Post-Chemotherapeutic Administration of Interleukin-12 Retards Tumor Growth and Enhances Immune Cell Function: Combination Therapy Using Paclitaxel and IL-12

Abstract

The antineoplastic agent paclitaxel (TAXOL) is a potent inhibitor of tumor cell division that also suppresses lymphocyte proliferative responses. Because chemotherapy-induced immunosuppression may limit the patient's antitumor responses, we investigated the possibility that the T cell stimulatory cytokine interleukin-12 (IL-12) could be used to reverse paclitaxel-mediated lymphocyte suppression. Recognizing that IL-12 treatment following paclitaxel exposure promotes T cell responses in vitro, we evaluated the antitumor efficacy of IL-12 administration concurrent and subsequent to paclitaxel treatment. Simultaneous administration of IL-12 and paclitaxel failed to limit tumor outgrowth or extend survival beyond chemotherapy alone, although IL-12 did not manifest negative effects. In contrast, post-chemotherapeutic IL-12 significantly delayed tumor outgrowth and extended survival in tumor-burdened BALB/c mice. Correlative enhancements in ex vivo immune cell effector function were also observed following paclitaxel and temporally delayed IL-12 therapy. Collectively, these data demonstrate an immunotherapeutic efficacy of IL-12 that augments the chemotherapeutic activities of paclitaxel when delivered in the appropriate temporal sequence.

Keywords:

• Immunotherapy
• Paclitaxel
• Interleukin-12
• Combination therapy.