title: Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death.
abstract: Although adoptive transfer of autologous tumor antigen-specific T-cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of the T-cell receptor (TCR) induced AICD, as a result of activating the DNA damage response pathway through ATM-mediated Ser15 phosphorylation of p53. Activation of this DNA damage response pathway also occurred upon antigen-specific restimulation in TCR-transduced TIL1383I T cells prepared for adoptive transfer to patients as part of a clinical trial. Notably, treatment with the antioxidant N-acetyl cysteine (NAC) significantly reduced upregulation of the DNA damage marker γH2AX, subsequent ATM activation, and cell death. In the Pmel mouse model of melanoma, the presence of NAC during ex vivo T-cell expansion improved the persistence of adoptively transferred cells, reduced tumor growth, and increased survival. Taken together, our results offer a preclinical proof of concept for the addition of NAC to current therapeutic T-cell expansion protocols, offering immediate potential to improve the quality and therapeutic efficacy of adoptive T-cell therapeutics infused into patients. Cancer Res; 76(20); 6006-16. ©2016 AACR.
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Scheffel
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois.
authors.forename: Gina
authors.initials: G
authors.lastname: Scurti
authors.affiliation: Flow Cytometry Core Facility, Loyola University Chicago, Maywood, Illinois.
authors.forename: Patricia
authors.initials: P
authors.lastname: Simms
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
authors.affiliation: Department of Surgery, Loyola University Chicago, Maywood, Illinois.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina. johnsocv@musc.edu.
authors.forename: Christina
authors.initials: C
authors.lastname: Voelkel-Johnson
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000975:Antioxidants; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; D000111:Acetylcysteine