Autologous designer antigen-presenting cells by gene modification of T lymphocyte blasts with IL-7 and IL-12

J Immunother. Jul-Aug 2007;30(5):506-16. doi: 10.1097/CJI.0b013e318046f3b1.

Abstract

An effective immune response to antigen requires professional antigen-presenting cell (APC), which not only present antigen, but also provide costimulation and cytokines (eg, IL-12) that drive T cell differentiation down the appropriate effector pathway (Tc1/TH1). For T cell-based immunotherapy protocols, the availability of large numbers of autologous professional APC is a major limitation because professional APC do not proliferate in vitro. T cells themselves can proliferate exponentially in vitro and have the ability to present antigen. They can also express costimulatory molecules after activation. Therefore, we hypothesized that if activated T cells were genetically modified to express proinflammatory cytokines required to polarize T cells toward a Tc1 response, they could fulfill the requirements for an abundant, autologous APC. To test this potential, T cells were activated by CD3/CD28 antibodies and pulsed with model HLA-A2+ peptides derived from CMVpp65, MAGE-3, and MART-1. Activated T-APC readily reactivated CD8 pp65 memory T cells from healthy CMV seropositive donors; however, the activation of MAGE-3 and MART-1-specific CD8 T cells required both IL-7 and IL-12, which could be provided either exogenously or by genetic modification of the T-APC. Responder T cells could be expanded to large numbers with subsequent stimulations using activated, peptide-pulsed T-APC and IL-2. Tumor antigen-specific T cell lines killed both peptide-pulsed target cells and tumor cell lines. Thus, T cells provide a platform for the generation of autologous APC that can be customized to express both antigens and therapeutic molecules for the induction of antigen-specific T cell immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / immunology*
  • Antigens, Neoplasm / immunology
  • B7-1 Antigen / biosynthesis
  • B7-1 Antigen / immunology
  • B7-2 Antigen / biosynthesis
  • B7-2 Antigen / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line
  • Cytomegalovirus
  • Cytomegalovirus Infections / immunology
  • Humans
  • Interleukin-12 / biosynthesis*
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-7 / biosynthesis*
  • Interleukin-7 / genetics
  • Interleukin-7 / immunology
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Lymphocyte Activation
  • MART-1 Antigen
  • Neoplasm Proteins / immunology
  • Phosphoproteins / immunology
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • Viral Matrix Proteins / immunology

Substances

  • Antigens, Neoplasm
  • B7-1 Antigen
  • B7-2 Antigen
  • Interleukin-7
  • MAGEA3 protein, human
  • MART-1 Antigen
  • MLANA protein, human
  • Neoplasm Proteins
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • Viral Matrix Proteins
  • cytomegalovirus matrix protein 65kDa
  • Interleukin-12