Could Combining Use of BTK Inhibition, CAR T-Cell Therapy Yield Better Outcomes in MCL?

As chimeric antigen receptor (CAR) T-cell therapy and Bruton’s tyrosine kinase (BTK) inhibitors become cornerstones of treatment for advanced mantle cell lymphoma (MCL) in their own right, some research has suggested the feasibility of combining the treatments for improved outcomes.

There are currently 3 approved BTK inhibitors in relapsed/refractory (R/R) MCL—first-generation ibrutinib and second-generation acalabrutinib and zanubrutinib. In 2020, CAR T-cell therapy entered the MCL market with the approval of brexucabtagene autoleucel in patients with R/R disease.

While both categories have yielded impressive efficacy for some patients, there are a group of patients who don’t achieve sufficient outcomes, including those who discontinue ibrutinib due to treatment intolerance, the development of resistance to BTK inhibitor treatment, and short-lived responses to CAR T-cell therapy due to a variety of factors, including T-cell exhaustion.

“Evidence suggests that concomitant administration of BTKi and CAR T-cell therapy may provide a greater treatment benefit than either agent alone,” suggested the researchers. “In vitro analyses demonstrate that stimulation of CAR T-cells with a BTKi enhances the Th1 response and T-cell effector activity by increasing cytokine production and cytolytic activity. In addition, exposure to a BTKi increases T-cell expansion, viability, and engraftment.”

With the jury still out on whether sequential administration of BTK inhibitors and CAR T-cell therapy is more beneficial than concomitant use, the group outlined recommended scenarios each approach. For example, the researchers recommend CAR T-cell therapy be used ahead of BTK inhibition in BTK inhibitor-naïve patients with high-risk disease characteristics as they will likely not achieve durable responses to a BTK inhibitor. According to the researchers, in cases like this, a BTK inhibitor could be used as a bridge in patients who did not respond or who had a partial response to CAR T-cell treatment.

The researchers recommend use of a covalent BTK inhibitor, either as monotherapy or in combination with another treatment like venetoclax, in patients who don’t respond to or relapse following CAR T-cell treatment and have not previously received BTK inhibitor treatment. Non-covalent BTK inhibitors are recommended, either alone or in combination with another treatment, in patients who have previously been treated with a covalent BTK inhibitor.

The researchers explained that to date, there is no approved option for concomitant use of CAR T-cell therapy and a BTK inhibitor—leaving an absence of standardized guidelines for the treatment approach—though the approach may be feasible in patients who are naïve to both, as a combination of the 2 may improve outcomes.

“Evidence supporting the use of concomitant BTKi and CAR T-cell therapy is mostly limited to studies in CLL, as patients with CLL typically have low rates of CR with CAR T-cell therapy, likely due to CLL-induced T-cell dysfunction,” explained the researchers. “In vitro studies suggest that ibrutinib may enhance CAR T-cell expansion and increase cell viability as well as improve cell engraftment, tumor clearance, and survival. Stimulation of CAR T-cells with ibrutinib or acalabrutinib enhanced CAR T-cell effector function; prolonged BTKi stimulation further increased cytokine production and Th1 differentiation.”

Drawing on the limited data available in CLL, the researchers suggest that a BTK inhibitor is used as bridging therapy and used during lymphodepletion in preparation for CAR T-cell therapy. The group noted that using a BTK inhibitor directly following CAR T-cell therapy may lead to drug-drug interactions, off-target toxicity, and immunomodulatory effects. They added that while no published data has yet pointed to increased toxicity or reduced efficacy associated with concomitant use of a BTK inhibitor during lymphodepletion or immediately after CAR T-cell therapy, providers should closely monitor patients for related toxicities and other adverse events.

Reference

Munoz J, Wang Y, Jain P, Wang M. BTK inhibitors and CAR T-cell therapy in treating mantle cell lymphoma—finding a dancing partner. Curr Oncol Rep. 2022; 24(10):1299–1311. doi:10.1007/s11912-022-01286-0