Dr Shah on the Rationale for Evaluating Zamto-Cel in R/R DLBCL

“One mechanism of resistance is that tumors can experience downregulation of CD19; therefore, 1 way to overcome that mechanism is through dual targeting [of CD19 and CD20]. CD20 is the most commonly targeted antigen in lymphoma with drugs [such as] rituximab [Rituxan] and obinutuzumab [Gazyva], so it made biological sense to do a trial like this.”

Nirav N. Shah, MD, associate professor, medicine, Division of Hematology and Oncology, Medical College of Wisconsin, discusses the rationale for examining the dual-directed CAR T-cell therapy zamtocabtagene autoleucel (zamto-cel; MB-CART2019.1) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

CD19-directed CAR T-cell therapy has proven to be an effective treatment for patients with relapsed/refractory lymphomas in multiple settings, Shah begins. Despite its efficacy, relapse remains a concern, with one key mechanism of resistance being the downregulation of CD19 expression on tumor cells, he states. To address this challenge, dual-targeting strategies that combine CD19-directed drugs with other antigens, such as CD20-directed agents, are being explored, Shah says. CD20 is a well-established target in lymphoma management, with CD20-directed therapies like rituximab (Rituxan) and obinutuzumab (Gazyva) widely used in clinical practice, making it biologically plausible to combine CD19 and CD20 targeting, he adds.

The rationale behind this dual-targeting approach is to overcome CD19 loss and leverage the established efficacy of CD20-targeted therapies, Shah continues. By targeting both antigens, the therapy may improve the persistence and efficacy of CAR T-cell treatments in patients who develop resistance to CD19 alone, he explains. This approach could enhance response rates and durability of treatment in patients with relapsed or refractory lymphoma, offering an important potential advancement in the field, he says.

Notably, findings from a phase 1 trial (NCT03019055) conducted at the Medical College of Wisconsin demonstrated a high overall response rate (ORR) and good initial efficacy with zamto-cel; this trial also identified a safe dose for further study in the phase 2 DALY II USA trial (NCT04792489). Results from DALY II USA, aspresented by Shah during the 2025 Transplant and Cellular Therapy Meetings, showed an ORR of 72.8% with zamto-cel in the intention-to-treat population (n = 59), with a complete remission rate of 50.8%.