Paracrine immunotherapy with interleukin-2 and local chemotherapy is synergistic in the treatment of experimental brain tumors

Potent immune responses against malignant brain tumors can be elicited by p aracrine intracranial (IC) immunotherapy with interleukin (IL)-2, Additiona lly, IC delivery of carmustine via biodegradable polymers has been shown to significantly prolong survival in both animal models and clinical trials. In this study, we show that the combination of paracrine immunotherapy, wit h nonreplicating genetically engineered tumor cells that produce IL-2, and local delivery of chemotherapy by biodegradable polymers prolongs survival in a synergistic manner in mice challenged intracranially with a lethal mur ine brain tumor. Animals receiving IL-2-transduced cells and polymers conta ining 10% 1,3-bis(2-chloroethyl)-1-nitrosourea had significantly improved s urvival compared with animals receiving IL-2-transduced cells or 10% 1,3-bi s(2-chloroethyl)-1-nitrosourea alone. Median survival for the control group was 19 days. Survival in animals receiving IL-2-transduced cells and 1% ca rboplatin-containing polymers was also significantly improved compared with either therapy alone. Histopathological examination on day 14 of animals r eceiving combination treatment showed rare degenerating tumor cells. In add ition to tissue necrosis surrounding the polymer, a marked inflammatory rea ction was observed. In long-term survivors (all animals receiving combinati on treatment), no tumor was observed and the inflammatory reaction was comp letely resolved. The brains of animals receiving combination therapy showed both tissue necrosis due to Local chemotherapy and strong inflammation due to paracrine immunotherapy, The demonstration of synergy between paracrine IL-2 and local IC delivery of antineoplastic drugs is novel and may provid e a combined treatment strategy for use against both primary and metastatic IC tumors.