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

Rubinstein, Mark; Su, Ee; Suriano, Samantha; Cloud, Colleen; Andrijauskaite, Kristina; Kesarwani, Pravin; Schwartz, Kristina; Williams, Katelyn; Johnson, C.; Li, Mingli; Scurti, Gina; Salem, Mohamed; Paulos, Chrystal; Garrett-Mayer, Elizabeth; Mehrotra, Shikhar; Cole, David

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.

INTERLEUKIN-12; ANTINEOPLASTIC agents; CD8 antigen; HUMAN T cells; MELANOMA; CANCER immunotherapy; LABORATORY mice; PATIENTS

Cancer Immunology, Immunotherapy, 2015, Vol 64, Issue 5, p539

0340-7004

Academic Journal

10.1007/s00262-015-1655-y