Figure 2.

The immune mediated gene therapy consisting of Ad-TK [plus Ganciclovir (GCV)], and Ad-Flt3L. Glioma cells can be efficiently transduced with Ad-TK, which encodes the conditionally cytotoxic HSV1-Thymidine Kinase (TK). TK can convert the prodrug GCV, a nucleotide analog, to GCV-phosphate, which is further phosphorilated into GCV-triphosphate by intracellular kinases. GCV-triphosphate is a purine analog and can inhibits DNA replication, inducing Immunogenic Cell Death (ICD). Dying cells release Damage-Associated Molecular Patterns (DAMPs), i.e., HMBG1, calreticulin, and ATP. Glioma cells transduced with Ad-Flt3L, express and secret Flt3L that recruits dendritic cells (DC) into the tumor microenvironment, where they uptake tumor associated antigens and get activated by DAMPs. Mature antigen presenting cells (APC) migrate to the regional lymph nodes and prime anti-tumor cytotoxic CD8+ T lymphocytes. Cytotoxic T cells recognize and kill tumor cells. Following T cells exposure to tumor antigen, immunological memory is developed. Memory T cells activate an anti-tumor response leading to inhibition of tumor recurrence.