Immunotherapy and COX-2 inhibition against malignant brain tumors

Sammanfattning: Glioblastoma multiforme (GBM) is the most common primary brain tumor in the central nervous system and the prognosis is very poor despite conventional therapies including surgery, chemo- and radiotherapy. Peripheral vaccination with irradiated tumor cells represent a novel therapy that targets both dividing and non-dividing tumor cells and minimizes the risk of therapy resistance by presenting multiple tumor antigens. In this doctoral thesis, we report enhanced cure of rats and mice with malignant brain tumors after peripheral immunizations with irradiated tumor cells, either unmodified or transduced to produce the immunostimulatory cytokines interferon-γ (IFN-γ) or granulocyte macrophage-colony stimulating factor. The preclinical studies demonstrate that immunotherapy is further enhanced by simultaneous administration of the selective cyclooxygenase-2 (COX-2) inhibitors parecoxib and valdecoxib. Increased amounts of IFN-γ and proliferating T cells in blood corresponded with the induced immune responses and the T cells were committed to the T helper 1 (Th1) lineage, indicating that immunotherapy and COX-2 inhibition induces a strong anti-tumor Th1 response. Finally, immunotherapy and COX-2 inhibition protected against secondary tumors and the memory response was associated with systemic and intratumoral presence of CD8+ T cells, thereby further strengthening the Th1 response. Prostaglandin E2 (PGE2) was also present in tumor cultures and plasma samples of patients with malignant brain tumors (GBMs, medulloblastomas and ependymoma). Furthermore, plasma PGE2high, IFN-γhigh and interleukin-10low corresponded with prolonged survival in GBM patients following peripheral IFN-γ immunotherapy, implying that the combination of these cytokines can be used to detect an ongoing anti-tumor immune response and consequently predict the therapeutic outcome. In conclusion, the combination of immunotherapy and COX-2 inhibition induce cure in experimental brain tumor models and blood cytokines and PGE2 define an ongoing anti-tumor response, as determined in both animals and humans.