10.1158/1078-0432.CCR-21-4384
Abstract
Purpose: Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes, and the risk for uncontrollable off-tumor toxicities. mRNA-based T-cell modifications are an emerging safe, rapid, and cost-effective alternative to overcome these challenges, but are underexplored against glioblastoma. Experimental Design: We generated mouse and human mRNA-based multifunctional T cells coexpressing a multitargeting CAR based on the natural killer group 2D (NKG2D) receptor and the proinflammatory cytokines IL12 and IFNα2 and assessed their antiglioma activity in vitro and in vivo. Results: Compared with T cells that either expressed the CAR or cytokines alone, multifunctional CAR T cells demonstrated increased antiglioma activity in vitro and in vivo in three orthotopic immunocompetent mouse glioma models without signs of toxicity. Mechanistically, the coexpression of IL12 and IFNα2 in addition to the CAR promoted a proinflammatory tumor microenvironment and reduced T-cell exhaustion as demonstrated by ex vivo immune phenotyping, cytokine profiling, and RNA sequencing. The translational potential was demonstrated by image-based single-cell analyses of mRNA-modified T cells in patient glioblastoma samples with a complex cellular microenvironment. This revealed strong antiglioma activity of human mRNA-based multifunctional NKG2D CAR T cells coexpressing IL12 and IFNα2 whereas T cells that expressed either the CAR or cytokines alone did not demonstrate comparable antiglioma activity. Conclusions: These data provide a robust rationale for future clinical studies with mRNA-based multifunctional CAR T cells to treat malignant brain tumors.
Authors with CRIS profile
Involved external institutions
Universitätsspital Zürich (USZ)
Switzerland (CH)
BioNTech / Biopharmaceutical New Technologies
Germany (DE)
Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich
Switzerland (CH)
Universitätsklinikum Freiburg
Germany (DE)
Geisel School of Medicine
United States (USA) (US)
Switzerland (CH)
BioNTech / Biopharmaceutical New Technologies
Germany (DE)
Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich
Switzerland (CH)
Universitätsklinikum Freiburg
Germany (DE)
Geisel School of Medicine
United States (USA) (US)
How to cite
APA:
Meister, H., Look, T., Roth, P., Pascolo, S., Sahin, U., Lee, S.,... Weiss, T. (2022). Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity against Glioblastoma. Clinical Cancer Research, 28(21), 4747-4756. https://doi.org/10.1158/1078-0432.CCR-21-4384
MLA:
Meister, Hanna, et al. "Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity against Glioblastoma." Clinical Cancer Research 28.21 (2022): 4747-4756.
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