Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial

作者：Exley Mark A^*; Friedlander Phillip; Alatrakchi Nadia; Vriend Lianne; Yue Simon; Sasada Tetsuro; Zeng Wanyong; Mizukami Yo; Clark Justice; Nemer David; LeClair Kenneth; Canning Christine; Daley Heather; Dranoff Glenn; Giobbie Hurder Anita; Hodi F Stephen; Ritz Jerome; Balk Steven P

来源：Clinical Cancer Research, 2017, 23(14): 3510-3519.

DOI：10.1158/1078-0432.CCR-16-0600

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 clinical responses. Therefore, a phase I 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 peripheral blood mononuclear cell (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 IL2 in vitro to obtain up to approximately 10(9) cells.
Results: Expanded iNKT cells produced IFN gamma, but limited or undetectable IL4 or IL10. 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 PBMCs after some infusions, particularly when GM-CSF was also given. IFN gamma responses to alpha-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses to Candida increased in 5 of 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 antitumor potential.

• 出版日期2017-7-15
• 单位Biogen Idec