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 10- to 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 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.

Immune Responses Raised in an Experimental Colon Carcinoma Model Following Oral Administration of Lactobacillus casei

“…Both IFN-γ and IL-12 are associated with enhanced anti-tumor activity [39,40]. IL-12 in particular induces proliferation of NK and T cells, as well as production of cytokines involved in cytotoxicity, including IFN-γ.…”

T‐cell receptor gene therapy — ready to go viral?

“…Several modifications to the prevailing ex vivo expansion protocols of T cells have been suggested to enable in vitro proliferation while limiting differentiation. Expansion of T cells in the presence of homeostatic cytokines, such as IL‐7 and IL‐15 (Cha et al., 2010; Cieri et al., 2013; Gomez‐Eerland et al., 2014; Xu et al., 2014), IL‐21 (Chapuis et al., 2013; Hinrichs et al., 2008; Li et al., 2005a), IL‐12 (Rubinstein et al., 2015) or IL‐12 together with IL‐7 or IL‐21 (Yang et al., 2013), have been suggested superior to IL‐2 in inducing a T SCM /T CM phenotype. This phenotype is associated with increased capacity to expand, survive and persist in vivo , to migrate into secondary lymphoid organs, and to perform antitumor activity in mouse tumor models.…”

A Self-Assembled Non-Viral vector as Potential Platform for mRNA-Based Vaccines

“…Using TLR7/8 inhibitors, we proved the concept that inhibition of this pathway, with the consequent block of type-I IFN and IL-12 secretion, affect the anti-tumour cytotoxic immune response. Indeed, it is well known that IL-12 enhances the function and anti-tumour activity in murine and human CD8+ T-cells [43].…”