Zamto-Cel Represents Potential New CAR T Approach in R/R DLBCL

Employing a unique mechanism of action targeting both CD19 and CD20, plus an expedited manufacturing process, the investigational CAR T-cell therapy zamtocabtagene autoleucel (zamto-cel; MB-CART2019.1) could represent a potentially significant addition to the treatment landscape of relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to Nirav N. Shah, MD.

Findings from the 2 DALY II USA trial (NCT04792489) presented by Shah during the 2025 Transplant and Cellular Therapy Meetings demonstrated that patients with DLBCL in the modified intention-to-treat population (n = 59) experienced an overall response rate (ORR) of 72.8%, including a complete remission (CR) rate of 50.8%.1 Notably, CRs were observed across patient subgroups; patients who relapsed following their last line of therapy (n = 9), those who underwent prior autologous stem cell transplant (n = 9), and those who received at least 3 prior lines of therapy (n = 9) experienced the highest CR rates at 82%, 64%, and 60%, respectively.

“[Zamto-cel showed] favorable efficacy in a very difficult-to-treat patient population,” Shah said in an interview with OncLive®. “We [saw this activity] with a very favorable safety profile. It could [also] be given potentially as an outpatient [therapy]. There are several differentiators that could make this the next-generation product for patients with DLBCL.”

In the interview, Shah discussed the properties that make zamto-cel unique among CAR T-cell therapies, the background of DALY II USA, key findings from the study, and the next steps for the agent’s development.

Shah is an associate professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin in Madison.

OncLive: What was the rationale for examining a dual-directed CAR T-cell therapy in patients with relapsed/refractory DLBCL?

Shah: CD19[-directed] CAR T-cell therapy is a great therapy for [patients with] relapsed/refractory lymphomas that is approved in multiple settings. However, we know that patients relapse after CD19[-directed] CAR T-cell therapy, so better treatments are indicated. 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. We performed the phase 1 trial [NCT03019055] at the Medical College of Wisconsin, and those data showed that this dual-targeted CAR had a high ORR and good initial efficacy, and we found a safe dose that led to DALY II USA.

What were the notable enrollment criteria for DALY II USA?

This study [enrolled] adult patients with relapsed/refractory DLBCL. They had to have 2 or more prior lines of treatment and measurable disease at the time of enrollment. This trial also used a novel CAR T manufacturing paradigm. It used a closed device called the CliniMACS Prodigy that allows for rapid, reproducible manufacturing within a short time period.

Another unique [aspect] is that the cells are both collected fresh and sent to the central facility for manufacturing, and then they are delivered fresh after they’re harvested at the end of production. This means that lymphodepletion starts during the manufacturing process, allowing patients to get the CAR T[-cell agent] with a very quick turnaround from the time of apheresis. With the fresh product, we truly have a 14-day vein-to-vein time.

This trial was for CAR [T-cell therapy]–naive patients. There were 59 evaluable patients [who] had a median age of 65 [years], and many of them were high risk. The majority had high International Prognostic Indexscores at the time of enrollment and elevated lactate dehydrogenase [levels, which are] biomarkers of difficult-to-treat disease.

What were the key efficacy data you presented during the meeting?

Despite some of these poor prognostic indicators, we were happy to report that the ORR was [72.8%], with [50.8%] of patients achieving a CR. Many of these remissions were durable; the 6-month progression free survival [rate] was 55%. We need to continue to follow these patients and get more mature data, and we hope at a future time point to report 1- and 2-year outcomes. This is an interim analysis of this study population.

The median duration of response [DOR] was 11.4 months, and for patients [who achieved a CR], the median DOR was not yet reached [NR]. The median overall survival in the overall population was NR, regardless of response. It’s good to know that patients are still alive, even among those who may have relapsed.

What was found regarding the safety of zamto-cel?

One of the [questions] when you target more than 1 protein is: are you going to see a different toxicity profile? Are you going to see more toxicity? The answer to that question was a clear and resounding no [in this study].

When we think about CAR T toxicity, [we think of] cytokine release syndrome [CRS] and immune effector cell­–associated neurotoxicity syndrome [ICANS]. Low-grade CRS and ICANS have become manageable; we are worried about grade 3 or higher CRS.

In this trial, no patients experienced grade 3 or higher CRS, meaning no patients needed pressors to get through their CRS. In terms of grade 3 or higher ICANS, we only saw that in 4.3% of patients. Overall, we’re very satisfied and excited by the safety profile, which in combination with the rapid manufacturing and dual targeting of more than 1 B-cell protein makes this product a viable option should it get FDA approved the future.

What are the next steps for this research?

This is a US study in third-line DLBCL, and in Europe, the same agent is being studied as a second-line treatment for transplant-ineligible patients with DLBCL in a randomized, controlled setting. We’re hoping that the results of these 2 clinical trials will lead to an FDA approval.

Should it get approved, I believe what you’re seeing would be the first next-generation CAR T[-cell therapy] that is available. The differentiators of this product are the [dual] CD19 plus CD20 targeting and its rapid manufacturing [process] so patients get it within 14 days, and they get a fresh product. There are some data suggesting that freezing CAR T cells before administration may be deleterious to the CAR T-cell product, which is why we [wanted] a fresh infusion.

Disclosures: Shah reports participation on advisory boards and/or consultancy for Gilead-Kite, BMS-Juno, Miltenyi Biomedicine, Lilly Oncology, Incyte, Abbvie, Cargo, Beigene, Kite, Allogene, AstraZeneca, BMS, Ipsen, and Galapagos. He has also received research funding from Genentech, Miltenyi Biomedicine, and Lilly Oncology, and serves on a scientific advisory board for Tundra Therapeutics.

Reference

Shah N, Klysz D, McKinney M, et al. Tandem CD20-CD19-directed non-cryopreserved CAR T cells - zamtocabtagene autoleucel (zamto-cel) in patients with relapsed/refractory diffuse large B cell lymphoma - interim results from a phase 2 pivotal study (DALY II USA). Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Abstract 43.