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

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.

• Authors: Angelos D Gritzapis, Ioannis F Voutsas, Constantin N Baxevanis
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 61 Issue 3 Pg. 397-407 (Mar 2012) ISSN: 1432-0851 [Electronic] Germany
• PMID: 21928125 (Publication Type: Journal Article)

Chemical References

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

Topics

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