Ontak reduces the immunosuppressive tumor environment and enhances successful therapeutic vaccination in HER-2/neu-tolerant mice

Cancer Immunol Immunother. 2012 Mar;61(3):397-407. doi: 10.1007/s00262-011-1113-4. Epub 2011 Sep 18.

Abstract

Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion of regulatory T cells (Tregs) increases endogenous anti-tumor immunity and the efficacy of active immunotherapy in experimental tumor models. HLA-A2.1/HLA-DR1 (A2.1/DR1) × BALB- neuT+ (neuT+) triple transgenic mice represent an improvement over neuT+ mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. We questioned whether depletion of Tregs with Denileukin diftitox (Ontak) enhances the efficacy of a therapeutic vaccine consisting of HER-2(85-94) (p85) CTL and HER-2(776-790) (p776) Th peptides against the growth of TUBO.A2 transplantable tumor in male A2.1/DR1 × neuT+ Tg mice. While the therapeutic vaccine primed the tumor-reactive CD8+ CTLs and CD4+ effector T lymphocytes (Teffs) compartment, inducing activation, tumor infiltration, and tumor rejection or delay in tumor growth, treatment with Ontak 1 day prior to vaccination resulted in enhanced CD4+ and CD8+ T-cell-mediated vaccine-specific immune responses in the periphery. This was closely associated with greater infiltration and a striking change in the intratumor balance of Tregs and vaccine-specific CTLs/Teffs that directly correlated with markedly enhanced antitumor activity. The data suggest that Tregs control both CD4+ and CD8+ T-cell activity within the tumor, emphasize the importance of the intratumor ratio of vaccine-specific lymphocytes to Tregs, and demonstrate significant inversion of this ratio and correlation with tumor rejection during Ontak/vaccine immunotherapy.

MeSH terms

  • Animals
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Diphtheria Toxin / immunology
  • Diphtheria Toxin / pharmacology*
  • Female
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology
  • HLA-DR1 Antigen / genetics
  • HLA-DR1 Antigen / immunology
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / immunology
  • Immunosuppressive Agents / immunology
  • Immunosuppressive Agents / pharmacology
  • Interleukin-2 / immunology
  • Interleukin-2 / pharmacology*
  • Male
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Rats
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / immunology*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Burden / drug effects
  • Tumor Burden / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Vaccination / methods*

Substances

  • Antineoplastic Agents
  • Cancer Vaccines
  • Diphtheria Toxin
  • HLA-A2 Antigen
  • HLA-DR1 Antigen
  • Immunosuppressive Agents
  • Interleukin-2
  • Recombinant Fusion Proteins
  • denileukin diftitox
  • Receptor, ErbB-2