ASH2020: New Studies Showcase Potential of CAR-T Therapy to Treat More Cancers

Results of two promising cell therapy studies involving Kite Pharma’s Yescarta were discussed at the 62nd American Society of Hematology Annual Meeting & Exposition (ASH 2020). A study that used CAR T cells to successfully reduce the cancer burden in patients with advanced non-Hodgkin’s Lymphoma (NHL) suggested this therapy may be a viable option for patients who do not respond to chemotherapy. Another study investigated why CAR T may not be a universal, one-size-fits-all approach but requires precise engineering to target different patient populations. It explains why some patients do not respond to CD19-CAR T cell therapy, although it has dramatically improved outcomes for patients with some hematological malignancies.

“Getting more data on CD19-CAR T-cell therapy in the high-risk non-Hodgkin lymphoma population is very important,” noted press briefing moderator Catherine Bollard, MD, of Children’s National Research Institute. “We know that CD19-CAR T-cell therapy does not work for some patients, so these studies underscore the need to better understand the immune evasion mechanisms T-cells might be susceptible to and not just focus on their role as a vehicle for the CAR. Doing so may improve our capacity to administer effective T-cell immunotherapies.”

Yescarta Impresses in Advanced Non-Hodgkin’s Lymphoma Trial

CAR T cell therapy involves deriving the patient’s own T cells and genetically modifying them to express a Chimeric antigen Receptor (CAR). When infused back into the patient, the CAR T cell designed to recognize and bind to a specific tumor antigen like CD19 seeks and destroys tumor cells.

The CAR T-cell therapy, Yescarta (axicabtagene ciloleucel or axi-cel), which has shown success in large B cell lymphoma, has now benefited patients with advanced non-Hodgkin lymphoma (NHL) by reducing cancer cells to undetectable levels in nearly 80% of NHL patients in Phase II, ZUMA-5 trial. The results are particularly encouraging because patients often relapse after standard treatments despite NHL’s slow-growing and less aggressive form of cancer.

“We were very impressed with the magnitude of the responses, and also the durability,” said Caron Jacobson, MD, of Dana-Farber Cancer Institute. “This treatment has meaningfully impacted high-risk patients with these diseases. I was also struck early on by how favorable the safety profile was compared to what we’ve been seeing in the fast-growing lymphomas.”

In previous trials for large B cell lymphoma, Yescarta reduced cancer cells below detectable levels, achieving a “complete response” in many patients. In the ZUMA-5 trial, investigators administered the therapy to 146 patients with follicular lymphoma (FL) or marginal zone lymphoma (MZL) — two slow-growing forms of non-Hodgkin lymphoma. All the participants had active lymphoma despite undergoing multiple previous treatments.

Among 84 FL patients who were followed up for at least 12 months and 20 MZL patients who had at least one month of follow-up, 92% achieved an objective response, which is a detectable reduction in their cancer 76% had a complete response. At the cutoff date for data collection, responses continued in 72% of all treated patients.

Almost all patients experienced adverse side effects, with 86% experiencing grade 3 or higher adverse events. Seven percent experienced grade 3 or higher cytokine release syndrome, and 19% experienced grade 3 or higher neurologic events. Response rates were slightly higher, and adverse effect rates were slightly lower for patients with FL than those with MZL.

Personalized Immunotherapy for Patients with Large B Cell Lymphoma

Yescarta achieves durable remission in about 40-50% of patients with B-cell lymphomas. However, this revolutionizing therapy does not work well for everyone. In a new study, researchers identified that a genetic event of CD58 inactivity is a likely cause why about one-quarter of patients do not respond well to this therapy.

CD58 mutations or loss are common and occur in 21% of patients with diffuse large B-cell lymphoma (DLBCL), and its expression is deregulated in approximately 67% of all patients with DLBCL. Genetic samples from 51 patients treated with axi-cel, revealed that 25% of them lacked a fully functioning version of CD58 on their cancer cells, expression of which is necessary for T cell-mediated cytotoxicity. Without a functional CD58 protein, CAR T cells are less effective.

To overcome CD58 loss, researchers re-engineered the CARs by integrating another protein, called CD2, to reestablish T cell efficacy. They determined that the cross-linking between CD2 and CD58 plays a role in driving CAR signaling that encourages the T-cells to kill target tumor cells. Researchers believe that the re-engineered CAR T cells could significantly increase the number of patients who are likely to benefit from axi-cel therapy and impact other malignancies where CD58 mutations are common.

“Achieving an uptick of 20-25% in the complete response rate would really bring cures to a large number of additional patients,” said senior study author Robbie G. Majzner, MD, of Stanford University School of Medicine. “Ultimately, we could potentially screen patients for CD58 status and provide a more precision approach to this therapy.”

By Sangeeta Chakraborty, Ph.D.

Editor: Rajaneesh K. Gopinath, Ph.D.

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References

1. https://ash.confex.com/ash/2020/webprogram/Paper136834.html
2. https://ash.confex.com/ash/2020/webprogram/Paper139605.html
3. https://www.prnewswire.com/news-releases/genome-editing-and-cellular-therapies-show-promise-for-treating-blood-disorders-cancers-301186839.html

Author

Sangeeta Chakraborty