title: Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial.
abstract: 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 IFNγ production, and iNKT IFNγ production may stratify for survival. Previous clinical trials using iNKT cell activating ligand α-galactosylceramide have shown clinical responses. Therefore, a phase I clinical trial was performed of autologousin vitroexpanded 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 IL2in vitroto obtain up to approximately 109cells.Results:Expanded iNKT cells produced IFNγ, 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. IFNγ responses to α-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses toCandidaincreased 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:Autologousin vitroexpanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with antitumor potential.Clin Cancer Res; 23(14); 3510-9. ©2017 AACR.
authors.affiliation: Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. mexley@partners.org sbalk@bidmc.harvard.edu.|Gastroenterology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts.|University of Manchester, Manchester, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Exley
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Phillip
authors.initials: P
authors.lastname: Friedlander
authors.affiliation: Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nadia
authors.initials: N
authors.lastname: Alatrakchi
authors.affiliation: Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lianne
authors.initials: L
authors.lastname: Vriend
authors.affiliation: Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Simon
authors.initials: S
authors.lastname: Yue
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sasada
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Wanyong
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yo
authors.initials: Y
authors.lastname: Mizukami
authors.affiliation: Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Justice
authors.initials: J
authors.lastname: Clark
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Nemer
authors.forename: Kenneth
authors.initials: K
authors.lastname: LeClair
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Christine
authors.initials: C
authors.lastname: Canning
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Heather
authors.initials: H
authors.lastname: Daley
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Biostatistics & Computational Biology, Dana Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. mexley@partners.org sbalk@bidmc.harvard.edu.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D005260:Female; D005699:Galactosylceramides / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology / Q000627:therapeutic use; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology / Q000637:transplantation*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*
chemical_list: D017252:CD3 Complex; D005699:Galactosylceramides; C508594:IL2 protein, human; D007376:Interleukin-2; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma