Cytokine Immunotherapy

The immune system protects the body not only from invasion by foreign infectious agents but also from abnormal self-cells with the capacity to cause disease. Several lines of evidence suggest that the immune system can effectively rid the body of cells with malignant potential under normal physiologic conditions and tumor development results from a failure of the immune system. There are also rare cases of spontaneous regression of an established tumor, suggesting that the immune system can regain control if stimulated in the appropriate manner, despite the potentially immunosuppressive nature of the tumor microenvironment. Therapeutic manipulation of the cytokine balance may be such an appropriate stimulation. Cytokines are key immunomodulatory agents that shape responses by the immune system and, conversely, are also involved in the suppression of a response. By manipulating the cytokine milieu, endogenous protection may be reestablished or even enhanced. It is therefore no surprise that cytokine immunotherapy holds great theoretical promise for the treatment of cancer. This theoretical promise has been borne out in a wide variety of preclinical models but unfortunately, clinical trials have to date failed to recapitulate these results. In this chapter, we discuss the activities of the more promising cytokines as monotherapies, multiple cytokine therapies or paired with other treatment modalities. Our growing understanding of each cytokine alone and within the complex microenvironment of the tumor will lead to the refinement of protocols and improve their therapeutic efficacy. We present the outcomes of some clinical trials and the preclinical models that informed their design; highlighting what the achievements as well as the failures can teach us going forward. We also discuss the many challenges faced by this field and the areas of inquiry in which focused efforts will bear the most fruit. Ultimately, understanding which differences between preclinical and clinical protocols account for the discrepancy in outcomes will help us in designing more effective treatments for those cancers that remain refractory to therapy.