Trending topics and news in HCT and Cellular Therapy

The Critical Role of the Endogenous Immune Compartment After Car T Cell Therapy in Recurrent GBM

Researchers at the University of Pennsylvania have found that CAR T-cell therapy response in recurrent glioblastoma (GBM) is affected by divergent remodeling of the immune system. Published in Cell, the study showed that expansion of cytotoxic natural killer (NK) cells was associated with longer survival, whereas regulatory T-cell expansion and pre-existing immunosuppressive myeloid cells were linked to poorer outcomes. This suggests that modifying the endogenous immune compartment could improve CAR T-cell therapy for GBM.

GBM is the most common malignant primary brain tumor in adults, with median survival shorter than 15 months and no effective standard treatment after recurrence. A previous phase 1 trial of intracerebroventricular bivalent CAR T-cells targeting EGFR and IL13Rα2 produced tumor regression in some patients, but responses were often short-lived. To delineate response and resistance, the researchers performed single-cell RNA-seq and immune profiling of 62 longitudinal cerebrospinal fluid samples from 18 patients, alongside infusion products and matched pre- and post-treatment tumor tissue. Patients received either a high dose (n=12) or low dose (n=6), and samples were examined before infusion, around the day 7 expansion peak, and during contraction at days 18 to 21.

CAR T cells became highly activated and cytotoxic in cerebrospinal fluid by day 7 but progressively acquired exhaustion markers by day 21. Early expansion of CD56^dimCD16⁺ cytotoxic NK cells was greater among responders (median increase 31.0% vs 8.9%; p=0.0022). Patients above the median NK-cell increase had longer progression-free survival (5.8 vs 1.05 months; p=0.002) and overall survival (19.3 vs 7.4 months; p=0.03). Combining NK and CAR T cells also increased tumor killing in glioblastoma organoids compared with either cell type alone. Conversely, high baseline expression of an immunosuppressive scavenger myeloid program was associated with shorter overall survival (p=0.009), while regulatory T-cell expansion correlated with less tumor shrinkage. These findings suggest that treatment success expands to a wider host immune response, supporting combinations that enhance NK activity while limiting myeloid and regulatory T-cell suppression.

Reference:

Freeburg NF, Chafamo D, Konanur Gopikrishna G, et al. The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM. Cell. Published online June 15, 2026. https:/doi.org/10.1016/j.cell.2026.05.026