The adoptive T-cell receptor therapy afamitresgene autoleucel—which targets the MAGE-A4 cancer antigen—achieved clinically significant results for patients with multiple solid tumor types in a phase I clinical trial, according to a novel study published by Hong et al in Nature Medicine. Initial data from this trial were presented at the 2020 ASCO Annual Meeting (Abstract 102).
Background
The goal of T-cell receptor therapies is to more accurately target solid tumor cells without affecting normal cells, therefore potentially avoiding the toxicities often associated with chimeric antigen receptor–based cell therapies—which recognize designated surface proteins. T-cell receptor therapies such as afamitresgene autoleucel can target proteins normally found inside the cell. Using the T cell’s native receptor, this type of therapy can recognize protein fragments—in this case, from MAGE-A4—bound to immune-related proteins on the cell surface.
Study Methods and Results
In the new study, a total of 38 patients who had received an average of three prior lines of therapy were treated with afamitresgene autoleucel. Fifty-eight percent of the trial participants identified as male, and 92% identified as White; the rest identified as Asian. The study included 16 patients with synovial sarcoma; 9 with ovarian cancer; 3 with head and neck cancer; 2 each with esophageal carcinoma, non–small cell lung cancer, urothelial cancer, and myxoid/round cell liposarcoma; and 1 each with gastric cancer and melanoma.
All of the patients experienced treatment-related adverse events—most commonly lymphopenia, leukopenia, neutropenia, anemia, and thrombocytopenia. Prolonged cytopenia persisting at 4 weeks after afamitresgene autoleucel treatment occurred in 45% of patients (n = 17). There were two trial-related deaths, which resulted in the lowering of the maximum age at screening and the discontinued use of the high-dose cyclophosphamide lymphodepletion regimen.
The median duration of response was 26 weeks across all patients and 28 weeks in the synovial sarcoma subgroup. The findings were especially noteworthy in the subgroup of patients with synovial sarcoma, where patients treated with afamitresgene autoleucel achieved an objective response rate of 44% compared to the overall response rate of 24% across all cancer types—and resulted in the launching of an ongoing phase II trial further examining the efficacy of afamitresgene autoleucel to treat patients with advanced synovial sarcoma or myxoid/round cell liposarcoma.
The researchers highlighted that these early results demonstrated a proof-of-concept for the novel cell therapy approach in solid tumors.
“These high response rates are significant because patients with synovial sarcoma really have very few options after high-dose chemotherapy with ifosfamide,” highlighted principal investigator David S. Hong, MD, Professor of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “The overall toxicity from [afamitresgene autoleucel] was manageable, and we saw evidence of early activity in other cancer types. These results suggest this is an approach with the potential to work in solid tumors, where there are currently no approved cellular therapies.”
Conclusions
Early results of the afamitresgene autoleucel trial led to another phase I trial evaluating the next generation of the T-cell receptor therapy—known as ADP-A2M4CD8. This new therapy expresses a CD8 co-receptor with the goal of broadening immune response rates for patients with solid tumors.
Disclosure: The research in this study was supported by Adaptimmune Therapeutics. For full disclosures of the study authors, visit nature.com.
