A new generation of CAR T-cell therapy has shown encouraging results in patients with relapsed or refractory B-cell lymphoma who had previously failed standard treatments, including existing CAR T therapies. In a Phase I trial published in The New England Journal of Medicine, researchers at the University of Pennsylvania tested huCART19-IL18—a novel “armored” CAR T therapy designed to overcome tumor-induced immune suppression by secreting interleukin 18 (IL-18), a pro-inflammatory cytokine.
Of the 21 patients treated, 81% experienced tumor reduction, and 52% achieved a complete response. Notably, nearly all participants had previously received CAR T therapy without success. “I’m thrilled that this new generation of CAR T-cell therapy, created here at Penn, was highly effective in patients who have already tried everything available to treat their lymphoma,” said study investigator Dr. Jakub Svoboda.
Supercharging the Immune Response
Like conventional CAR T therapies for B-cell cancers, huCART19-IL18 targets the CD19 surface antigen. But by arming the cells with IL-18, the therapy boosts immune recruitment and activity within the tumor microenvironment, potentially overcoming the exhaustion that limits the efficacy of earlier CAR T products.
“Our results suggest that adding IL-18 protects the CAR T-cells and helps them perform better by recruiting additional immune cells,” explained co-developer Dr. Carl June. Importantly, the trial reported no unexpected safety issues beyond the known risks of cytokine release syndrome and neurotoxicity associated with CAR T therapy, which were successfully managed.
Fast-Track Manufacturing and Broader Applications
In addition to enhancing therapeutic activity, the huCART19-IL18 cells were manufactured in just three days—significantly shorter than the typical 9–14 day process. For patients with rapidly progressing cancers, this accelerated timeline could be lifesaving.
This marks the first time a cytokine-enhanced CAR T product has been tested in humans with blood cancer. Based on strong preclinical rationale and early clinical success, the Penn team is planning additional trials in acute and chronic lymphocytic leukemia, as well as non-Hodgkin lymphoma.
“Based on these results, we believe that incorporating cytokine secretion into CAR T-cell design will have broad implications for enhancing cellular therapies, even beyond blood cancers,” said Dr. June.
With further trials underway and new manufacturing partnerships established, the IL-18-augmented CAR T-cell represents a potentially transformative advance for patients with few remaining options.
