PLEASE NOTE - THIS SEMINAR WILL TAKE PACE ON TUESDAY 2 MAY
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 tumor 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 tumor 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+ tumors and established metastases, some in excess of 150 mm2, in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Tumor 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 tumors were resistant to rechallenge with the same Her2+ tumor cells and partially resistant to rechallenge with Her2- tumor 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.
To explore the translational potential for using the dual specific CAR T cell strategy, we established methods to transduce the T cells from human peripheral blood with both a TCR specific for gp100 and a CAR for Her2. From as little as 1 ml of human buffy coat, we could generate more than 109 dual-specific CAR T cells, which is sufficient for a course of treatment. The stimulation of gp100 through TCR enhanced the human dual-specific CAR T cell proliferation, secretion of IFN-g and killing of Her2+ human cancer cells in vitro. These characteristics were identified to be important for eradicating tumors in the mouse models. Taken together, our data provide valuable information for the development of CAR T cell therapies for patients with solid cancers.