Nirav Shah, MD, Associate Professor of Medicine, Medical College of Wisconsin, highlights a first in-human study of YTB323, an autologous CD19-directed CAR T-cell therapy, for the treatment of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). These data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

Transcript

Dr Nirav Shah: Hi, my name is Nirav Shah. I am an Associate Professor of Medicine at the Medical College of Wisconsin. Happy here to discuss an abstract that I was a co-author on.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Shah: This project involves using a CAR T-cell product targeting CD19, which is a protein on B-cells.

This product, the lentiviral vector used for this CAR T-cell, is already FDA approved in the form of Kymriah (tisagenlecleucel) for the treatment and management of both pediatric ALL and for adult DLBCL that has failed 2 prior lines of chemotherapy.

This ongoing project is about improving that process around the manufacturing of the CAR T-cells.

There's a belief—and I'm one of those believers—that thinks that how you manufacture the CAR T-cells can greatly impact the functionality, persistence, then, most importantly, clinical outcomes, for patients who are getting CAR T-cell therapy.

What was happening in this project, is that they were using a novel manufacturing process called T-Charge, which basically minimizes the time that the CAR T-cells are in culture.

The idea here is by minimizing that time you have a more potent CAR T-cell product. One that has more naive—and we think naive T-cells are important for things like persistence and functionality.

Because they were changing the manufacturing process so significantly, this was a phase 1 clinical trial to determine the safety of this new manufacturing process, but using the same construct that was used previously in the drug that is known as (tisagenlecleucel).

OLN: Could you briefly describe the study and its findings?

Dr Shah: This was describing the clinical outcomes for patients who were treated with DLBCL.

They had to fail 2 prior lines of therapy. It was a dose escalation study. They had 2 dose levels that were reported in large numbers. Dose level 1 and dose level 2.

If you look at the dose level 2, which had a large cohort of patients, the overall response rates (ORR) were very high. The complete response (CR) rates were also high. You can see in the waterfall pluck in the abstract, that many of those responses were durable. Now, this is obviously a small number of patients in the low 20s. We need more data, but I would say that the results here are encouraging.

More so, what we learned is that the manufacturing process also is different. So, even though a lower number of CAR T-cells were delivered into the patient, they still saw very nice expansion in vivo.

When they compared this to products made using the older methodology, they saw differences favoring this new manufacturing process.

They saw nice levels of persistence. Most importantly, the safety profile of this was not found at least again with small number of patients to be remarkably different than what we've seen with other CD19 CAR T-cell products.

OLN: Were any of the outcomes particularly surprising?

Dr Shah: You are seeing such nice clinical responses with a lower number of CAR T-cells, goes to show that these CAR T-cells are more potent.

I think that's a very interesting finding. Just by changing your manufacturing process, you are changing the potency of these CAR-T cells. You can administer a lower number of cells, but then get the same clinical outcome.

That was the hypothesis going into this project, but it's nice when a hypothesis plays out in the actual clinical trial.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Shah: This is an early phase clinical trial. There's enough data here to support the sponsor of the study to do further investigation.

I think—I'm going to speak on my own opinion here—that this novel manufacturing process is promising. If they can prove that it leads to equivalent, or ideally better clinical outcomes, it may be an opportunity to replace that existing drug, (tisagenlecleucel), and then improve it with this newer manufacturing system.

Now, they would have to treat a lot more patients, have a lot more data to go to the FDA and register a product like this. These early findings are exciting and promising, and I look forward to continuing my collaborations with the sponsor and participating in future trials.

OLN: Do you and your co-investigators intend to expand upon this research? If so, what will be your next steps?

Dr Shah: We're a participating site on this industry sponsored trial. I'll have to defer to the company, Novartis, which was a sponsor of this trial about what their future direction is. We, at the Medical College of Wisconsin have had a nice partnership with Novartis. We look forward to maintaining that as they move this product forward.