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Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, e0144787Article in journal (Refereed) Published
Abstract [en]

CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G) CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G) CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.

Place, publisher, year, edition, pages
2015. Vol. 10, no 12, e0144787
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-270504DOI: 10.1371/journal.pone.0144787ISI: 000367092600032PubMedID: 26700307OAI: oai:DiVA.org:uu-270504DiVA: diva2:889903
Funder
Swedish Childhood Cancer Foundation, PROJ08/028Swedish Cancer Society, CAN 2008/936Swedish Research Council, K2008-64P-20744-01-4AFA InsuranceÅke Wiberg FoundationMagnus Bergvall Foundation
Available from: 2015-12-29 Created: 2015-12-29 Last updated: 2017-12-01Bibliographically approved

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Karlsson, HannahJarvius, MalinOlsson-Strömberg, UllaLoskog, Angelica

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Karlsson, HannahJarvius, MalinOlsson-Strömberg, UllaLoskog, Angelica
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Science for Life Laboratory, SciLifeLabClinical ImmunologyDepartment of Immunology, Genetics and PathologyCancer Pharmacology and Computational MedicineHaematology
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