title: 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.affiliation: Cancer Immunology and Immunotherapy Center, St Savas Cancer Hospital, 171 Alexandras Avenue, 115 22, Athens, Greece.
authors.forename: Angelos D
authors.initials: AD
authors.lastname: Gritzapis
authors.forename: Ioannis F
authors.initials: IF
authors.lastname: Voutsas
authors.forename: Constantin N
authors.initials: CN
authors.lastname: Baxevanis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D014611:Vaccination / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D004167:Diphtheria Toxin; D015789:HLA-A2 Antigen; D015798:HLA-DR1 Antigen; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox