Augmentation of Host Immunity to Tumors with Costimulators and Cytokines

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Cell-mediated immunity to tumors may be enhanced by expressing costimulators and cytokines in tumor cells and by treating tumor-bearing individuals with cytokines that stimulate the proliferation and differentiation of T lymphocytes and NK cells. As discussed earlier in this chapter, tumor cells may induce weak immune responses because they lack costimulators and usually do not express class II MHC molecules, so they do not activate helper T cells. Two potential approaches for boosting host responses to tumors are to artificially provide costimula-tion for tumor-specific T cells and to provide cytokines that can enhance the activation of tumor-specific T cells, particularly CD8+ CTLs (Fig. 17-7). Many cytokines also have the potential to induce nonspecific inflammatory responses, which by themselves may have anti-tumor activity.

The efficacy of enhancing T cell costimulation for antitumor immunotherapy has been demonstrated by animal experiments in which tumor cells were transfected with genes that encode B7 costimulatory molecules and used to vaccinate animals. These B7-expressing tumor cells induce protective immunity against unmodified tumor cells injected at a distant site. The successes with experimental tumor models have led to therapeutic trials in which a sample of a patient's tumor is propagated in vitro, transfected with costimulator genes, irradiated, and reintroduced into the patient. Such approaches may succeed even if the immunogenic antigens expressed on tumors are not known.

It may be possible to use cytokines to enhance adaptive and innate immune responses against tumors. In mouse experiments, injection of live tumor cells transfected with cytokine genes (e.g., IL-2 GM-CSF) caused the rejection of established tumors. This approach has been attempted in cancer patients without success.

Cytokines may also be administered systemically for the treatment of various human tumors (Table 17-3). The largest clinical experience is with high-dose IL-2, which stimulates the production of other cytokines by T cells, such as TNF and IFN-y, and these cytokines act on vascular endothelium and other cell types. IL-2 has been effective in inducing measurable tumor regression responses in about 10% of patients with advanced melanoma and renal cell carcinoma and is currently an approved therapy for these cancers. IFN-a is approved for treatment of malignant melanoma, in combination with chemotherapy, and carcinoid tumors. It is also used to treat certain lymphomas and leukemias. The mechanisms of the antineoplastic effects of IFN-a probably include inhibition of tumor cell proliferation, increased cytotoxic activity of NK cells, and increased class I MHC

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