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Cytokine “Armor” Offers CAR T Cells a Second Chance

June 14, 2024

Abstract: A fourth-generation chimeric antigen receptor (CAR) T-cell therapy, targeting CD19 and endowed with IL-18 expression, yielded durable responses in most patients with non-Hodgkin lymphoma whose cancer advanced despite earlier CAR T-cell treatments. This first-in-human trial data, from 20 study participants, highlights the potential of cytokine “armor” to enhance the antitumor activity of adoptive cell therapies.

CD19-directed cells equipped with transgenic IL18 overcome resistance to standard CAR T-cell therapies in non-Hodgkin lymphoma.

Chimeric antigen receptor (CAR) T cells engineered to secrete the pro-inflammatory cytokine IL18 can elicit lasting remissions in patients with non-Hodgkin lymphoma whose cancers relapse after treatment with commercially available CAR T-cell therapies directed at the same antigenic target, CD19.

In a first-in-human trial, armored T cells equipped with a CD19-directed CAR plus a transgene for IL18 produced complete responses (CR) in 10 of 20 participants, all of whom had experienced disease progression despite prior anti-CD19 CAR T-cell therapy, with another six showing partial responses.

In comparison, CR rates for similar patients using other treatment modalities—antibody–drug conjugates, bispecific antibodies, radiotherapy, checkpoint inhibitors, or another approved CAR T-cell therapy—are generally below 35%.

The median duration of response was 10 months, with some patients experiencing remissions lasting 2 years or longer. The integration of the IL18 payload did not introduce any novel or unexpected safety concerns, manifesting only the known side effects associated with other CAR T-cell therapies.

“The treatment was feasible, very well tolerated, and we’ve seen durable remissions in patients who were relapse/refractory after prior CD19 CARs,” said trial leader Jakub Svoboda, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Svoboda presented the findings in June at the 2024 annual meetings of the American Society for Clinical Oncology and the European Hematology Association.

CAR T cells that release transgenic cytokines—so-called TRUCK (T cells redirected for universal cytokine-mediated killing) cells or fourth-generation CAR T cells—have gained momentum as a strategy to boost the cancer-fighting capacities of engineered T-cell therapies and to modulate the immunosuppressive properties of many tumor microenvironments.

The TRUCK concept has been explored using a range of cytokines, including IL7, IL12, IL15, IL23, and combinations thereof. But according to Hinrich Abken, MD, PhD, of University Hospital Regensburg in Germany, “IL18 is one of the most exciting at the moment.”

Less systemically toxic than some other cytokines, IL18 promotes the antitumor activity of CAR T cells by stimulating the production of IFNγ, which improves the expansion and persistence of adoptively transferred cells. What’s more, IL18 secretion shifts the tumor microenvironment toward a more proinflammatory state, with bystander effects on myeloid cells and natural killer cells that could prove especially beneficial in treating solid tumors. Abken and his colleagues are currently testing this approach using a GD2-directed, CAR-inducible IL18-releasing construct in patients with neuroblastoma (Clin Cancer Res 2024 Apr 24 [Epub]).

In Svoboda’s trial, researchers built the autologous CAR T-cell product, termed huCART19-IL18, using a 4-1BB costimulatory domain and an expedited manufacturing protocol that enables quicker treatment, albeit with fewer cells than is typical of other CD19-directed CAR T-cell therapies.

With the IL18 transgene built in, however, those low doses proved highly effective, noted Abken, who was not involved in the trial. “These are very viable cells,” he said. “They amplify like hell—which is very exciting.”

Of note, patients who had previously received CAR T cells featuring CD28 signaling domains—axicabtagene ciloleucel (Yescarta; Gilead) or brexucabtagene autoleucel (Tecartus; Gilead)—tended to have higher response rates, and their therapeutic cells expanded to greater numbers, compared with patients treated first with 4-1BB–containing CAR T cells such as tisagenlecleucel (Kymriah; Novartis) or lisocabtagene maraleucel (Breyanzi; Bristol Myers Squibb).

This difference was “quite striking,” said Svoboda, and he has several theories to explain the discrepancy in cell fates and clinical outcomes. It is possible, he noted, that 4-1BB–engineered CAR T cells, which tend to persist longer in the bloodstream, might still have been present in low numbers in the starting material used for huCART19-IL18 production, which could have impaired the expansion of the IL18-secreting cells. “We are also investigating any immune memory that the prior CAR had induced and that could contribute to eliminating huCART19-IL18,” he said.

Meanwhile, Svoboda and his colleagues have begun phase I testing of another 4-1BB–containing CAR product with the capacity to secrete IL18, but with an optimized CD19 binder. Other IL18-armored CAR T-cell therapies in development include a clinical candidate from Eutilex directed against GPC3 in early trials in South Korea for the treatment of hepatocellular carcinoma, as well as another CD19-targeted agent and a DLL3-specific therapy, both from CoImmune, that could soon enter trials for the treatment of acute lymphoblastic leukemia and small cell lung cancer, respectively.

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