The first pivotal trial of a tandem CD20-CD19 directed non-cryopreserved CAR T-cell product for patients with third-line relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) demonstrated encouraging activity and a favorable safety profile, according to a pre-planned interim analysis presented by Nirav Shah, MD, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.

This pre-planned interim analysis reports on efficacy and safety outcomes from the phase 2 DALY II USA clinical trial of zamtocabtagene autoleucel (zamto-cel), an investigational autologous tandem CD20-CD19-directed non-cryopreserved CAR-T cell product.

Dr Shah presented these results at the 66^th ASH Annual Meeting in San Diego, California.

“Among the 59 evaluable patients at the interim analysis, there is encouraging activity and a favorable safety profile in DLBCL patients treated with zamto-cel,” wrote Dr Shah and colleagues. “Unlike currently registered CAR-T cell products, zamto-cel is administered as a fresh product with a short vein-to-vein time of 14 days with lymphodepletion initiated during the manufacturing process.”

“With a manufacturing success rate of 91% we have demonstrated the feasibility of this process among high-risk patients with R/R DLBCL,” they added.

Transcript:

Hi, my name is Nirav Shah. I'm an associate professor of medicine at the Medical College of Wisconsin in Milwaukee. I'm here at ASH 2024 and excited to share data that was presented yesterday as an oral presentation from the DALY II clinical trial. 

The DALY II clinical trial is based on developing a novel strategy for CAR T-cell for the treatment of relapsed/refractory diffuse large B-cell lymphoma. We know that single targeting of CAR T is very effective in patients with relapsed/refractory disease, but not effective for everyone. And so, what we did at the Medical College of Wisconsin was work with our industry partners to develop a dual-targeted tandem anti-CD20, anti-CD19 CAR T-cell product. This product is unique in that it can target more than one B-cell receptor with the goal of improving clinical outcomes.

As part of a previously published phase 1 clinical trial, we identified a safe dose for infusion. But we also did something different in that we administered the cells fresh to patients without prior preservation, and actually saw that fresh cells look to be a little bit more active than when you have to freeze them down and then thaw them and subsequently infuse them. This phase 1 data led to the development of this multi-center phase 2 DALY II USA clinical trial. This was a third line diffuse large B-cell lymphoma study for relapsed/refractory disease in adult patients. It uses the same paradigm of this tandem anti-CD20, anti-CD19 CAR T-cell product. 

And again, the goal was to administer the cells as a fresh infusion what this meant is that the cells were sent to the manufacturing facility fresh, manufactured, and during the manufacturing process lymphodepletion was started in order to facilitate that fresh infusion. Cells were harvested and infused at the treating site within 36 hours.
We're now reporting a pre-planned, interim analysis of the first 59 patients treated. In terms of the patient population, they had high risk diffuse large B-cell lymphoma having failed a median of 2 lines of prior therapy, most had high LDH and most had high IPI disease, consistent with sort of a bad group of clinical patients. These patients received a single infusion of this product, also now called zamtocabtagene autoleucel. 

We’re now able to report for this interim analysis which demonstrated that patients had an overall response rate of 73% and a CR rate of 51%. We have some durability data with a six-month progression free survival of 55%, but again we need longer follow up to show the 1- and 2-year data.

One question that came up, is the safety of a fresh product and targeting more than one antigen a feasible thing to do? And the good news was that this product was actually very well tolerated. There was no grade 3 or higher cytokine release syndrome and only 4% of patients had grade 3 or higher ICANS, which was reversible and manageable with treatment. 

So sort of in conclusion, we have demonstrated a new paradigm for CAR T using a manufacturing system that was automated, reproducible, allowing us to administer the product fresh starting lymphodepletion during the CAR T manufacturing process and for the first time as part of a large multi-center trial targeting more than one protein so not just CD19 or CD 20 alone.

We're excited by these results, we think that a CAR like this with a vein-to-vein time of 14 days, makes it more accessible to patients. And consistent with that, no patient died waiting to get their CAR T-cells, but you can understand why because we had such a rapid timeline, which is important for patients with high-risk relapse/refractory disease.
We're going to continue to enroll on this study, in fact we're almost done and hope to, you know, present the full results at a future congress and continue to have longer follow up, but we're really excited by this data and look forward to sharing more in the future.
 

Source:

Shah N, Maziarz R, Jacobson C, et al. Interim Results from a Phase 2 Pivotal Study (DALY II USA) of Tandem CD20-CD19-Directed Non-Cryopreserved CAR-T Cells - Zamtocabtagene Autoleucel (Zamto-Cel) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Presented at the 66^th ASH Annual Meeting & Exposition; December 7-10, 2024; San Diego, California. Abstract 68.