title: Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Qunrui
authors.initials: Q
authors.lastname: Ye
authors.forename: Maria
authors.initials: M
authors.lastname: Loisiou
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Megan M
authors.initials: MM
authors.lastname: Suhoski
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
mesh_terms: D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D058045:Artificial Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods*; D049109:Cell Proliferation / Q000187:drug effects; D000939:Epitopes / Q000276:immunology; D005818:Genetic Engineering; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D010641:Phenotype
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D000939:Epitopes; D007376:Interleukin-2