Dual-Targeted CAR-T Products May Provide New Options for Difficult to Treat Cancers

Nirav Shah, MD

On March 15, 2024, Bristol Myers Squibb’s chimeric antigen receptor T-cell (CAR-T) therapy lisocabtagene maraleucel (liso-cel; Breyanzi) became the first CAR-T product to be approved by the FDA for a chronic lymphocytic leukemia (CLL) indication.¹ Notably, it is a monospecific CD19-directed CAR-T therapy.

Nirav Shah, MD, an associate professor of medicine at Medical College of Wisconsin, and his colleagues, however, are interested in the potential of an investigational bispecific CD19/CD20-targeted CAR-T product, LV20.19, to treat relapsed/refractory CLL, including patients with Richter’s transformation (RT).² Shah presented data from the phase 1/2 clinical trial (NCT04186520) evaluating LV20.19 at the 2024 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024. The day after the presentation, CGTLive® interviewed Shah about the key results. At the time, no CAR-T product had yet been FDA-approved for a CLL indication, and currently there are still no CAR-T products FDA-approved for RT.

CGTLive: Can you tell us about the presentation you gave on LV20.19 at Tandem?

Nirav Shah, MD: We had an oral presentation yesterday, talking about dual-targeted CD20/CD19 CAR T-cells for patients with CLL and RT. We reported initial outcomes from a phase 1 clinical trial. In the relapsed/refractory state, those patients with CLL who are double-refractory—have failed oral agents—options are limited. As part of a phase 1 study, we evaluated the aforementioned CAR construct that we have looked at in other histologies and we found that it was very efficacious. The overall response rate was in the 70% to 80% range. The majority of those were partial responders using the criteria we use for CLL, but many of those responses were durable. Similarly, in our RT population, a very difficult to treat group of patients, about 80% had a response and 4 of those 6 had a durable remission after the dual-targeted CAR.

What are the big-picture implications that doctors and the healthcare community should take away from this?

One thing that we did see in this trial was a unique toxicity signal, especially in our patients with CLL. We found that they had this new syndrome called immune effector cell hemophagocytic lymphohistiocytosis like syndrome (IEC-HS), which is a hemophagocytic lymphohistiocytosis-like syndrome. It’s sort of an unusual toxicity that we haven't seen with other CAR constructs. As such, we're actually modifying the dose in future CLL patients to sort of ameliorate the toxicity and get a better balance of safety and efficacy. I think that these data are demonstrating that maybe targeting more than 1 protein might be a way to make a better CAR T-cell product and lead to better clinical outcomes. This is very early data; we have about 20 patients. With more time and more data, we hope to really define this product in these diseases and get a better sense of: “Is it really making a difference for patients?” and “Could it be better than the current CD19-based CART-cell products that we have?”

Can you discuss areas of interest for further research in relation to this?

There are lots of other groups doing dual-targeted CARs and so I think we really need to learn: What is the best next CAR-T? We're really happy with CD19-targeted CAR-T in blood cancers. It's clearly saved lives—but we can do better. So is it a CD20/CD19 CAR? Is it a CD22/CD19 CAR? Is it a combination of all of these? Lots of different groups are working on figuring out that perfect combination to really get the best outcome possible.

Is there anything else you want to add?

We want to share that this trial is actively enrolling and we're one of the few groups that actually have an active CAR-T trial in CLL. We have that opportunity available for patients and, at least as of today, there's not a CAR-T approved in CLL. We think this is a good option and we continue to develop this work and want to share with the people who are visiting this website to consider this if you think it's a good option for your patients.

This transcript has been edited for clarity.

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REFERENCES
1. U.S. FDA Approves Bristol Myers Squibb’s Breyanzi as the First and Only CAR T Cell Therapy for Adults with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). News release. Bristol Myers Squibb. March 14, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Breyanzi--as-the-First-and-Only-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx
2. Shah NN, Atallah EL, Abedin S, et al. Phase 1 trial of LV20.19 CAR T-cells for relapsed, refractory CLL and Richter’s transformation. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas. Abstract #40