Autologous designer antigen-presenting cells by gene modification of T lymphocyte blasts with IL-7 and IL-12.
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.
Foster
Aaron E
AE
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA.
Leen
Ann M
AM
Lee
Timothy
T
Okamura
Takayuki
T
Lu
An
A
Vera
Juan
J
Atkinson
Rachel
R
Bollard
Catherine M
CM
Dotti
Gianpietro
G
Rooney
Cliona M
CM
D000938:Antigen-Presenting Cells / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D009363:Neoplasm Proteins / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology
D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015851:Interleukin-7; C072013:MAGEA3 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D018664:Interleukin-12