Combining T-cell vaccination and application of agonistic anti-GITR mAb (DTA-1) induces complete eradication of HPV oncogene expressing tumors in mice

J Immunother. Feb-Mar 2010;33(2):136-45. doi: 10.1097/CJI.0b013e3181badc46.

Abstract

We generated an adenovirus-based T-cell vaccine (Ad-p14) that reliably elicits T-cell responses to human papillomavirus (HPV) oncogenes of the 2 most common high-risk HPV serotypes. The artificial gene used to create the vaccine comprising 415 aa (1248 bp) was cloned by fusing 14 polymerase chain reaction fragments of HPV16 and HPV18 E6 and E7 oncogenes devoid of sequences with transforming potential. Although ensuring maximal biologic safety, the construct includes approximately 70% of the relevant T-cell epitopes. In a tumor model for cervical cancer (C3), therapeutic vaccination led to complete eradication in 100% of the mice. In a second model (TC1), it induced initial tumor mass reduction, but 90% of the animals showed delayed tumor progression. To further improve the therapeutic effect, vaccination was combined with systemic application of imiquimod, anti-CD4, alpha-interferon, or anti-GITR. Although adding alpha-interferon improved the therapeutic potential of Ad-p14 by 40%, the combination with anti-GITR resulted in complete and permanent eradication of all TC1 tumors. Ad-p14 has clinical potential for treating HPV-induced lesions, and the added effect of immune response modifiers stresses the importance of combined protocols for immunotherapy of malignant tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacology
  • Cancer Vaccines*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism
  • Female
  • Fibrosarcoma / immunology
  • Fibrosarcoma / pathology
  • Fibrosarcoma / therapy*
  • Forkhead Transcription Factors / biosynthesis
  • Genetic Engineering
  • Glucocorticoid-Induced TNFR-Related Protein
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / immunology*
  • Human papillomavirus 18 / genetics
  • Human papillomavirus 18 / immunology*
  • Humans
  • Interferon-gamma / metabolism
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / immunology
  • Oncogene Proteins, Viral / metabolism
  • Receptors, Nerve Growth Factor / agonists
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Tumor Necrosis Factor / agonists
  • Receptors, Tumor Necrosis Factor / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Tumor Burden / drug effects
  • Tumor Burden / immunology
  • Uterine Cervical Neoplasms / immunology
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / therapy*

Substances

  • Antibodies, Monoclonal
  • Cancer Vaccines
  • Epitopes, T-Lymphocyte
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Glucocorticoid-Induced TNFR-Related Protein
  • Oncogene Proteins, Viral
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNFRSF18 protein, human
  • Interferon-gamma