衔接癌症疫苗的体外筛选与体内疗效

mRNA cancer vaccines represent a next-generation immunotherapy platform with the potential to elicit robust, antigen specific immune responses. Upon in vivo delivery, mRNA vaccines are taken up by antigen-presenting cells (APCs), translated into the tumor associated antigen and presented via MHC molecules to activate adaptive immunity. However, standard mouse models with murine MHC molecules are not suitable for evaluating these MHC-restricted immune responses. GemPharmatech has developed an in vitro and in vivo mRNA vaccine drug evaluation service platform, including the in vitro and in vivo immunogenicity evaluation, in vivo anti-tumor efficacy and safety evaluation. For in vitro immunogenicity, dendritic cells derived from autologous monocytes (moDCs) are matured and loaded with specific antigen peptides using electroporation or administered with LNP-mRNA. The peptide-pulsed moDCs are then co-cultured with T cells from the same donor. The antigen-specific T-cell response is detected by ELISpot or flow cytometry. In vitro immunogenicity evaluation is applicable to early antigen peptide screening, assessing the affinity of antigen peptides for corresponding HLA molecules and their immunostimulatory capacity. For in vivo evaluation of cancer vaccine, GemPharmatech has developed a series of HLA-humanized mouse models across multiple mouse backgrounds including the immunocompetent mice B6, BALB/c, CB6F1 and the immunodeficient NCG derived mice. These models express human HLA molecules, enabling the accurate evaluation of antigen presentation, immunogenicity, and therapeutic efficacy of mRNA vaccines. The HLA-humanized mice exhibit strain-dependent humoral and cellular immune responses, satisfying various evaluation needs. HLA humanized mice exhibited strain specific humoral and cellular immune responses, but are sufficient to satisfy various evaluation needs. CB6F1 exhibited good combination of humoral and cellular immune response to the same immunogen, making them more suitable for assessing vaccine immunogenicity. In NCG-M-hHLA-A2.1 mice engrafted with hematopoietic stem cells, HLA-A2.1-restricted immune responses were observed, reflecting successful reconstitution of human DCs and functional T cells. Therapeutic studies using TA-1 (mRNA vaccine) or anti-PD1 in a patient derived xenograft (PDX) demonstrated that TA-1 or anti-PD-1 inhibited tumor growth, while combination therapy led to greater tumor inhibition. In conclusion, GemPharmatech has established a comprehensive vaccine evaluation platform that integrates in vitro screening with in vivo models to provide more options for preclinical evaluation of tumor vaccines.