INSERM publishes first in vivo proof of concept of an engineered Chimeric Antigen Receptor T cell directed against IL-1RAP expressed by leukemia stem cells using TransCure’s full human immune system hu-mouse models.
This new publication shows how researchers have used TransCure’s hu-mouse models to:
- isolate the human T cells directly from the fully reconstituted human immune system of the hu-mice;
- re-engineer these T-cells (CAR-T) for injection into the same hu-mouse to target in vivo quiescent human IL-1RAP-bearing leukemia cells;
- induce a specific cytotoxic response against these cancer cells, raising hopes for a new treatment option against leukemia.
These findings come in as leukemia researchers are looking for new therapeutic approaches to complement the standard Tyrosine Kinase Inhibitors (TKI) regimens, for which relapses affect more than 50% of patients.
TransCure full human immune system hu-mouse models permit efficient CAR-T cells treatment in combination with immune Check Point Inhibitors (CPI) to generate more predictive and clinically actionable data.
Lukasz Kuryk, Anne-Sophie W. Møller & Magnus Jaderberg
Abstract 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.