Early results from a new study have demonstrated that the novel chimeric antigen receptor (CAR) T-cell therapy AT101 resulted in favorable complete response rates at higher dose levels in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, according to new findings simultaneously published by Zhang et al in Molecular Cancer and presented at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 2096).
Background
CAR T-cell therapy has revolutionized treatment for many patients with hematologic malignancies who have not responded to previous therapies. Although many patients may experience long-term responses to CAR T-cell therapy, some patients may experience relapsed or recurrent disease. Currently, all of the U.S. Food and Drug Administration (FDA)-approved CAR T-cell therapies target CD19 through the FMC63 epitope. The novel AT101 therapy works by using a distinct binding mechanism to target CD19.
Study Methods and Results
In the new phase I trial (ClinicalTrials.gov identifier NCT05338931), the researchers developed and tested AT101 in 12 patients with relapsed or refractory B-cell non-Hodgkin lymphoma with the goal of making anti-CD19 CAR T-cell therapy more effective for a higher proportion of patients. Using cells originating from the same patient, the researchers engineered the therapy to target CD19 through a different epitope located closer to the cell membrane—via the h1218 antibody.
In preclinical studies, the researchers demonstrated that AT101 was effective at decreasing T-cell exhaustion and improved control compared with standard anti-CD19 CAR T-cell therapies.
The researchers noted that the new 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, the researchers found that the patients who received dose level two or higher experienced a 100% complete response rate and no relapsed disease.
Additionally, the researchers reported that the novel therapy was found to be safe, with manageable side effects. Cytokine-release syndrome was reported in four patients, and immune cell–related neurotoxicity syndrome occurred in three patients. One patient experienced grade 3 sepsis that resolved, followed by fatal neutropenic septic shock outside the dose-limiting toxicity time frame.
Conclusions
“We’ve learned that the way you design your CAR [T-cell therapy] really matters. Designing a different CAR might drastically change the way the T cells work, potentially allowing that CAR T-cell product to work where other CAR T-cell products have failed,” highlighted senior study author Marco Ruella, MD, Assistant Professor of Hematology-Oncology and Scientific Director of the Lymphoma Program at the University of Pennsylvania Perelman School of Medicine. “We were not expecting such a drastic early difference in this study. The [anti-CD19 CAR T-cell] products that are already FDA-approved are very effective, and it’s not easy to do better. While there is not a randomized trial of this product yet, the initial results seem very promising, and we look forward to moving into the planned phase II portion of the study,” he concluded.
In the phase II expansion trial, the researchers will include patients who have previously received anti-CD19 CAR T-cell therapy.
Disclosure: For full disclosures of the study authors, visit molecular-cancer.biomedcentral.com and ash.confex.com.
