Tumor antigen - Specific T-cell expansion is greatly facilitated by in vivo priming

Yushe Dang, Keith L. Knutson, Vivian Goodell, Corazon Dela Rosa, Lupe G. Salazar, Doreen Higgins, Jennifer Childs, Mary L. Disis

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26 Scopus citations

Abstract

Purpose: Adoptive T-cell therapy is a promising strategy for the treatment of patients with established tumors but is often limited to specific cancers where tumor-infiltrating lymphocytes, the source of T cells for ex vivo culture, can be obtained. In this study, we evaluated the feasibility of expanding HER-2/neu - specific T cells derived from peripheral blood ex vivo following in vivo priming with a HER-2/neu peptide vaccine. Experimental Design: Peripheral blood mononuclear cells from cytomegalovirus (CMV)-seronegative and CMV-seropositive donors as well as HER-2/neu - positive cancer patients who had or had not been vaccinated with a HER-2/neu peptide - based vaccine was used as a source of T lymphocytes. Antigen-specific T-cell lines were generated by in vitro stimulation with antigen followed by nonspecific expansion on CD3/CD28 beads. The ability to expand antigen-specific T cells was assessed using IFN-γ and granzyme B enzyme-linked immunosorbent spot. The phenotype of the resultant T-cell lines was evaluated by flow cytometry, including the presence of FOXP3-expressing CD4+ T cells. Results: The frequencies of CMV-specific T cells generated from CMV+ donors were >11-fold higher than the frequencies from CMV- donors (P = 0.001), with 22-fold increase of total number of CD3+ T cells. The frequencies of HER-2/neu - specific T cells generated from the primed patients were >25-fold higher than the frequencies from unvaccinated patients (P = 0.006), with an average of a 19-fold increase of total number of CD3+ T cells. Using peripheral blood as the source of T cells did not result in concurrent expansion of FOXP3+CD4+ regulatory T cells despite the use of interleukin-2 in in vitro culture. Both CD4+ and CD8+ HER-2/neu - specific T cells could be expanded. The extent of ex vivo expansion correlated with the magnitude of immunity achieved during immunization (P = 0.008). Conclusion: Tumor-specific T cells can be efficiently expanded from the peripheral blood ex vivo following in vivo priming with a vaccine. This approach provides an effective method to generate tumor-specific polyclonal T cells for therapeutic use that could be applied to cancer patients with any tumor type.

Original languageEnglish (US)
Pages (from-to)1883-1891
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number6
DOIs
StatePublished - Mar 15 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Dang, Y., Knutson, K. L., Goodell, V., Dela Rosa, C., Salazar, L. G., Higgins, D., Childs, J., & Disis, M. L. (2007). Tumor antigen - Specific T-cell expansion is greatly facilitated by in vivo priming. Clinical Cancer Research, 13(6), 1883-1891. https://doi.org/10.1158/1078-0432.CCR-06-2083