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In Situ Tumor Vaccination with Interleukin-12-encapsulated Biodegradable Microspheres: Induction of Tumor Regression and Potent Antitumor Immunity¹

Departments of Immunology [N. K. E., R. B. B.] and Surgery [M. S. S.], Roswell Park Cancer Institute, Buffalo, New York 14263, and Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island 02912 [Y. S. J., J. S. J., E. M.]

An alternative technology for the local and sustained delivery of cytokines to tumors for cancer immunotherapy was evaluated and shown here to induce tumor regression, suppression of metastasis, and development of systemic antitumor immunity. Treatment of tumor-bearing BALB/c mice with a single intratumoral injection of biodegradable polylactic acid microspheres loaded with recombinant interleukin-12 (IL-12) promoted complete regression of the primary tumor and prevented the metastatic spread to the lung. Mice that experienced tumor regression after being treated rejected a subsequent challenge with live tumor cells, which indicated the development of systemic antitumor immunity. In situ tumor vaccination, i.e., injection of IL-12 microspheres into existing tumors, was superior to vaccination of mice with mixtures of tumor cells (live or irradiated) and IL-12 microspheres in inducing systemic antitumor immunity. The sustained release of IL-12 from the microspheres was superior to bolus injection of free IL-12, and intratumoral delivery of microspheres was more effective than other routes of administration. These studies establish the utility of biodegradable polymer microspheres as a clinically feasible alternative to systemic cytokine therapy and cytokine gene-modified cell vaccines for the treatment of neoplastic disease.

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