Chimeric antigen receptor T-cell (CAR-T) therapy has been shown to have minimal anticancer activity when administered alone in the setting of solid tumors. But, the combination of CAR-T and the use of birinapant, an inhibitor of apoptosis protein (IAP) antagonist that is also a second mitochondrial-derived activator of caspases (SMAC) mimetic, showed significant reductions in the growth of in vitro and in vivo solid tumor models (P < .05), according to a study published online on January 16, 2019, in the Journal of Cancer Immunology.1
Although high levels of efficacy have been observed for CAR-T therapy in the treatment of some hematological malignancies, it has been observed to be considerably less efficacious in the solid tumor setting. Explanations for this difference include tumor-associated immunosuppression of solid tumors, including inhibition of T-cell function through blockage of immune checkpoint receptors on tumor cells. Furthermore, CAR-T cells are less likely to penetrate into solid tumors, making them less able to attack and kill malignant cells.
SMAC-mimetics have been shown to sensitize tumor cells to tumor necrosis factor (TNF), an important cytokine involved in systemic inflammation that is produced by cytotoxic T-cell effectors upon recognition of their targets. Hence, it was proposed that the combination of a SMAC mimetic with CAR-T therapy might compensate for the limited tumor penetrance by CAR-T cells into solid tumors through TNF destruction of antigen-negative tumor cells.
In this study, mice CAR-T cells capable of recognizing the human HER2 antigen were shown to secrete TNF and interferon gamma when exposed to human HER2-expressing colon cancer cells. Moreover, a significant increase in cell death occurred when birinapant was added to mouse CAR-T cells cocultured with cells derived from HER2-expressing solid tumors when compared with exposure of these cells to CAR-T cells only. However, when anti-TNF was added to the cell culture, a reduction in the efficacy of birinapant to facilitate CAR-T cell-related cell death was observed.
In addition, HER2-expressing colorectal tumoroids derived from patient biopsies were not sensitive to TNF or birinapant alone, but an enhancement in cell death was observed when these 2 approaches were combined. Interestingly, when tumoroids were embedded in Matrigel, which functions as an extracellular matrix, and exposed to the either birinapant, HER2-directed CAR-T cells alone, or the combination of these approaches, only the latter approach was effective in promoting cell death. This effect was also substantially diminished through the addition of TNF inhibitors. These results suggest that birinapant acts to increase sensitivity to TNF which, in turn, enhances the antitumor activity of CAR-T cells.
“We demonstrated that IAP antagonism by birinapant sensitized tumor cells to CAR T-cell–derived TNF, significantly enhancing the antitumor activity of CAR T-cell therapy both in vitro and in vivo. The results pave the way for a combination therapy that may improve the efficacy of adoptive cell therapy in solid malignancies,” the authors concluded.
- Michie J, Beavis PA, Freeman AJ, et al. Antagonism of IAPs enhances CAR T-cell efficacy [published online on January 16, 2019]. Cancer Immunol Res. doi: 10.1158/2326-6066.CIR-18-0428