Antitumor effects of L-BLP25 antigen-specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model.

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.

• Authors: Gregory T Wurz, Audrey M Gutierrez, Brittany E Greenberg, Daniel P Vang, Stephen M Griffey, Chiao-Jung Kao, Michael Wolf, Michael W DeGregorio
• Journal: Journal of translational medicine (J Transl Med) Vol. 11 Pg. 64 (Mar 13 2013) ISSN: 1479-5876 [Electronic] England
• PMID: 23496860 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Cytokines
• Inflammation Mediators
• L-BLP25
• Membrane Glycoproteins
• Mucin-1
• Urethane
• Cyclophosphamide

Topics

• Adenoma (drug therapy, immunology, pathology, therapy)
• Animals
• Antigens, Neoplasm (immunology)
• Cancer Vaccines (immunology)
• Carcinogenesis (pathology)
• Cyclophosphamide (pharmacology, therapeutic use)
• Cytokines (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Immunity (drug effects)
• Immunotherapy
• Inflammation Mediators (metabolism)
• Lung Neoplasms (drug therapy, immunology, pathology, therapy)
• Membrane Glycoproteins (immunology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Mucin-1 (immunology)
• Th1 Cells (drug effects, immunology)
• Time Factors
• Urethane