Shared target antigens on cancer cells and tissue stem cells: go or no-go for CAR T cells?

ABSTRACT

Introduction: Adoptive therapy with chimeric antigen receptor (CAR) T cells redirected towards CD19 produces remissions of B cell malignancies, however, it also eradicates healthy B cells sharing the target antigen. Such ‘on-target off-tumor’ toxicity raises serious safety concerns when the target antigen is also expressed by tissue stem cells, with the risk of lasting tissue destruction.

Areas covered: We discuss CAR T cell targeting of activation antigens versus lineage associated antigens on the basis of recent experimental and animal data and the literature in the field.

Expert commentary: Targeting an activation associated antigen which is transiently expressed by stem cells seems to be safe, like CAR T cells targeting CD30 spare CD30⁺ hematopoietic stem and progenitor cells while eliminating CD30⁺ lymphoma cells, whereas targeting lineage associated antigens which increase in expression during cell maturation, like folate receptor-β and CD123, is of risk to destruct tissue stem cells.

KEYWORDS:

• Adoptive cell therapy
• CAR
• chimeric antigen receptor
• CD30
• CD123
• hematopoietic stem and progenitor cell
• HSPCs
• stem cell
• SP6/PI9
• T cell

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Work in the author’s laboratory was supported by the Deutsche Forschungsgemeinschaft, Bonn, the Deutsche Krebshilfe, Bonn, the Else Kröner-Fresenius Stiftung, Bad Homburg v.d.H., the Wilhelm Sander-Stiftung, München, the José Carreras Leukämie-Stiftung, München and the Medical Faculty of the University.