34 Rejection of cytokine gene transfected mouse tumors: Therapeutical implications

Abstract

Cytokines provided locally at the tumor site may initiate an effective anti-tumor immune response which leads to rejection of a tumor which otherwise grows progressively. Experimentally, this can be tested by gene transfer into cultured tumor cells followed by the analysis of the tumorigenicity of such genetically engineered cells. This approach allows to analyse the function of a given cytokine in vivo and to elucidate the therapeutical value of genetically engineered tumor cells as vaccines. Our experience includes experiments with about ten cytokines and the results can be summarized as follows: (1) some cytokines possess antitumor activity in this system, others do not; (2) a local and continuous cytokine supply seems to be essential for tumor rejection; (3) the tumor cell derived cytokines act in a dose-dependent manner and in the absence of systemic toxicity; (4) the immunological effector mechanisms induced by different cytokines are partly cytokine-specific, partly redundant (and usually involve T cell dependent and independent mechanisms; (5) tumor rejection and mechanism thereof may be different with different tumor cell lines transfected with the same cytokine gene. Cytokine gene modified tumor cells as vaccines are currently tested in first clinical trials. However, critical parameters such as vaccine potency of cytokine gene transfected tumor cells, optimal level of cytokine expression, reasons for varying vaccine effects in different tumor models, influence of irradiation of vaccine cells on their efficacy and attempts to improve vaccine efficacy (e.g. by coexpression of cytokines and T cell costimulatory molecules as B7) have to be further addressed in experimental tumor models.