CAR-T and ibrutinib vs CLL: sequential or simultaneous?

In this issue of Blood, Gauthier and colleagues present the results of a pilot study evaluating the safety and feasibility of administrating ibrutinib concurrently with CD3zeta, 4-1BB-signaling anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory chronic lymphocytic leukemia (CLL).¹  Minimal residual disease (MRD) assessment was performed on bone marrow (BM) at an early time point (4 weeks) following CAR T-cell infusion. The study enrolled 19 CLL patients, one of whom died 4 days after infusion from a presumed ibrutinib-related cardiac arrhythmia during grade 2 cytokine release syndrome (CRS). At the 4-week time point, 15 of the remaining 18 patients responded, with 4 patients achieving a complete response. Remarkably, 11 patients had undetectable BM MRD as measured by IGH sequencing. One-year progression-free survival (PFS) of the 18 evaluable patients was 38%. The authors compared these results to 19 CLL patients who were previously treated with a very similar regimen but without concurrent ibrutinib²  and found that severity of CRS was lower with concomitant ibrutinib, but PFS was unchanged.

This study raises several questions.

First, with the novel highly successful target therapies available for CLL, do we actually need complex strategies such as CAR T-cell treatment? Novel drugs that inhibit either key kinases of the B-cell receptor–signaling pathway, such as the Bruton tyrosine kinase inhibitor ibrutinib, or specific antiapoptotic proteins, such as the Bcl-2 inhibitor venetoclax, have recently been shown to be valuable additions to the therapeutic arsenal of CLL. However, these agents are costly and are to be taken continuously with potential long-term toxicities and development of resistance. Novel combinations of such agents aimed at early treatment cessation are promising but cannot, at this point, be expected to be curative. Therefore, indeed an unmet need exists for the development of additional effective yet tolerable treatment options with alternative mechanisms of action.

Second, is there a need to improve CAR T-cell therapeutic regimens in CLL? A proof-of-concept that T-cell–based therapies have curative potential in CLL comes from observations that allogeneic hematopoietic stem cell therapy, which can induce long-term remissions through T cell–mediated graft-versus-leukemia effects. However, the applicability of allogeneic T cells is severely hampered by high levels of treatment-related morbidity and mortality due to treatment-related toxicity and graft-versus-host disease. An additional impediment is the limited availability of HLA-matched donors. CAR-reprogrammed patient T cells that provide a cellular antitumor response might, therefore, be a highly attractive approach for CLL. However, CAR T-cell treatment regimens have shown disappointingly low response rates in CLL.³  A likely factor in the limited responses in CLL is the acquired T-cell dysfunction that we, and others, have described. T-cell abnormalities include impaired synapse formation, impaired proliferative capacity, an exhausted phenotype, and diminished T-cell cytotoxicity.^4,5  Increasing evidence suggests that T-cell dysfunction in CLL occurs through direct and indirect interactions of CLL cells with both CD4⁺ and CD8⁺ T cells through mechanisms that are yet not fully understood. By studying the metabolic function of T cells in CLL, we recently linked the acquired abnormalities of CLL-derived T cells to the lack of CAR T-cell persistence and clinical responses.⁶  Hence, acquired T-cell dysfunction in CLL currently hampers successful implementation of CAR T-cell therapy in CLL.⁷ 

What strategies could improve CAR T-cell efficacy in CLL? When CAR T-cells are used in the setting of active disease, both during the leukapheresis process and during product infusion, interactions between T cells and CLL cells are expected to occur. Ibrutinib does not only target Bruton tyrosine kinase, but also interleukin-2–inducible T-cell kinase, and both in vitro and ex vivo observations showed improved T-cell function upon ibrutinib treatment.⁸  More recently, also in the context of CAR T-cell therapy in CLL, ibrutinib was shown to augment responses: first, ibrutinib improved the expansion of CAR T cells, which was associated with decreased expression of programmed cell death protein 1 (PD1) on T cells and of CD200 on CLL cells. Second, in a human xenograft model of CLL, ibrutinib exposure improved CAR T-cell engraftment and survival.⁹  Gauthier and colleagues’ observations are very instructive in that the rescue of ibrutinib-nonresponsive CLL patients with anti-CD19 CAR T cells,²  and the concurrent treatment of ibrutinib-refractory CLL patients with ibrutinib and CD19 CAR T cells result in comparable response rates. Disappointingly, the complete response rates were not higher than previously reported by others.⁷ 

Third, what are possible other strategies to improve CAR T-cell efficacy in CLL? As T-cell function in CLL is not intrinsically imprinted but can be restored following depletion of leukemia cells,^5,6  1 approach might be to use CAR T-cell therapy not as salvage therapy for highly refractory patients but as consolidation treatment following successful tumor debulking. A better alternative therefore may be to use ibrutinib, possibly combined with therapeutic apheresis to remove mobilized tumor cells. Preclinical studies from Fraietta et al demonstrated that the enhanced antitumor efficacy of CLL CD19 CAR T cells was only observed after at least 5 prior cycles on ibrutinib.⁹  Hence, the combined debulking with ibrutinib with concurrent T-cell function recovery might represent the next iteration in CLL-directed precision targeting. Along the same line, we recently observed normalization of T-cell function and a specific decrease of follicular T-helper cells, regulatory T cells, and PD1⁺ CD8⁺ cells following 1 year of treatment with a venetoclax containing regimen.¹⁰ 

Hence, Gauthier and colleagues have here and in their previous study provided support for a synergistic approach of CLL targeting with both CAR-reprogrammed T cells and ibrutinib; the question remains, however, whether the concurrent treatment of patients with both drugs really results in superior responses.