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

Gregory T. Wurz, Audrey M. Gutierrez, Brittany E. Greenberg, Daniel P. Vang, Stephen M Griffey, Chiao Jung Kao, Michael Wolf, Michael W. DeGregorio

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number64
JournalJournal of Translational Medicine
Volume11
Issue number1
DOIs
StatePublished - Mar 13 2013

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Neoplasm Antigens
Immunotherapy
Tumors
Lung Neoplasms
Antigens
Cytokines
Neoplasms
Cyclophosphamide
Lung
Urethane
Assays
Carcinogenesis
L-BLP25
Phase III Clinical Trials
Chemotherapy
Biomarkers
Interleukin-12
Intraperitoneal Injections
Serum
Inbred C57BL Mouse

Keywords

  • Cytokines
  • Immunotherapy
  • L-BLP25
  • Lung cancer
  • MUC1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Antitumor effects of L-BLP25 Antigen-Specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model. / Wurz, Gregory T.; Gutierrez, Audrey M.; Greenberg, Brittany E.; Vang, Daniel P.; Griffey, Stephen M; Kao, Chiao Jung; Wolf, Michael; DeGregorio, Michael W.

In: Journal of Translational Medicine, Vol. 11, No. 1, 64, 13.03.2013.

Research output: Contribution to journalArticle

Wurz, Gregory T. ; Gutierrez, Audrey M. ; Greenberg, Brittany E. ; Vang, Daniel P. ; Griffey, Stephen M ; Kao, Chiao Jung ; Wolf, Michael ; DeGregorio, Michael W. / Antitumor effects of L-BLP25 Antigen-Specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model. In: Journal of Translational Medicine. 2013 ; Vol. 11, No. 1.
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AU - Greenberg, Brittany E.

AU - Vang, Daniel P.

AU - Griffey, Stephen M

AU - Kao, Chiao Jung

AU - Wolf, Michael

AU - DeGregorio, Michael W.

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N2 - 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.

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