title: Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8(+) T cells.
abstract: Mouse CD8(+) T cells conditioned with interleukin (IL)-12 ex vivo mediate the potent regression of established melanoma when transferred into lymphodepleted mice. However, the quantitative and qualitative changes induced by IL-12 in the responding mouse CD8(+) T cells have not been well defined. Moreover, the mechanisms by which IL-12-conditioning impacts human CD8(+) T cells, and how such cells might be expanded prior to infusion into patients is not known. We found that ex vivo IL-12-conditioning of mouse CD8(+) T cells led to a tenfold-100-fold increase in persistence and anti-tumor efficacy upon adoptive transfer into lymphodepleted mice. The enhancing effect of IL-12 was associated with maintenance of functional avidity. Importantly, in the context of ongoing ACT clinical trials, human CD8(+) T cells genetically modified with a tyrosinase-specific T cell receptor (TCR) exhibited significantly enhanced functional activity when conditioned with IL-12 as indicated by heightened granzyme B expression and elevated peptide-specific CD107a degranulation. This effect was sustainable despite the 20 days of in vitro cellular expansion required to expand cells over 1,000-fold allowing adequate cell numbers for administration to cancer patients. Overall, these findings support the efficacy and feasibility of ex vivo IL-12-conditioning of TCR-modified human CD8(+) T cells for adoptive transfer and cancer therapy.
authors: Department of Surgery, Medical University of South Carolina, 86 Jonathan Lucas Street, HO506, Charleston, SC, 29425, USA, markrubinstein@musc.edu.
authors: Mark P
authors: MP
authors: Rubinstein
authors: Ee Wern
authors: EW
authors: Su
authors: Samantha
authors: S
authors: Suriano
authors: Colleen A
authors: CA
authors: Cloud
authors: Kristina
authors: K
authors: Andrijauskaite
authors: Pravin
authors: P
authors: Kesarwani
authors: Kristina M
authors: KM
authors: Schwartz
authors: Katelyn M
authors: KM
authors: Williams
authors: C Bryce
authors: CB
authors: Johnson
authors: Mingli
authors: M
authors: Li
authors: Gina M
authors: GM
authors: Scurti
authors: Mohamed L
authors: ML
authors: Salem
authors: Chrystal M
authors: CM
authors: Paulos
authors: Elizabeth
authors: E
authors: Garrett-Mayer
authors: Shikhar
authors: S
authors: Mehrotra
authors: David J
authors: DJ
authors: Cole
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053804:Granzymes / Q000096:biosynthesis; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; D011948:Receptors, Antigen, T-Cell; D018664:Interleukin-12; D053804:Granzymes