Ibrutinib Boosts Efficacy of CAR T-Cell Treatment in Patients with Refractory B-NHL

As some patients with refractory B-cell non-Hodgkin lymphoma (B-NHL) who received chimeric antigen receptor (CAR) T-cell therapy experienced efficacy shortcomings, researchers studied whether using the treatment a second time, following ibrutinib, may salvage treatment. They found that adding the Bruton's tyrosine kinase (BTK) inhibitor to CAR T-cell therapy improved efficacy.

Following their second CAR-T cell treatment, 6 of 7 patients achieved a complete response (CR) and 1 patient achieved partial remission (PR). According to the researchers, findings suggest that receiving ibrutinib improves the activity of anti-CD19-CAR T cells.

“Multiple preclinical and clinical studies have proven that ibrutinib could improve anti-CD19-CAR T-cell therapy in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but clinical studies on the effect of ibrutinib treatment on the efficacy of 2 anti-CD19-CAR T-cell treatments in the same patients are limited,” wrote the researchers.

Their findings, published in Cancer Science, were based on results from 3 patients with refractory MCL and 4 patients with refractory follicular lymphoma (FL). Each of these patients demonstrated stable disease (SD), PR, or progressive disease (PD) following their first treatment with CAR T-cell therapy.

Patients received ibrutinib as a salvage treatment and maintained SD for at least 7 months following their first treatment with CAR T-cell therapy. When their disease began to progress, they then received their second CAR T-cell treatment.

The researchers noted there were no differences in the transduction efficiency and proliferation between the 2 CAR T-cell treatments, although the second treatment did result in higher peaks of anti-CD19 CAR T-cells, as well as anti-CD19-CAR gene copies.

“Ibrutinib could improve T-cell function by increasing the persistence of activated T-cells, decreasing the Treg/CD4+ T-cell ratio, and diminishing the immune-suppressive properties through BTK-dependent and BTK-independent mechanisms in CLL patients,” explained the researchers. “In addition, inhibition of interleukin (IL)-2-inducible T-cell kinase (ITK) activity would lead to the inhibition of Th2 cell differentiation and promotion of a Th1 cell immune response.”

Assessing the safety impact, researchers found the second CAR T-cell treatment did demonstrate higher grades of cytokine release syndrome, with notable events being grade 0-2 for the first treatment and grades 2-4 the second treatment. There were also more serious hematological toxicities following the second treatment, with grades 1-3 reported after the first treatment and grades 3 and 4 after the second treatment.

Reference:

Liu M, Deng H, Mu J, et al. Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma. Cancer Sci. Published online May 1, 2021. doi:10.1111/cas.14915