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Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion.

Abstract
Adoptive cell transfer (ACT) of in vitro expanded autologous tumor-infiltrating lymphocytes (TIL) has been shown to exert therapeutic efficacy in melanoma patients. We aimed to develop an ACT protocol based on tumor-specific T cells isolated from peripheral blood and in vitro expanded by Dynabeads® ClinExVivo™CD3/CD28. We show here that the addition of an in vitro restimulation step with relevant peptides prior to bead expansion dramatically increased the proportion of tumor-specific T cells in PBMC-cultures. Importantly, peptide-pulsed dendritic cells (DCs) as well as allogeneic tumor lysate-pulsed DCs from the DC vaccine preparation could be used with comparable efficiency to peptides for in vitro restimulation, to increase the tumor-specific T-cell response. Furthermore, we tested the use of different ratios and different types of Dynabeads® CD3/CD28 and CD3/CD28/CD137 T-cell expander, for optimized expansion of tumor-specific T cells. A ratio of 1:3 of Dynabeads® CD3/CD28 T-cell expander to T cells resulted in the maximum number of tumor-specific T cells. The addition of CD137 did not improve functionality or fold expansion. Both T-cell expansion systems could generate tumor-specific T cells that were both cytotoxic and effective cytokine producers upon antigen recognition. Dynabeads®-expanded T-cell cultures shows phenotypical characteristics of memory T cells with potential to migrate and expand in vivo. In addition, they possess longer telomeres compared to TIL cultures. Taken together, we demonstrate that in vitro restimulation of tumor-specific T cells prior to bead expansion is necessary to achieve high numbers of tumor-specific T cells. This is effective and easily applicable in combination with DC vaccination, by use of vaccine-generated DCs, either pulsed with peptide or tumor-lysate.
AuthorsMarie Klinge Brimnes, Anne Ortved Gang, Marco Donia, Per Thor Straten, Inge Marie Svane, Sine Reker Hadrup
JournalCancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 61 Issue 8 Pg. 1221-31 (Aug 2012) ISSN: 1432-0851 [Electronic] Germany
PMID22237888 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD28
  • Antigens, CD3
  • Cancer Vaccines
Topics
  • Antigens, CD28 (immunology, metabolism)
  • Antigens, CD3 (immunology, metabolism)
  • Cancer Vaccines (immunology, metabolism)
  • Cell Culture Techniques (methods)
  • Clinical Trials as Topic
  • Flow Cytometry
  • Humans
  • Immunotherapy, Adoptive (methods)
  • T-Lymphocytes (cytology, immunology, metabolism)

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