Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8+ T cells

• DOI: 10.1007/s00262-015-1655-y
• Publication Date: 2015-02-12T04:53:26Z
• Authors: Mark P. Rubinstein; Ee Wern Su; Samantha Suriano; Colleen A. Cloud; Kristina Andrijau...; Pravin Kesarwani; Kristina M. Schwartz; Katelyn M. Williams; C. Bryce Johnson; Mingli Li; Gina M. Scurti; Mohamed L. Salem; Chrystal M. Paulos; Elizabeth Garrett...; Shikhar Mehrotra; David J. Cole
• Keywords: Adoptive Cell Transfer; Ex vivo

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.