Combining the time-limited Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib with CD19-directed chimeric antigen receptor (CAR) T cells reduces CAR T-cell toxicity, improves CAR T-cell expansion, and may overcome TP53 mutation in mantle cell lymphoma (MCL), according to a study published in Blood.
“Durable remissions are possible if you withdraw a BTKi in patients who have received T-cell products,” said corresponding author Michael Dickinson, MBBS, DMedSci, of Peter MacCallum Cancer Center in Melbourne, Australia.
The single-arm phase II study is one of the first to prospectively study CAR T cells as part of second-line therapy.
For patients with relapsed or refractory (R/R) MCL, the routine second-line treatment is BTKis; the only standard treatment after BTKis is CAR T-cell therapy.
Researchers aimed to test the hypothesized advantages of the CD19-directed CAR-T product tisagenlecleucel in conjunction with ibrutinib. Tisagenlecleucel is associated with lower rates of adverse events, specifically neurotoxicity, while ibrutinib has been shown to enhance T-cell fitness, promote better CAR T-cell expansion, and reduce the severity of cytokine release syndrome (CRS).
The primary endpoint was complete response rate (CRR) at four months. The secondary endpoints were safety and measurable residual disease (MRD), and subgroup analysis was planned based on TP53 aberrancy.
The study included 20 patients (median age = 66 years, 75% male) with R/R MCL after at least one prior line of therapy. Ten patients (50%) had prior BTKi exposure, and 9 (45%) were refractory to BTKis.
Patients received ibrutinib 560 mg daily beginning at seven days prior to leukapheresis, through infusion and beyond, and, for those in complete response (CR) and without MRD detectable by flow cytometry at 10-5 in peripheral blood, discontinued at six months after infusion.
Overall, patients showed an overall response rate and CRR of 80% at the primary endpoint, with CRR remaining durable at 12 months (estimated progression-free survival = 75%). Fourteen of the 16 patients in CR were MRD-negative by flow cytometry (70% overall MRD negativity rate) and ceased ibrutinib at six months.
Patients with longer ibrutinib exposure had reduced CAR T-cell exhaustion markers and improved expansion kinetics. “That strengthens the hypothesis that BTK inhibition, and particularly ibrutinib, can improve T-cell fitness,” Dr. Dickinson said, although this ultimately requires confirmation in a randomized study.
Deeper responses also showed more robust expansion of cells with higher peak levels (7,691 vs. 2,587 CAR copies/µg gDNA; p=0.03) than those who progressed or were MRD-positive.
Furthermore, seven of eight patients (88%) with TP53-mutated MCL achieved a CR, and of these, four of six evaluable responding patients (67%) demonstrated molecular MRD negativity. These findings “build on a literature that T-cell directed therapies ... may be among the most effective treatments we have seen for P53-mutated MCL,” Dr. Dickinson said.
Finally, the rate of infection was low. Although CRS occurrence was similar as that seen in alternative CAR-T products (75% of patients; no grade 4 CRS), immune effector cell-associated neurotoxicity syndrome was rare, showing in two patients and resolving completely after two days.
Researchers noted the small size and lack of control group as limitations to their study.
Researchers hope to explore this combination with bispecific antibodies and “build on the hypothesis that T-cell redirection may be very important for eradicating poor-risk MCL.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Minson AG, Hamad N, Cheah CY, et al. CAR T-cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: phase II TARMAC study (published online ahead of print 2023 Oct 26). Blood. doi: 10.1182/blood.2023021306.
