Summary
Invariant Natural Killer T (iNKT) cells are evolutionarily conserved innate T cells that influence inflammatory responses. We have shown that iNKT cells, previously thought to be rare in huamns, were highly enriched in human and murine adipose tissue, and that as adipose tissue expands in obesity, iNKT cells were depleted, correlating with proinflammatory macrophage infiltration. iNKT cell numbers were restored in mice and humans after weight loss. Mice lacking iNKT cells had enhanced weight gain, larger adipocytes, fatty livers and insulin resistance on high fat diet. Adoptive transfer of iNKT cells into obese mice or in vivo activation of iNKT cells with their lipid ligand alpha-galactocylceramide decreased body fat, triglycerides, leptin, fatty liver, and improved insulin sensitivity through Th2 cell-type cytokine production by adipose-derived iNKT cells. This finding highlights the potential of iNKT cell-targeted therapies, previously proven to be safe in humans, in the management of obesity and its consequences.
Purpose
Invariant NKT cells (iNKT) are innate-like CD1d-restricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFN-gamma production, and iNKT IFN-gamma production may stratify for survival. Previous clinical trials using iNKT cell activating ligand alpha-galactosylceramide have shown responses. Therefore, a phase 1 clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB-IV melanoma.
Experimental Design
Residual iNKT cells (<0.05% of patient PBMC) were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL-2 in vitro to obtain up to ~109 cells.
Results
Expanded iNKT cells produced IFN-gamma, but limited or undetectable IL-4 or IL-10. Three iNKT infusions each were completed on 9 patients, and produced only grade 1–2 toxicities. The 4th patient onward received systemic GM-CSF with their second and third infusions. Increased numbers of iNKT cells were seen in PBMC after some infusions, particularly when GM-CSF was also given. IFN-gamma responses to alpha-galactosylceramide were increased in PBMC from some patients after infusions, and DTH responses to Candida increased in 5/8 evaluated patients. Three patients have died, three were progression-free at 53, 60 and 65 months, three received further treatment and were alive at 61, 81, and 85 months. There was no clear correlation between outcome and immune parameters.
Conclusions
Autologous in vitro expanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with anti-tumor potential.
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