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Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001.

ABSTRACT: Understanding the basis of a successful clinical response after treatment with therapeutic cancer vaccines is essential for the development of more efficacious therapy. After vaccination with the single telomerase (hTERT) 16-mer peptide, GV1001, some patients experienced clinical responses and long-term survival. This study reports in-depth immunological analysis of the T-cell response against telomerase (hTERT) in clinically responding patients compared with clinical non-responders following vaccination with the single hTERT 16-mer peptide, GV1001. Extensive characterization of CD4+ T-cell clones specific for GV1001 generated from a lung cancer patient in complete remission after vaccination demonstrated a very broad immune response to this single peptide vaccine with differences in fine specificity, HLA restriction, affinity and function. Some CD4+ T-cell clones were cytotoxic against peptide-loaded target cells and also recognized processed recombinant hTERT protein. Furthermore, T-cell responses against several unrelated hTERT epitopes, some of which are novel, were detected, indicating extensive epitope spreading which was confirmed in other clinical responders. In contrast, patients responding immunologically, but not clinically, after vaccination did not display this intramolecular epitope spreading. Multifunctional CD4+ T-cell clones specific for novel hTERT epitopes were generated and shown to recognize a melanoma cell line. Pentamer analysis of T cells in peripheral blood also demonstrated the presence of an important CD8+ T-cell response recognizing an HLA-B7 epitope embedded in GV1001 not previously described. These results indicate that the highly diverse hTERT-specific T-cell response, integrating both T helper and CTL responses, is essential for tumor regression and the generation of long-term T-cell memory.

SUBMITTER: Inderberg-Suso EM

PROVIDER: S-EPMC3429571 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001.

Inderberg-Suso Else-Marit EM Trachsel Sissel S Lislerud Kari K Rasmussen Anne-Marie AM Gaudernack Gustav G

Oncoimmunology 20120801 5

Understanding the basis of a successful clinical response after treatment with therapeutic cancer vaccines is essential for the development of more efficacious therapy. After vaccination with the single telomerase (hTERT) 16-mer peptide, GV1001, some patients experienced clinical responses and long-term survival. This study reports in-depth immunological analysis of the T-cell response against telomerase (hTERT) in clinically responding patients compared with clinical non-responders following va ...[more]

PMID: 22934259

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Project description:Infections with varicella-zoster virus (VZV) are associated with a range of clinical manifestations. Primary infection with VZV causes chicken pox. The virus remains latent in neurons, and it can reactivate later in life, causing herpes zoster (HZ). Two different vaccines have been developed to prevent HZ; one is based on a live attenuated VZV strain (Zostavax), and the other is based on adjuvanted gE recombinant protein (Shingrix). While Zostavax efficacy wanes with age, Shingrix protection retains its efficacy in elderly subjects (individuals 80 years of age and older). In this context, it is of much interest to understand if there is a role for T cell immunity in the differential clinical outcome and if there is a correlate of protection between T cell immunity and Shingrix efficacy. In this study, we characterized the Shingrix-specific ex vivo CD4 T cell responses in the context of natural exposure and HZ vaccination using pools of predicted epitopes. We show that T cell reactivity following natural infection and Zostavax vaccination dominantly targets nonstructural (NS) proteins, while Shingrix vaccination redirects dominant reactivity to target gE. We mapped the gE-specific responses following Shingrix vaccination to 89 different gE epitopes, 34 of which accounted for 80% of the response. Using antigen presentation assays and single HLA molecule-transfected lines, we experimentally determined HLA restrictions for 94 different donor/peptide combinations. Finally, we used our results as a training set to assess strategies to predict restrictions based on measured or predicted HLA binding and the corresponding HLA types of the responding subjects.IMPORTANCE Understanding the T cell profile associated with the protection observed in elderly vaccinees following Shingrix vaccination is relevant to the general definition of correlates of vaccine efficacy. Our study enables these future studies by clarifying the patterns of immunodominance associated with Shingrix vaccination, as opposed to natural infection or Zostavax vaccination. Identification of epitopes recognized by Shingrix-induced CD4 T cells and their associated HLA restrictions enables the generation of tetrameric staining reagents and, more broadly, the capability to characterize the specificity, magnitude, and phenotype of VZV-specific T cells.

Project description:BackgroundTherapeutic cancer vaccines represent a promising approach to improve clinical outcomes with immune checkpoint inhibition. UV1 is a second generation telomerase-targeting therapeutic cancer vaccine being investigated across multiple indications. Although telomerase is a near-universal tumor target, different treatment combinations applied across indications may affect the induced immune response. Three phase I/IIa clinical trials covering malignant melanoma, non-small cell lung cancer, and prostate cancer have been completed, with patients in follow-up for up to 8 years.Methods52 patients were enrolled across the three trials. UV1 was given as monotherapy in the lung cancer trial and concurrent with combined androgen blockade in the prostate cancer trial. In the melanoma study, patients initiated ipilimumab treatment 1 week after the first vaccine dose. Patients were followed for UV1-specific immune responses at frequent intervals during vaccination, and every 6 months for up to 8 years in a follow-up period. Phenotypic and functional characterizations were performed on patient-derived vaccine-specific T cell responses.ResultsIn total, 78.4% of treated patients mounted a measurable vaccine-induced T cell response in blood. The immune responses in the malignant melanoma trial, where UV1 was combined with ipilimumab, occurred more rapidly and frequently than in the lung and prostate cancer trials. In several patients, immune responses peaked years after their last vaccination. An in-depth characterization of the immune responses revealed polyfunctional CD4+ T cells producing interferon-γ and tumor necrosis factor-α on interaction with their antigen.ConclusionLong-term immunomonitoring of patients showed highly dynamic and persistent telomerase peptide-specific immune responses lasting up to 7.5 years after the initial vaccination, suggesting a plausible functional role of these T cells in long-term survivors. The superior immune response kinetics observed in the melanoma study substantiate the rationale for future combinatorial treatment strategies with UV1 vaccination and checkpoint inhibition for rapid and frequent induction of anti-telomerase immune responses in patients with cancer.

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Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001.

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Widespread CD4+ T-cell reactivity to novel hTERT epitopes following vaccination of cancer patients with a single hTERT peptide GV1001.

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