Generation of chimeric antigen receptor T cells targeting p95HER2 in solid tumors

The redirection of T lymphocytes against tumor-associated or tumor-specific antigens, using bispecific antibodies or chimeric antigen receptors (CAR), has shown therapeutic success against certain hematological malignancies. However, this strategy has not been effective against solid tumors. Here, we describe the development of CAR T cells targeting p95HER2, a tumor-specific antigen found in HER2-amplified solid tumors. These CAR T cells display robust activity against p95HER2-expressing cell lines but demonstrate limited efficacy against patient-derived xenografts. As p95HER2 is invariably detectable on tumor cells that overexpress HER2, but not those that express HER2 at normal levels, we arm p95HER2-specific CAR T cells with affinity-tuned bispecific antibodies against HER2 and CD3 in order to redirect them only to HER2-amplified cells. The combination of p95HER2.CAR T cells and HER2 x CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models. This combination represents a promising strategy to redirect T cells against a subset of HER2-positive tumors. Chimeric antigen receptor T (CAR-T) cell therapy is efficient in certain haematologic malignancies, but clinical success in solid tumours has been hampered by scarcity of tumour-specific antigens. Here authors show that combination therapy using CAR T cells targeting p95HER2 and bispecific antibodies against HER2 and CD3 consistently leads to complete regression in HER2-positive, patient-derived xenografts tumours in mouse models.