Investigation of immunogenicity and antitumor efficacy of human PD1-based TWIST1 DNA vaccine

Abstract

As a cancer vaccine, DNA vaccines against tumors aim to enhance the host's immune response systematically. This study highlighted a novel human PD1-based TWIST1 DNA vaccine (huPD1-T1) that utilizes dendritic cell (DC) -targeted antigen delivery via PD-1 and its ligands interaction. TWIST1 (T1), a tumor- associated antigen, was incorporated into the vaccine construct. The high amino acid sequence identity between human and mouse T1 allowed human vaccine testing in mouse models. We compared huPD1-T1 with two vaccines encoding T1 antigen solely or mutant PD1 (mutPD1-T1), respectively. Three vaccines were delivered via electroporation in Balb/c and C57BL/6N mouse models. Immunogenicity was assessed by measuring T1-specific T cell and antibody responses. The results demonstrated that huPD1-T1 significantly enhanced both immune responses in Balb/c mice compared to the conventional T1 vaccine. Notably, while the T1 vaccine induced primarily antigen-specific cellular immunity with weak humoral responses, huPD1-T1 elicited strong responses in both arms of the adaptive immunity. The mutPD1-T1 vaccine also induced two types of responses but showed greater variability within groups. The antitumor efficacy of various treatments was evaluated in the AB1 mesothelioma mouse model. While monotherapy with huPD1-T1 did not significantly reduce tumor growth, survival curve analysis revealed significant differences for both huPD1-T1 and mutPD1-T1 groups. In the therapeutic setting, all treatment groups showed significant improvements in survival compared to the mock control. Notably, both the huPD1-T1 + anti-CTLA4 and T1 + anti-CTLA4 combinations demonstrated significant tumor inhibition (p < 0.0001). However, the huPD1-T1 + anti-CTLA4 group showed the highest survival rate at 62.5% (5/8), followed by T1 + anti-CTLA4 and anti-CTLA4 groups at 50%, while the T1 group had a survival rate of 12.5% (1/8). These results suggest a potential synergistic effect of combination treatments, particularly for the huPD1- T1 + anti-CTLA4 therapy. However, further research with larger sample sizes and additional controls is needed to determine the superior efficacy of such therapy. The vaccine's ability to induce both strong cellular and humoral immune responses, coupled with the significant anti-tumor effects combined with a monoclonal antibody, position it as a promising candidate for cancer immunotherapy. In summary, the study provides preclinical evidence for the efficacy of huPD1-T1 vaccine in the treatment of T1-expressing tumors, particularly mesothelioma.