Immunotherapeutic approaches using chimeric antigen receptor (CAR) T cells or bispecific T cell engagers (BiTEs) can induce powerful immune responses in patients with liquid tumours but have so far had limited success in patients with solid tumours. Now, Marcela Maus and colleagues demonstrate that combining the two modalities in one cell is effective in mouse models of glioblastoma (GB), a brain tumour with a dismal prognosis.
The authors had previously shown that CAR T cells directed at EGFRvIII, a GB-specific antigen, can shrink tumours in mice, but in patients this treatment generally fails due to antigen escape. The resulting tumours are EGFRvIII– but express large amounts of wild-type EGFR. By engineering EGFR-directed BiTEs, which tether T cells to tumour cells, into the EGFRvIII-CAR T cells, the authors sought to engineer a dual-targeted platform to prevent antigen escape.
Indeed, the resulting CART.BiTE cells efficiently killed both EGFRvIII+ and EGFRvIII– glioma cells and patient-derived GB cells in vitro. The simultaneous activation through CARs and BiTEs resulted in the preferential differentiation of central memory T cells rather than effector memory T cells, which is favourable as the latter are prone to exhaustion. Importantly, the secreted BiTEs also induced bystander T cell activation.
In vivo, intraventricular administration of CART.BiTE cells induced durable regression of established tumours in a mouse model of EGFRvIII– human GB. Encouragingly, the CART.BiTE cells (even when injected systemically) did not show any on-target toxicity similar to that observed with other anti-EGFR therapies, indicating that there may be a therapeutic window for CAR T cells secreting low levels of BiTEs that are targeted at antigens present on healthy tissue.
“CART.BiTE cells induced durable regression of established tumours”
The authors propose that the approach could be expanded to other types of solid tumour. Compared to BiTE treatment alone, CART.BiTE cells obviate the need for continuous infusion, and, compared to other CAR T cell therapies, they have the advantage of activating bystander T cells. Moreover, stimulation through the CAR appears to enhance local BiTE production by expanding the cell population that secretes them.
Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. https://doi.org/10.1038/s41587-019-0192-1 (2019)