Cancer Care · asia
Adding Anti-TGFβ Armor to CAR-T: First-in-Human Trial Shows Tumor Responses in Advanced Liver Cancer
GPC3-targeting C-CAR031 uses a modified receptor to resist immunosuppression in the tumor microenvironment; among 36 patients who had received multiple lines of treatment, the objective response rate reached 44.4%, but short-lived responses, safety risks, and the early-stage single-arm design still limit the conclusions.
CAR-T cell therapy has reshaped the treatment pathway for some patients with blood cancers, but has repeatedly encountered obstacles in solid tumors: the cells must not only find cancer cells, but also navigate a tumor environment that suppresses immune responses. A first-in-human study published in *Nature* showed that the “armored” C-CAR031 could induce tumor shrinkage in a group of patients with advanced hepatocellular carcinoma who had limited treatment options, providing early clinical evidence for overcoming this barrier.
C-CAR031 is derived from patients’ own T cells and targets GPC3, a surface protein often highly expressed in hepatocellular carcinoma. Researchers also equipped the cells with a dominant-negative type II TGFβ receptor, making them less susceptible to suppression by transforming growth factor beta (TGFβ). TGFβ is an important immune brake in the tumor microenvironment; the aim of this design is to enable CAR-T cells to maintain their ability to attack after reaching the tumor.
In the phase 1, single-arm trial NCT05155189, 36 patients with refractory advanced hepatocellular carcinoma who had received multiple lines of treatment received one of four doses ranging from 750,000 to 4 million cells per kilogram. The study reported that target lesions shrank in 32 patients, with an objective response rate of 44.4%; the median best reduction in tumor size was 41.6%, while the median duration of response was 4.4 months.
In terms of disease control, the median progression-free survival was 4.2 months, and the median overall survival was 14.2 months. These figures indicate that the therapy has activity, but cannot directly demonstrate that it is superior to current treatments: the trial was small and had no randomized control group, while patients’ prior treatments and doses were not entirely consistent. Survival outcomes may also have been affected by individual disease status and subsequent treatment.
Safety is likewise a hurdle that further development must overcome. Of the 36 patients, 34 developed cytokine release syndrome, including two grade 3 cases; nine patients also experienced grade 3 or higher non-hematologic adverse events. The research team described the overall safety profile as manageable, but such a high incidence of cytokine release syndrome means that the treatment still needs to be evaluated in a medical setting equipped to monitor and manage cell therapies.
The study also outlined possible sources of relapse and resistance. Tumor sample analyses and functional validation showed that loss of the GPC3 antigen by cancer cells, or a further increase in intratumoral TGFβ, could weaken the effect of C-CAR031. This serves as a reminder that even when CAR-T cells are given a layer of anti-suppressive “armor,” tumors may still find alternative escape routes. C-CAR031 was previously developed in China through a collaboration between AbelZeta and AstraZeneca and is now being advanced independently by AstraZeneca under the name AZD7003; larger, controlled trials are still needed to determine whether the efficacy can be sustained and which patients are most likely to benefit.