Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes

J Transl Med. 2011 Aug 9;9:131. doi: 10.1186/1479-5876-9-131.

Abstract

Background: Development of a standardized platform for the rapid expansion of tumor-infiltrating lymphocytes (TILs) with anti-tumor function from patients with limited TIL numbers or tumor tissues challenges their clinical application.

Methods: To facilitate adoptive immunotherapy, we applied genetically-engineered K562 cell-based artificial antigen presenting cells (aAPCs) for the direct and rapid expansion of TILs isolated from primary cancer specimens.

Results: TILs outgrown in IL-2 undergo rapid, CD28-independent expansion in response to aAPC stimulation that requires provision of exogenous IL-2 cytokine support. aAPCs induce numerical expansion of TILs that is statistically similar to an established rapid expansion method at a 100-fold lower feeder cell to TIL ratio, and greater than those achievable using anti-CD3/CD28 activation beads or extended IL-2 culture. aAPC-expanded TILs undergo numerical expansion of tumor antigen-specific cells, remain amenable to secondary aAPC-based expansion, and have low CD4/CD8 ratios and FOXP3+ CD4+ cell frequencies. TILs can also be expanded directly from fresh enzyme-digested tumor specimens when pulsed with aAPCs. These "young" TILs are tumor-reactive, positively skewed in CD8+ lymphocyte composition, CD28 and CD27 expression, and contain fewer FOXP3+ T cells compared to parallel IL-2 cultures.

Conclusion: Genetically-enhanced aAPCs represent a standardized, "off-the-shelf" platform for the direct ex vivo expansion of TILs of suitable number, phenotype and function for use in adoptive immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology*
  • Antigens, Neoplasm / immunology
  • Artificial Cells / cytology*
  • Artificial Cells / drug effects
  • Artificial Cells / immunology
  • CD28 Antigens / metabolism
  • Cell Culture Techniques / methods*
  • Cell Proliferation / drug effects
  • Epitopes / immunology
  • Genetic Engineering*
  • Humans
  • Interleukin-2 / pharmacology
  • Lymphocyte Subsets / drug effects
  • Lymphocyte Subsets / immunology
  • Lymphocytes, Tumor-Infiltrating / cytology*
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Phenotype

Substances

  • Antigens, Neoplasm
  • CD28 Antigens
  • Epitopes
  • Interleukin-2