The Bruton tyrosine kinase inhibitor ibrutinib has been approved by the FDA as a treatment of mantle-cell lymphoma and chronic lymphocytic leukaemia (CLL). Now, experimental data reveal that prolonged treatment with ibrutinib, unlike other treatments of CLL, can reverse the T-cell defects associated with this form of leukaemia, and thus enhance the effectiveness of autologous chimeric antigen receptor (CAR) T-cell therapy.

Using a translational approach, researchers found that T cells from patients with CLL, compared with those derived from patients with multiple myeloma (MM) or acute lymphocytic leukaemia (ALL), have proliferative defects that significantly reduce the ex vivo expansion of these cells in response to synthetic antigens. However, T cells from patients with CLL who received 5–11 cycles of ibrutinib treatment seemed to lose these proliferative defects and had levels of ex vivo expansion similar to T cells from patients with MM. Furthermore, T cells from these ibrutinib-treated patients exhibited robust and uniform expansion ex vivo after anti-CD19 gene transfer, unlike many of those derived from patients who were ibrutinib-naive, or had received only one cycle of ibrutinib treatment; this improved T-cell viability was maintained in vivo, 90 days after infusion into patients with CLL.

mice that received the combination of ibrutinib and CTL019 T cells had significantly improved CTL019-cell engraftment

To test the effectiveness of ibrutinib administered with anti-CD19 (CTL019) CAR T cells, researchers used a mouse xenograft model of advanced-stage human CLL. Treatment with ibrutinib alone, or infusion of CTL019 cells alone, had no notable therapeutic effect; however, mice that received the combination of ibrutinib and CTL019 T cells had significantly improved CTL019-cell engraftment, and significantly increased overall survival.

These data reveal a promising interaction between ibrutinib and CAR T-cell viability and engraftment that has the potential to improve the outcomes of CAR T-cell therapy in patients with CLL, and possibly the outcomes of patients with other cancers.