BACKGROUND: Combined tumor treatment with cytokines, e. g., interferons (IFN), and radiotherapy was initially of phenomenological nature but has increasingly been based on a radiobiological rationale. However, an improved understanding of the complex interactions of the cytokine network within the immune system warrants the rationale for such studies to be reviewed. METHODS: Based on published clinical studies, the results of treatment with interferons in combination with radiotherapy are reviewed. New strategies for antitumoral application of cytokines, illustrated by interleukin-(IL-)2 and IL-12 in preclinical and clinical studies, are presented. RESULTS: The initially high expectations regarding the antitumoral action of IFN-alpha, IFN-beta and IFN-gamma in combination with radiotherapy have, with few exceptions, not been fulfilled. In particular, toxicity has been a problem after systemic application. Recent advances in immunology, however, have emphasized the importance of local interactions between antigen-presenting cells and effector cells such as natural killer (NK) cells and cytotoxic T-lymphocytes in the immune reaction against tumors. Preclinical studies with IL-2 und IL-12 have shown efficacy mainly against early metastases, but immune reactions against primary tumors have also been observed. Furthermore, the method and timing of the application have proven to be critical. CONCLUSION: A few positive clinical studies give cause for hope that a therapeutic benefit may be achieved by targeted, local application of cytokines. Recent preclinical studies indicate the importance of cellular cytokine production in the interaction between the components of the immune system. Gene therapy might contribute to reduce the toxicity associated with cytokine treatment.
BACKGROUND: Combined tumor treatment with cytokines, e. g., interferons (IFN), and radiotherapy was initially of phenomenological nature but has increasingly been based on a radiobiological rationale. However, an improved understanding of the complex interactions of the cytokine network within the immune system warrants the rationale for such studies to be reviewed. METHODS: Based on published clinical studies, the results of treatment with interferons in combination with radiotherapy are reviewed. New strategies for antitumoral application of cytokines, illustrated by interleukin-(IL-)2 and IL-12 in preclinical and clinical studies, are presented. RESULTS: The initially high expectations regarding the antitumoral action of IFN-alpha, IFN-beta and IFN-gamma in combination with radiotherapy have, with few exceptions, not been fulfilled. In particular, toxicity has been a problem after systemic application. Recent advances in immunology, however, have emphasized the importance of local interactions between antigen-presenting cells and effector cells such as natural killer (NK) cells and cytotoxic T-lymphocytes in the immune reaction against tumors. Preclinical studies with IL-2 und IL-12 have shown efficacy mainly against early metastases, but immune reactions against primary tumors have also been observed. Furthermore, the method and timing of the application have proven to be critical. CONCLUSION: A few positive clinical studies give cause for hope that a therapeutic benefit may be achieved by targeted, local application of cytokines. Recent preclinical studies indicate the importance of cellular cytokine production in the interaction between the components of the immune system. Gene therapy might contribute to reduce the toxicity associated with cytokine treatment.
Authors: Dirk M Maybauer; Marc O Maybauer; Csaba Szabó; Martin Westphal; Lillian D Traber; Perenlei Enkhbaatar; Kanneganti G K Murthy; Yoshimitsu Nakano; Andrew L Salzman; David N Herndon; Daniel L Traber Journal: Biochem Biophys Res Commun Date: 2008-10-23 Impact factor: 3.575