Tisagenlecleucel in combination with ibrutinib in adults with relapsed and/or refractory large B-cell lymphomas

The mechanisms underlying chimeric antigen receptor (CAR) T-cell failure are not fully understood; however, T-cell differentiation and presence of an immunosuppressive tumor microenvironment are thought to contribute. Ibrutinib, a Bruton tyrosine kinase inhibitor, has been shown to modify both T-cell phenotype and tumor microenvironment. Preliminary data suggest that combining ibrutinib with tisagenlecleucel may improve efficacy of CAR T-cell therapy; however, it is unknown whether the timing of ibrutinib treatment affects clinical outcomes. This phase 1b exploratory study assessed tisagenlecleucel in combination with ibrutinib for safety, efficacy, and feasibility in adult patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Ibrutinib (560 mg/d) was started ≥21 days before apheresis (preapheresis arm, n = 4) or after apheresis for ≥21 days before tisagenlecleucel infusion (postapheresis arm, n = 6). Both arms received ibrutinib continuously thereafter for up to 24 months after infusion. As of study termination (1 November 2021), 10 patients were treated and underwent posttisagenlecleucel response assessment. Final product manufactured from patients in the preapheresis arm had higher interferon gamma and interleukin-2 release and a reduction in senescent T cells. Fewer patients in the preapheresis arm vs the postapheresis arm experienced cytokine release syndrome (1/4 vs 5/6) or death (1/4 vs 4/6). Although increased tisagenlecleucel expansion was observed in the postapheresis arm, a higher response rate was observed in the preapheresis arm (4/4 vs 3/6). Altogether, these findings suggest administering ibrutinib before leukapheresis may modify T-cell characteristics in the collected material, thereby improving final CAR T-cell product quality and clinical outcomes for patients with R/R LBLC treated with tisagenlecleucel. This trial was registered at www.clinicaltrials.gov as #NCT03876028.