Combined chemotherapy and immunotherapy against experimental malignant brain tumors

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor in adults. Despite standard treatment including surgery, radiotherapy and temozolomide (TMZ)-based chemotherapy, the prognosis for GBM patients is dismal, and there is a need for novel treatments. One possible therapeutic treatment modality presented here is immunotherapy, either alone or combined with intratumoral TMZ. In this doctoral thesis, I report enhanced cure of rats and mice with malignant brain tumors after peripheral immunizations using irradiated whole tumor cells transduced to produce different immunostimulatory cytokines such as interferon-gamma (IFNγ), interleukin-7 (IL-7) and granulocyte macrophage-colony stimulating factor (GM-CSF). In the N32 rat glioma model there is a synergistic therapeutic effect when combining immunization with IFNγ- and- IL7-producing tumor cells and this coincides with enhanced systemic proliferation of CD4+ and CD8+ T cells, and an increase in the plasma levels of IFNγ, thereby strengthening the anti-tumor immune response. In addition the synergistic therapeutic effect of immunization with irradiated GM-CSF-producing tumor cells and recombinant IFNγ in the GL261 mouse glioma model is mediated by both CD4+ and CD8+ T cells, and evokes a long-term memory response that protects against secondary tumors without any further treatment. Further I report that TMZ and cisplatin, two chemotherapeutic agents, could cure 41-45% of GL261 tumor-bearing mice when delivered intratumorally using micro-osmotic pumps. When immunization with irradiated GM-CSF-producing tumor cells is combined with intratumorally administered TMZ, the survival of tumor-bearing mice is synergistically enhanced, while systemic delivery of TMZ abrogates the effect of the immunotherapy. Cisplatin however, does not boost the effect of the immunotherapy. In conclusion, immunotherapy improves survival in experimental glioma models, and the therapeutic effect is enhanced by intratumoral, but not systemic TMZ treatment