Early results from a Phase I clinical trial of AT101, a novel CAR T cell therapy that uses a distinct binding mechanism to target CD19, show a 100 percent complete response (CR) rate at the highest dose levels studied in the trial, according to with the researchers. from the University of Pennsylvania Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center. The findings were published today in Molecular Cancer and presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 2096).
CAR T cell therapy has revolutionized the treatment of many people with blood cancers who had run out of other treatment options. While some patients experience long-lasting responses to CAR T cell therapy, it doesn’t work—or the cancer eventually returns—for others. CD19 CAR T cell therapies currently approved target CD19 through the same epitope (FMC63). To try to make CD19 CAR T cell therapy more effective for more patients, Marco Ruella, MD, assistant professor of Hematology-Oncology and Scientific Director of the Lymphoma Program, and his research team, along with the Korean company AbClon Inc. developed a CAR T product (AT101), using cells derived from the same patient, that targets CD19 through a different epitope, located closer to the cell membrane, through a novel antibody (h1218). In preclinical studies, the team previously showed that h1218-CART19 had reduced T cell exhaustion and improved control compared to FMC63-CART19.
The first-in-human Phase I clinical trial (NCT05338931) was conducted in South Korea and included 12 patients with relapsed or refractory non-Hodgkin’s B-cell lymphoma (NHL). The study was designed to increase the dose level of AT101 after safety was confirmed in the first six patients. After a median follow-up of 6.5 months, all six patients who received a level 2 dose or higher had a complete response and their cancer has not recurred.
“We’ve learned that how you design your CAR really matters. Designing a different CAR can dramatically change the way T cells work, potentially allowing this CAR T cell product to work where other CAR T cells have failed,” Ruella said. . “We did not expect such a drastic early difference in this study. The CART19 products already approved by the FDA are very effective and it is not easy to do better. Although there is not yet a randomized trial of this product, the initial results they look very promising and we look forward to moving forward with the planned Phase II portion of the study.”
The drug was found to be safe, with manageable side effects, including cytokine release syndrome in four patients and immune cell-related neurotoxicity syndrome in three patients. One patient presented with grade 3 sepsis that resolved. The same patient later developed fatal neutropenic septic shock outside the time frame of dose-limiting toxicity.
The Phase I study enrolled patients who had not previously received any other CAR19 therapy. In the Phase II extension, the study will also include patients previously treated with CAR19.