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Open Access Research

Antitumor effects of L-BLP25 Antigen-Specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model

Gregory T Wurz1, Audrey M Gutierrez1, Brittany E Greenberg1, Daniel P Vang1, Stephen M Griffey2, Chiao-Jung Kao1, Michael Wolf3 and Michael W DeGregorio1*

Author Affiliations

1 Department of Internal Medicine, Division of Hematology and Oncology, School of Medicine, University of California, Davis, 4501 X Street Suite 3016, Sacramento, CA, 95817, USA

2 Comparative Pathology Laboratory, UC Davis School of Veterinary Medicine, University of California, Davis, CA, USA

3 ImmunoOncology, Merck Serono Research, Merck KGaA, Germany

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Journal of Translational Medicine 2013, 11:64  doi:10.1186/1479-5876-11-64

Published: 13 March 2013

Abstract

Background

L-BLP25 antigen-specific cancer immunotherapeutic agent is currently in phase III clinical trials for non-small cell lung cancer. Using a novel human MUC1 transgenic (hMUC1.Tg) lung cancer mouse model, we evaluated effects of L-BLP25 combined with low-dose cyclophosphamide (CPA) pretreatment on Th1/Th2 cytokine production and antitumor activity.

Methods

A chemically-induced lung tumor model was developed in hMUC1.Tg C57BL/6 mice by administering 10 weekly 0.75-mg/g doses of the chemical carcinogen urethane by intraperitoneal injection. Serum cytokines associated with Th1/Th2 polarization and inflammation were measured by multiplex cytokine assay during tumorigenesis. Antitumor activity of L-BLP25 (10 μg) with CPA (100 mg/kg) pretreatment was evaluated following either one or two eight-week cycles of treatment by preparing lung whole mounts and counting tumor foci, and assessing IFN-γ production by ELISpot assay.

Results

During the carcinogenesis phase, no detectable Th1- or Th2-associated cytokine responses were observed, but levels of pro-inflammatory cytokines were increased with distinctive kinetics. A single cycle of L-BLP25 consisting of eight weekly doses was ineffective, whereas adding a second cycle given during tumor progression showed a significant reduction in the incidence of tumor foci. Administering two cycles of L-BLP25 induced Th1 cytokines IL-12, IL-2 and IFNγ at 24 h after the last dose, while Th2 and inflammatory cytokines were elevated to a lesser extent.

Conclusions

Urethane-induced lung tumors in hMUC1.Tg mice can be used as a model to assess the efficacy of the MUC1 antigen-specific cancer immunotherapeutic agent L-BLP25. The results indicate that the antitumor response to L-BLP25 requires at least two cycles and pre-treatment with CPA. In addition, monitoring pro-inflammatory serum cytokines may be useful as a biomarker of L-BLP25 response. Taken together, the preclinical lung tumor model can be utilized for determining effective combinations of L-BLP25 with chemotherapy and/or other immunotherapies.

Keywords:
L-BLP25; MUC1; Immunotherapy; Lung cancer; Cytokines