Therapeutic cancer vaccines, especially DC-based vaccines, are extensively pursued immune approaches in addition to immune checkpoint blockade antibodies and chimeric antigen receptor T cells. DCs can engulf, process and present tumor antigens to T cells, thereby initiating a potent and tumor-specific immune response. However, clinical outcomes of therapeutic cancer vaccines still remain poor, with objective response rates that rarely exceed ~15%. The maturation and activation of DCs are necessary steps to trigger the antitumor responses. However, it is increasingly clear that tumor-infiltrating dendritic cells (TIDCs) usually have an immature or tolerated phenotype that plays central roles in developing tumor microenvironment (TME). As a consequence, malfunction of TIDCs could suppress the infiltration and function of tumor infiltrating T cells and convert them into immune suppressive regulatory T cells.~In our previous research, we constructed novel CAR-DCs (Chimeric antigen receptor engineered dendritic cells) containing a scFv domain targeting EphA2 antigen, CD8a transmembrane, tandem DC-specific activation domains. The engineered CAR-DCs were activated when contacting with tumor targets in TME, and consequently, augmented the cytotoxicity of antigen specific T cells in immune system humanized solid tumor mouse models. Our design of CAR-DCs provides an effective vaccine strategy for solid tumors. Therefore, we designed an autologous CAR-DC vaccine engineered with anti-EphA2 CAR and KRAS mutant peptide (KRAS-EphA-2-CAR-DC) , which can suppress the growth of tumors expressing the correlated KRAS mutant in animal models. In addition, the combination of ICB inhibitors could further reverse immunosuppressive TME and globally activate T cell responses. In this pilot study, we aim to assess the safety, efficacy and immune response of KRAS-EphA-2-CAR-DC combined with anti-PD-1 antibody in patients with local advanced/metastatic solid tumors.
This is a pilot clinical trial for subjects with local advanced/metastatic solid tumors to determine the safety, efficacy and immune response of autologous EphA2-targeting CAR-DC vaccine loaded with KRAS mutant peptide (KRAS-EphA-2-CAR-DC) in combination with anti-PD-1 antibody. It aims to: assess the safety and antitumor effects of KRAS-EphA-2-CAR-DC vaccine; detect T cell response against KRAS mutant peptide and tumor neoepitopes after the treatment with KRAS-EphA-2-CAR-DC vaccine and anti-PD-1 antibody.