title: Advanced generation anti-prostate specific membrane antigen designer T cells for prostate cancer immunotherapy.
abstract: BACKGROUND
  Adoptive immunotherapy by infusion of designer T cells (dTc) engineered with chimeric antigen receptors (CARs) for tumoricidal activity represents a potentially highly specific modality for the treatment of cancer. In this study, 2nd generation (gen) anti-prostate specific membrane antigen (PSMA) dTc were developed for improving the efficacy of previously developed 1st gen dTc for prostate cancer immunotherapy. The 1st gen dTc are modified with chimeric immunoglobulin-T cell receptor (IgTCR) while the 2nd gen dTc are engineered with an immunoglobulin-CD28-T cell receptor (IgCD28TCR), which incorporates a CD28 costimulatory signal for optimal T cell activation.
  
  
  METHODS
  A 2nd gen anti-PSMA IgCD28TCR CAR was constructed by inserting the CD28 signal domain into the 1st gen CAR. 1st and 2nd gen anti-PSMA dTc were created by transducing human T cells with anti-PSMA CARs and their antitumor efficacy was compared for specific activation on PSMA-expressing tumor contact, cytotoxicity against PSMA-expressing tumor cells in vitro, and suppression of tumor growth in an animal model.
  
  
  RESULTS
  The 2nd gen dTc can be optimally activated to secrete larger amounts of cytokines such as IL2 and IFNγ than 1st gen and to proliferate more vigorously on PSMA-expressing tumor contact. More importantly, the 2nd gen dTc preserve the PSMA-specific cytotoxicity in vitro and suppress tumor growth in animal models with significant higher potency.
  
  
  CONCLUSIONS
  Our results demonstrate that 2nd gen anti-PSMA designer T cells exhibit superior antitumor functions versus 1st gen, providing a rationale for advancing this improved agent toward clinical application in prostate cancer immunotherapy.
authors.affiliation: Department of Medicine, Biotherapeutics Development Lab, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
authors.forename: Qiangzhong
authors.initials: Q
authors.lastname: Ma
authors.forename: Erica M
authors.initials: EM
authors.lastname: Gomes
authors.forename: Agnes Shuk-Yee
authors.initials: AS
authors.lastname: Lo
authors.forename: Richard P
authors.initials: RP
authors.lastname: Junghans
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011467:Prostate / Q000276:immunology; D011471:Prostatic Neoplasms / Q000628:therapy*; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D007376:Interleukin-2; D011946:Receptors, Antigen; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma
keywords: CD28; PSMA; chimeric antigen receptor; gene therapy; lymphodepletion; non-myeloablative (NMA) conditioning