title: A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer.
abstract: To evaluate the safety, immune responses, and antitumor responses after the administration of alpha-galactosylceramide (alphaGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 x 10(9)/m(2)) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-gamma-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-gamma-producing cells (> or =2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of alphaGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-gamma-producing cells that result from alphaGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Motohashi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nagato
authors.forename: Naoki
authors.initials: N
authors.lastname: Kunii
authors.forename: Heizaburo
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Okita
authors.forename: Hideki
authors.initials: H
authors.lastname: Hanaoka
authors.forename: Naomi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yoshino
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Takehiko
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000628:therapy; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology*; D053208:Kaplan-Meier Estimate; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008175:Lung Neoplasms / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000628:therapy
chemical_list: D019496:Cancer Vaccines; D005699:Galactosylceramides; D007376:Interleukin-2; C493154:alpha-galactosylceramide; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor