Self-secretion of checkpoint blockade enhances antitumor immunity by murine chimeric antigen receptor-engineered T cells

2018-11-12In melanoma treatment, the immune checkpoint blockade and the adoptive cell transfer (ACT) have been shown to be associated with favorable prognosis especially in patients with advanced tumor. Besides, ACT with chimeric antigen receptor T cells (CAR-T cells) is an uprising therapeutic approach for melanomas and other solid tumors. Among the immune checkpoint blockade, the blockade of PD-1 pathway, such as anti-PD-1 antibodies, can inhibit the immune suppressive status in tumor and enhance the T cell function. To overcome T cell dysfunction in tumor microenvironment (TME), an anti-mouse-CD19 CAR self-secreting anti-mouse-PD-1 scFv (1D3 PD1 CAR) was designed and expressed on mouse T cells. The secretion of anti-mouse-PD-1 scFv was measured and the T cell function of 1D3 PD1 CAR-T cells was analyzed. Besides, the expression of several inhibitory receptors on CAR-T cells was assessed to demonstrate the potential function of anti-mouse-PD-1 scFv on CAR-T cells in TME. In this study, 1D3 PD1 CAR-T cells was successfully engineered and the anti-PD-1 scFv can be efficiently and consistently secreted. The function of 1D3 PD1 CAR-T cells were enhanced after the specific antigen stimulation and the immune suppress surface marker on T cells were downregulated. The study indicates the possibility of applying CAR self-secreting immune checkpoint blockade scFv in solid tumor treatment