Chimeric antigen receptor (CAR) T cell therapy is a novel form of adoptive cellular therapy and has generated remarkable effects in patients with haematological cancers. However, the success against solid cancers has been modest. The major challenges are the hostile tumour microenvironment and the low efficiency of CAR T cells infiltrating the tumour. Here, we present a major advancement in CAR T therapy that eradicated large established solid cancers, some in excess of 150 mm2, in immunocompetent mice.
We hypothesized that a vaccine composed of a recombinant poxvirus could be used as an antigen delivery vehicle to specifically activate CAR T cells through their T cell receptor (TCR) and simultaneously change the tumour microenvironment, allowing the recruitment and activation of CAR T cells. The approach involves adoptive cell transfer incorporating vaccination (ACTIV) therapy. We generated dual-specific T cells expressing a CAR specific for the tumour antigen Her2 and a TCR specific for the melanocyte protein (gp100). Injection of T cells, together with recombinant vaccinia virus expressing gp100, induced durable complete remission of a variety of Her2+ tumours and established metastases, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Tumour destruction mediated by dual-specific T cells occurred rapidly over a period of seven days and was associated with an extensive proliferation and infiltration of the dual-specific CAR T cells. Mice that had rejected tumours were resistant to rechallenge with the same Her2+ tumour cells and partially resistant to rechallenge with Her2- tumour cells, indicating the formation of immune memory and epitope spreading. This mouse model study supports the view that it is possible to design a highly effective CAR T cell therapy for solid cancers and metastases, even when the target antigen is also expressed in vital tissues.