Comment on “Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma”

The authors of this study¹ should be commended on the important and complex undertaking of identifying multiple antigens for chimeric antigen receptor (CAR) T-cell therapy, which is one of several key limitations to the field. There are 2 levels of antigenic heterogeneity at play that require consideration—intrapatient variability, in which the existence of antigen-negative tumor cells may result in eventual recurrence, and interpatient variability, in which different expression patterns across all patients make identification of a single or "universal" therapeutic for treatment difficult, if not impossible. The authors state that by targeting 3 antigens: human epidermal growth factor receptor 2 (HER2), interleukin-13 receptor alpha 2 (IL13Rα2), and ephrin-A2 (EphA2) using a trivalent UCAR, they can "overcome intrapatient and interpatient variability" and that "trivalent T cells were able to approach killing in 100% of tumor cells in nearly all patients modeled." As investigators working in the field of immuno-oncology, we very much wish this to be the case; however, these conclusions are not supported by the data presented in the manuscript.