Does BTKi improve CAR T-cell therapy in MCL?

In this issue of Blood, Minson et al present the first clinical study investigating the combinatorial use of a Bruton tyrosine kinase inhibitor (BTKi) with CD19 chimeric antigen receptor (CAR) T cells in patients with relapsed/refractory mantle cell lymphoma (MCL), a cohort with historically poor outcomes.¹ Despite encouraging results in the phase 2 ZUMA-2 and TRANSCEND NHL-001 studies, which studied the use of brexucabtagene autoleucel and lisocabtagene maraleucel (liso-cel), respectively, there is a significant unmet clinical need to improve MCL outcomes after immune effector cell therapy.^2,3 A rationally designed combinatorial strategy using approved drugs with proven efficacy on MCL has the potential to deepen responses without relying on more intensive preclinical validation required for new drug approval. Many agents, ranging from small molecular inhibitors to monoclonal antibodies, have been investigated to boost CAR T-cell activity, yet none has reached phase 3. Requisite early-phase studies must demonstrate that the added agent does not interfere with antitumor effect or potentiate toxicities.

Building on promising preclinical data suggesting therapeutic synergism of the BTKi ibrutinib and CD19 CAR T cells in mouse models of chronic lymphocytic leukemia (CLL), as well as clinical activity shown in CLL,^4-6 the phase 1/2 TARMAC study establishes the use of ibrutinib, starting before apheresis, with CAR T cells to be both safe and feasible in patients with MCL.¹ Furthermore, correlative analyses presented by the authors successfully lay the foundation to prospectively determine whether Bruton tyrosine kinase inhibition augments CD19 CAR T-cell activity in patients with MCL and other lymphomas.

Minson et al are the first to report on the use of CTL019, the investigational form of tisagenlecleucel (tisa-cel,) in patients with MCL. Among the 20 patients treated in the TARMAC study, 9 were BTKi refractory and 9 had TP53 aberrancy,¹ highlighting significant representation of high-risk clinical features associated with poor outcomes. Patients who were previously on ibrutinib continued therapy, whereas ibrutinib-naïve patients started at least 7 days before apheresis. All patients continued treatment through 6 months after infusion unless they achieved less than a minimal residual disease (MRD)–negative complete response (CR), in which case treatment was continued until progression or unacceptable toxicity (see figure panel A). Intriguingly, 14 patients achieved MRD-negative CR, as determined by flow cytometry, and thus received time-limited ibrutinib, an important aspect of the study.¹ Relative to the complete response rates of 59% and 72% in ZUMA-2 and TRANSCEND NHL-001,^2,3 respectively, 80% of patients achieved a CR in the TARMAC study, suggesting both that tisa-cel has activity in MCL and that ibrutinib does not negatively impact CAR T-cell anti-tumor activity (see figure panel B). Safety signals were favorable, with 20% of patients experiencing grade ≥3 cytokine release syndrome (CRS) and only 10% experiencing ICANS (immune effector cell-associated neurotoxicity syndrome) of any grade, relative to 15% and 63% in ZUMA-2, and 1% and 31% in TRANSCEND NHL-001, respectively.^1-3 Tisa-cel, like liso-cel, bears a 4-1BB costimulatory domain; thus, the latter is a more biologically equivalent comparison. Toxicity outcomes in TARMAC are consistent with those of JULIET, the phase 2 study of tisa-cel in large-cell lymphoma.⁷ 

CAR T-cell treatment failure in lymphoma is associated with upregulation of effector differentiation and exhaustion transcriptional programs in the manufactured product.⁸ Meanwhile, clinical response after tisa-cel is associated with expansion of memory-like CD8 T cells.⁸ In addition to well-established direct inhibition of B-cell lymphoma growth, ibrutinib promotes type 1 helper–mediated CD8 T-cell expansion through inhibiting interleukin 2 (IL-2)–inducible T-cell kinase on type 2 helper CD4 T cells.⁹ The latter effect was surmised to reverse CLL-associated immune dysregulation, characterized by decreased proliferative capacity of circulating endogenous T cells. In fact, ibrutinib exposure in patients with CLL enhances in vivo CTL019 CAR T-cell expansion, a phenotype that correlates with improved disease response, and increases the proportion of central memory CAR T cells.^4,5 More important, Minson et al recapitulate these findings in MCL. Although limited by small numbers, immune subset analyses revealed that extended ibrutinib exposure (>100 days) was associated with a higher proportion of CD8⁺ naïve T cells and decreased exhaustion markers on central memory T cells at the time of apheresis.¹ There was also a trend toward increased peak CAR T-cell expansion and persistence by area under the curve in this cohort, suggesting possible dose-dependent improvement in CAR T-cell function with ibrutinib administration.¹ Although comparison to other diseases is inherently challenging, the overall CAR T-cell expansion and persistence metrics exceeded those of the JULIET study, possibly suggesting a contribution from ibrutinib.⁷ 

Future study of combining ibrutinib or newer BTKi with CD19 CAR T-cell therapy will importantly require a BTKi untreated comparator to confirm the additive effect of a combinatorial strategy vis-à-vis CAR T-cell monotherapy. Correlative studies would be further strengthened by immunophenotypic and functional profiling of preinfusion product and circulating peripheral blood CAR T cells in patients to corroborate preclinical findings. These analyses would enable investigators to more robustly determine whether differences in efficacy and toxicity outcomes correlate with ibrutinib-induced changes in CAR T-cell phenotype. For example, reduction in CAR T-cell–induced cytokine release in a xenograft mouse model of MCL was demonstrated after ibrutinib.¹⁰ One small clinical study conversely showed greater IL-6 release in ibrutinib-exposed relative to ibrutinib-naïve CAR T-cell–treated patients with CLL.⁵ Given emerging data that CRS is mediated by CD4 CAR T cells, it remains to be determined whether higher CD8 relative to CD4 CAR T cells after ibrutinib exposure both reduces cytokine release and improves anti-tumor effect in patients with lymphoma. Although significant questions remain as to the role of combinatorial treatments in CAR T-cell therapy, Minson et al confirm that additional study of BTKi combined with tisa-cel is safe, feasible, and warranted.

This study is the first of several imminent and ongoing clinical trials, including the Window-3 study (NCT05495464) and others (NCT04484012,) that will investigate the safety and efficacy of BTKi and CAR T-cell combinations for high-risk patients with MCL, including in earlier lines of therapy. We are hopeful that outcomes in these patients will be substantially better in the years to come.

Conflict-of-interest disclosure: M.L.P. has received compensation for participating in consulting activities with Bristol Myers Squibb, Novartis, Cellectar, and Synthekines. A.P.B. declares no competing financial interests.