To prevent glioblastoma (GBM) escape via antigen loss, Choi et al. designed CART.BiTE cells that express a CAR specific for EGFRvIII (a tumor-specific antigen expressed in many GBM tumors) and secrete a bispecific T cell engager against EGFR (overexpressed in GBM, but also expressed in normal tissues). Intracranially-delivered CART.BiTE cells cleared heterogeneous GBM tumors in mice. BiTEs redirected both CAR T cells and bystander T cells to tumor cells, and activation via CAR and BiTE together led to a less exhausted TCM phenotype. CART.BiTE cells did not cause toxicities in a human skin graft model.
Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.
Author Info: (1) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Department of Neurosurgery, Massachusetts General Hos
Author Info: (1) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (2) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (3) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (4) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (5) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (6) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (7) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (8) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (9) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (10) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (11) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (12) Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (13) Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (14) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (15) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (16) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (17) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (18) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (19) Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mvmaus@mgh.harvard.edu. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mvmaus@mgh.harvard.edu.
