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Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. (Angelica Loskog)
2016 (English)In: Biochemical Society Transactions, ISSN 0300-5127, E-ISSN 1470-8752, Vol. 44, no 2, 371-376 p.Article, review/survey (Refereed) Published
Abstract [en]

Chimaeric antigen receptor (CAR) T-cells have shown impressive results in patients with B-cell leukaemia. Yet, in patients with lymphoma durable responses are still rare and heavy preconditioning required. Apoptosis resistance is considered a hallmark of cancer, often conveyed by a halted apoptosis signalling. Tumours regularly skew the balance of the components of the apoptotic machinery either through up-regulating antiapoptotic proteins or silencing pro-apoptotic ones. Malignant B-cells frequently up-regulate anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins leading to therapy resistance. CAR T-cells kill tumour cells via apoptosis induction and their efficacy may be affected by the level of Bcl-2 family proteins. Hence, there is an interesting possibility to increase the effect of CAR T-cell therapy by combining it with apoptosis inhibitor blockade agents. Compounds that inhibit Bcl-2, B-cell lymphoma extra large (Bcl-xL) and Bcl-2-like protein 2 (Bcl-w), can restore execution of apoptosis in tumour cells or sensitize them to other apoptosis-dependent treatments. Hence, there is a great interest to combine such agents with CAR T-cell therapy to potentiate the effect of CAR T-cell killing. This review will focus on the potential of targeting the apoptotic machinery to sensitize tumour cells to CAR T-cell killing.

Place, publisher, year, edition, pages
2016. Vol. 44, no 2, 371-376 p.
Keyword [en]
ABT-737; B-cell lymphoma 2 (Bcl-2) family proteins; chimaeric antigen receptor (CAR) T-cells; inhibitor of apoptosis protein (IAP); Navitoclax
National Category
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-290391DOI: 10.1042/BST20150253ISI: 000377518000007PubMedID: 27068942OAI: oai:DiVA.org:uu-290391DiVA: diva2:925105
Conference
Chimeric Antigen Receptor Therapy in Haematology and Oncology: Current Successes and Challenges: Held at Charles Darwin House, London, U.K., 19–20 October 2015
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: 2016-04-29 Created: 2016-04-29 Last updated: 2016-07-22Bibliographically approved

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