Jakub Svoboda, MD, University of Pennsylvania, Philadelphia, Pennsylvania discusses preliminary research surrounding the safety and efficacy of novel engineered armored huCART19-IL18, an anti-CD19 chimeric antigen receptor (CAR), treatment among patients with relapsed/refractory (R/R) non-Hodgkin lymphoma that progressed after anti-CD19 CAR T-cells.

These preliminary results were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

Transcript:

Hi, my name is Jakub Svoboda, I'm an associate professor of medicine at the University of Pennsylvania. I had the opportunity to present our results of our clinical trial from the University of Pennsylvania with armored [chimeric antigen receptor] (CAR)-T at this year's ASCO meeting in Chicago.

Let me tell you a little bit about the results of the project. In the lymphoma world, we are well-aware that there's a great unmet need for patients with lymphoma who have relapsed/ refractory disease after treatment with the currently available anti-CD19, chimeric antigen receptors, and so we focus specifically on this population in our study, and we used a completely novel form of CAR-T. Sometimes we refer to this type of therapy as an armored CAR -T or fourth generation CAR-T.

Basically, it combines the specificity of the standard CARS, meaning that it expresses chimeric antigen receptor autologous T-cells that we get from patients. But it has this unique capacity to secrete transgenic protein, and in our product that was internally developed at [University of Pennsylvania] by Dr. Carl June and his lab, It's IL18, interleukin -18. These CAR-T cells are targeting CD-19, but at the same time are also able to deliver this pro-inflammatory cytokine that at least in preclinical studies has various properties that would enhance the efficacy of CAR-T cells.

We know that IL18 may increase the cytolytic potential of T-cells, so kind of like how the T-cells are fighting. It may also, and that's kind of where the novelty is, affect the tumor microenvironment and perhaps recruit certain types of cells into that microenvironment like macrophages and K-cells. And so again, that would be something that may help to improve the efficacy. And then finally, the IL18 in itself, we know from some studies, even clinical studies, where several years or 10 plus years ago, they've studied recombinant IL18 in [patients with] lymphoma and their immune responses.

The main takeaways from our presentation and from our trial was that we showed that in this first in-human study with armored CAR-T that it's a feasible strategy and that, at least in our study, there were no unprecedented or unexpected toxicities. In the 21 patients that were available for safety evaluation, we've seen [cytokine release syndrome] CRS, we've seen [Immune Effector Cell Associated Neurotoxicity Syndrome] ICANS, but in line to what we would see with the commercial products.

We were surprised by the efficacy, and that showed really targeting against CD19. I should mention that many people who are relapsing after CD19 CARs, the currently commercially available CD19 CARs, they retain the CD19 positivity on the surface of their lymphomas. So, we’re targeting it again, but with this extra push with the IL18, it seems like it's an effective strategy. We've seen responses at 3 months of 80%, with over 50% complete responses. These seem to be durable. In some cases, we've now seen remissions going over 2 years. So this strategy seems to be quite effective. It's all preliminary. It's only 21 patients, but you know, we've been impressed and [are] definitely pursuing these armored CAR-Ts further.

The final thought is that there's hope. I'm a lymphoma doctor. I treat lymphoma and focus on lymphoma, but there's hope that perhaps this way to enhance CARs with these transgenic proteins may open the door to some other settings, for example in solid malignancies where the development of CARs have been much slower and there are certain challenges that, again, the tumor microenvironment may prevent some of the efficacy in solid tumors. Having that extra armor on these CARs can maybe be applied in other settings.

Source:

Svoboda J, Landsburg D, Nasta S, et al. Safety and efficacy of armored huCART19-IL18 in patients with relapsed/refractory lymphomas that progressed after anti-CD19 CAR T cells. Presented at the ASCO Annual Meeting. May 31–June 4, 2024; Chicago, IL. Abstract 7004