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Paracrine Immunotherapy with Interleukin-2 and Local Chemotherapy Is Synergistic in the Treatment of Experimental Brain Tumors¹

Departments of Neurosurgery [P. S., J. H., F. D., B. M. T., H. B.], Pathology [D. B.], and Oncology [J. H., D. M. P., H. B.], The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, and Divisione di Neurochirurgia, Istituto Nazionale Neurologico C.Besta, Milan, Italy [F. D.]

Potent immune responses against malignant brain tumors can be elicited by paracrine intracranial (IC) immunotherapy with interleukin (IL)-2. Additionally, 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, with 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 murine brain tumor. Animals receiving IL-2-transduced cells and polymers containing 10% 1,3-bis(2-chloroethyl)-1-nitrosourea had significantly improved survival compared with animals receiving IL-2-transduced cells or 10% 1,3-bis(2-chloroethyl)-1-nitrosourea alone. Median survival for the control group was 19 days. Survival in animals receiving IL-2-transduced cells and 1% carboplatin-containing polymers was also significantly improved compared with either therapy alone. Histopathological examination on day 14 of animals receiving combination treatment showed rare degenerating tumor cells. In addition to tissue necrosis surrounding the polymer, a marked inflammatory reaction was observed. In long-term survivors (all animals receiving combination treatment), no tumor was observed and the inflammatory reaction was completely 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 provide a combined treatment strategy for use against both primary and metastatic IC tumors.

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