CML hematopoietic stem cells expressing IL-1RAP can be targeted by chimeric antigen receptor (CAR)-engineered T cells
Menée in vitro et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence la possibilité de cibler, à l'aide de lymphocytes CAR-T, les cellules souches hématopoïétiques exprimant la protéine accessoire du récepteur à l'interleukine IL-1 pour traiter définitivement une leucémie myéloïde chronique
Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of CML patients, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system-sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting interleukin-1 receptor-associated protein (IL-1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure. In this study, we produced and molecularly characterized a specific monoclonal anti-IL-1RAP antibody from which fragment antigen-binding nucleotide coding sequences were cloned as a single chain into a lentiviral backbone and secured with the suicide gene iCASP9/rimiducid system. Our CAR T cell therapy exhibited cytotoxicity against both leukemic stem cells and, to a lesser extent, monocytes expressing IL-1RAP, with no apparent effect on the hematopoietic system, including CD34+ stem cells. This suggests IL-1RAP as a tumor-associated antigen for immunotherapy cell targeting. IL-1RAP CAR T cells were activated in the presence of IL-1RAP+ cell lines or primary CML cells, resulting in secretion of pro-inflammatory cytokines and specifically killing in vitro and in a xenograft murine model. Overall, we demonstrate the proof of concept of a CAR T-cell immunotherapy approach in the context of CML that is applicable for young patients and primary TKI-resistant, intolerant, or allograft candidate patients.
Cancer Research 2018