Post-chemotherapeutic administration of interleukin-12 retards tumor growth and enhances immune cell function: combination therapy using paclitaxel and IL-12.
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.
Pressley
Jennifer S
JS
Department of Biological Sciences, Microbiology and Immunology Section, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 54061-0406, USA. presslej@mskcc.org
Elgert
Klaus D
KD
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005354:Fibrosarcoma / Q000188:drug therapy*; D018664:Interleukin-12 / Q000008:administration & dosage*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage*
D016207:Cytokines; D018664:Interleukin-12; D017239:Paclitaxel