Advances in the treatment of metastatic melanoma include recent approvals of the immunotherapy, ipilimumab, an anti-CTLA-4 monoclonal antibody, and of the targeted therapies, vemurafenib, dabrafenib, and trametinib, which are mitogen-activated protein kinase (MAPK)-pathway inhibitors. Cancer immunotherapy also includes adoptive transfer of autologous tumour-specific chimeric antigen receptor (CAR) T cells. CAR T cells are responsible for clinically significant tumour responses in leukemia and neuroblastoma patients. We have manufactured third-generation GD2-specific CAR T cells to be used in our active CARPETS phase I clinical trial of autologous GD2-CAR T cells in patients with GD2-expressing metastatic melanoma (ACTRN12613000198729).
However, although these promising new targeted- and immuno-therapies can produce complete or partial tumour responses, tumour resistance via alteration or bypass of the targeted molecules inevitably occurs. Combination therapies have been proposed as a way to exploit the high-level but short-term responses associated with kinase-inhibitor therapies and the low-level but longer-term responses associated with immunotherapy, and could potentially overcome tumour resistance by targeting multiple tumour-associated molecules. To this end, we have performed in vitro studies to investigate the effects of vemurafenib, dabrafenib and trametinib on functions of the GD2-CAR T cells including cytolysis of BRAF inhibitor sensitive and resistant melanoma cell lines. While dabrafenib does not inhibit effector functions at concentrations equivalent to reported plasma concentrations in treated patients, the combination of BRAF and MEK inhibitors has variable effects on CAR T cell function in vitro. We have also performed additional studies to investigate the effects of PD1 blockade in vitro. Although these effects were observed to depend on whether GD2-CAR T-cell activation occurs via the native TCR or the CAR and upon the nature of apoptosis resistance in the GD2-expressing melanoma target cells. Initial clinical data from the CARPETS trial will be presented.