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

Research output: Contribution to journalArticle

25 Citations (Scopus)

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
Externally publishedYes

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Neoplasm Antigens
T-Lymphocytes
Cytomegalovirus
Neoplasms
Subunit Vaccines
Tissue Donors
Antigens
Tumor-Infiltrating Lymphocytes
Granzymes
Cell Line
Immunosorbents
Therapeutic Uses
Regulatory T-Lymphocytes
Cell- and Tissue-Based Therapy
Interleukin-2

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dang, Y., Knutson, K. L., Goodell, V., Dela Rosa, C., Salazar, L. G., Higgins, D., ... 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

Tumor antigen - Specific T-cell expansion is greatly facilitated by in vivo priming. / Dang, Yushe; Knutson, Keith L; Goodell, Vivian; Dela Rosa, Corazon; Salazar, Lupe G.; Higgins, Doreen; Childs, Jennifer; Disis, Mary L.

In: Clinical Cancer Research, Vol. 13, No. 6, 15.03.2007, p. 1883-1891.

Research output: Contribution to journalArticle

Dang, Y, Knutson, KL, Goodell, V, Dela Rosa, C, Salazar, LG, Higgins, D, Childs, J & Disis, ML 2007, 'Tumor antigen - Specific T-cell expansion is greatly facilitated by in vivo priming', Clinical Cancer Research, vol. 13, no. 6, pp. 1883-1891. https://doi.org/10.1158/1078-0432.CCR-06-2083
Dang, Yushe ; Knutson, Keith L ; Goodell, Vivian ; Dela Rosa, Corazon ; Salazar, Lupe G. ; Higgins, Doreen ; Childs, Jennifer ; Disis, Mary L. / Tumor antigen - Specific T-cell expansion is greatly facilitated by in vivo priming. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 6. pp. 1883-1891.
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AU - Dela Rosa, Corazon

AU - Salazar, Lupe G.

AU - Higgins, Doreen

AU - Childs, Jennifer

AU - Disis, Mary L.

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N2 - 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.

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