Cancer Immunology, Immunotherapy

, Volume 58, Issue 10, pp 1565–1576

Incubation of antigen-sensitized T lymphocytes activated with bryostatin 1 + ionomycin in IL-7 + IL-15 increases yield of cells capable of inducing regression of melanoma metastases compared to culture in IL-2

  • Hanh K. Le
  • Laura Graham
  • Catriona H. T. Miller
  • Maciej Kmieciak
  • Masoud H. Manjili
  • Harry Douglas Bear
Original Article

Abstract

Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). We hypothesized that B/I-activated T cells cultured in IL-7 + IL-15 might proliferate and survive in culture better than cells cultured in IL-2, and that these cells would have equal or greater anti-tumor activity in vivo. Tumor antigen-sensitized DLN lymphocytes from either wild-type or T cell receptor transgenic mice were harvested, activated with B/I, and expanded in culture with either IL-2, IL-7 + IL-15 or a regimen of alternating cytokines. Cell yields, proliferation, apoptosis, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for anti-tumor activity against melanoma lung metastases established by prior i.v. injection of B16 melanoma cells. IL-7 + IL-15 or alternating cytokines resulted in much faster and prolonged proliferation and much less apopotosis of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately tenfold greater yields of viable cells. Culture in IL-7 + IL-15 yielded higher proportions of CD8+ T cells and a higher proportion of cells with a central memory phenotype. Despite this, T cells grown in IL-7 + IL-15 had higher IFN-γ release responses to tumor antigen than cells grown in IL-2. Adoptive transfer of B/I-activated T cells grown in IL-7 + IL-15 or the alternating regimen had equal or greater efficacy on a “per-cell” basis against melanoma metastases. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in adoptive immunotherapy of cancer.

Keywords

Adoptive immunotherapy Melanoma IL-7 IL-15 IL-2 T lymphocytes 

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Hanh K. Le
    • 1
  • Laura Graham
    • 2
  • Catriona H. T. Miller
    • 3
  • Maciej Kmieciak
    • 3
  • Masoud H. Manjili
    • 3
  • Harry Douglas Bear
    • 2
  1. 1.Department of Physiology and BiophysicsVirginia Commonwealth University’s Medical College of VirginiaRichmondUSA
  2. 2.Division of Surgical Oncology, Department of Surgery and the Massey Cancer CenterVirginia Commonwealth University’s Medical College of VirginiaRichmondUSA
  3. 3.Department of Microbiology and ImmunologyVirginia Commonwealth University’s Medical College of Virginia and the Massey Cancer CenterRichmondUSA

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