Importance, Mechanisms and Limitations of the Distant Bystander Effect in Cancer Gene Therapy of Experimental Liver Tumors

GCV-ablation of transplanted TK-positive liver tumors or the application of syngenic and allogenic HSV-TK/GCV oncolysates significantly reduced the size of synchronously growing untreated sister tumors in the liver. These TK-negative liver tumors constantly showed an increased infiltration by mononuclears (x4). The relative abundance of CD 4/8, NK and monocyte subtypes remained constant. The distant bystander effect was associated with a strong induction of GMCSF and IL-12 expression in the untreated TK-negative liver tumors. Analysis of the vbeta T-cell receptor profiles from TK-negative tumors did not point to clonal lymphocyte expansions. These results support the view of the 'distant bystander effect' as a predominantly local phenomenon, which is mediated by resident immune effectors rather than by MHC I restricted CD 3 positive lymphocytes.