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

Authors

  • Hanh K. Le
    • Department of Physiology and BiophysicsVirginia Commonwealth University’s Medical College of Virginia
  • Laura Graham
    • Division of Surgical Oncology, Department of Surgery and the Massey Cancer CenterVirginia Commonwealth University’s Medical College of Virginia
  • Catriona H. T. Miller
    • Department of Microbiology and ImmunologyVirginia Commonwealth University’s Medical College of Virginia and the Massey Cancer Center
  • Maciej Kmieciak
    • Department of Microbiology and ImmunologyVirginia Commonwealth University’s Medical College of Virginia and the Massey Cancer Center
  • Masoud H. Manjili
    • Department of Microbiology and ImmunologyVirginia Commonwealth University’s Medical College of Virginia and the Massey Cancer Center
    • Division of Surgical Oncology, Department of Surgery and the Massey Cancer CenterVirginia Commonwealth University’s Medical College of Virginia
Original Article

DOI: 10.1007/s00262-009-0666-y

Cite this article as:
Le, H.K., Graham, L., Miller, C.H.T. et al. Cancer Immunol Immunother (2009) 58: 1565. doi:10.1007/s00262-009-0666-y

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

Copyright information

© Springer-Verlag 2009