The CAR T-cell therapies brexucabtagene autoleucel and lisocabtagene maraleucel have US Food and Drug Administration (FDA) approval for use in patients with relapsed/refractory mantle cell lymphoma (MCL). However, since CAR T-cell therapy is not suitable for all patients and because resistance to treatment is an emerging issue, research into novel strategies for these individuals is ongoing.

Patients with MCL who come to the clinic with disease progression after BTK inhibitors (among other risk factors for high-risk MCL) have what is considered high-risk disease. After progressing on at least 2 lines of standard-of-care treatments (eg, chemoimmunotherapy and a BTK inhibitor), patients are candidates to receive a CAR T-cell therapy. Determining whether CAR T-cell therapy is suitable for an individual patient is based on their comprehensive clinical profile, including their functional status, performance status, type of MCL, and risk for cytopenias and infections, among other factors. For example, an older patient with a poor performance status and cardiovascular and other clinically significant comorbidities may not be a suitable candidate for CAR T-cell therapy because of the potential risk for toxicities that could compromise their quality of life and increase their risk of CAR T cell–related death.

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Some patients have MCL that is resistant to CAR T-cell therapy, and these individuals, unfortunately, have poor survival outcomes. Resistance mechanisms are being explored and may include a more immunosuppressive microenvironment and a higher number of myeloid-derived suppressor cells. There are a few strategies for treating patients whose MCL fails to respond to CAR T-cell therapy. For example, in those who have a good performance status, we may rechallenge with chemoimmunotherapy with the possibility of a stem cell transplant.

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In addition, newer alternative antigenic targets are under evaluation, bispecific CAR T cells are in development, and a more humanized version of CAR T cells is being explored. The more humanized version of CAR T cells may cause fewer adverse reactions than earlier forms. We are still looking at data on sequencing CAR T cells with BTK inhibitors, and some studies are evaluating CAR T cells as a frontline therapy for patients with high-risk MCL. For example, Window-3, our trial based out of The University of Texas MD Anderson Cancer Center, is evaluating acalabrutinib and rituximab followed by brexucabtagene autoleucel in patients with high-risk MCL.