The Era of Armored CAR Ts

Carl June’s research into CAR Ts led to the development of CAR T cell therapy. Now, June and other researchers at the Perelman School of Medicine at the University of Pennsylvania have reported promising results from a phase I clinical trial evaluating a next-generation “armored” CAR T cell therapy in patients with advanced B-cell lymphomas.

The cell therapy – huCART19-IL18 – has been genetically modified not only to target the CD19 antigen on B-cell lymphomas (like traditional CAR T cells), but also to secrete the cytokine interleukin 18 (IL18) to enhance immune activation. By adding IL18 as an “armor” to the CAR T cells, the researchers hope to make them more resilient and capable of mounting a sustained attack on tumors, especially in cases where traditional CAR T cells have failed. IL18 augments immune response by recruiting additional immune cells and counteracting T cell exhaustion, a common challenge in patients who do not respond to traditional CAR T therapies.

And the early results are promising. The therapy was tested in a cohort of 21 patients who had undergone a median of seven prior therapies, including commercial CAR T cell treatments; 81 percent of participants demonstrated tumor response, and 52 percent achieved complete remission. Some early enrollees have remained in durable remission for two years or longer.

“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 Jakub Svoboda, who led the clinical trial at Penn Medicine’s Abramson Cancer Center. “It’s also encouraging to see that the toxicity of this novel product was not different than what we already see with commercial CARs.”

Laboratory analyses of post-treatment patient samples supported the hypothesis that IL18 secretion contributed to improved treatment efficacy. The therapy did not introduce unexpected adverse events beyond the established side effect profile of CAR T treatments, including cytokine release syndrome and neurotoxicity, which were effectively managed.

The researchers have also developed a manufacturing process for the therapy that reduces production time to approximately three days, in contrast to the standard nine to 14 days required for existing CAR T cell products. This accelerated production timeline may benefit patients with aggressive disease by enabling earlier intervention, and prior research suggests that shortened manufacturing may also improve T cell potency.

Next, the team plans to expand clinical testing to include patients with acute lymphocytic leukemia and chronic lymphocytic leukemia. A parallel trial is underway for non-Hodgkin’s lymphoma using a similar IL18-armored CAR T cell construct.

“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 June. “With longer T cell persistence and expansion, this strategy could be powerful in settings where CAR T hasn’t performed as well, such as solid tumors.”