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A Phase I-II Study of -Galactosylceramide-Pulsed IL-2/GM-CSF-Cultured Peripheral Blood Mononuclear Cells in Patients with Advanced and Recurrent Non-Small Cell Lung Cancer¹

Shinichiro Motohashi^*,, Kaoru Nagato^*,, Naoki Kunii^*, Heizaburo Yamamoto^*, Kazuki Yamasaki^*, Kohsuke Okita^*, Hideki Hanaoka, Naomi Shimizu, Makoto Suzuki, Ichiro Yoshino, Masaru Taniguchi^¶, Takehiko Fujisawa and Toshinori Nakayama^2,*

^* Department of Immunology, Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, and Clinical Research Center, Division of Blood Transfusion, Chiba University Hospital, Chiba, Japan, and ^¶ Laboratory of Immune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

To evaluate the safety, immune responses, and antitumor responses after the administration of -galactosylceramide (GalCer) 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. GalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 x 10⁹/m²) 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 GalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN--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--producing cells (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 GalCer-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--producing cells that result from GalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Global Centers of Excellence Program, Global Center for Education and Research in Immune System Regulation and Treatment, by grants from Japan’s Ministry of Education, Culture, Sports, Science and Technology (MEXT), and by Grant-in-aid 17016010 for Scientific Research of Priority Areas, Grant-in-Aid 17390139 for Scientific Research (B), Grant-in-Aid 19591609 for Scientific Research (C), Exploratory Research Grant 19659121, and the Cancer Translational Research Project. This work was also supported by the Ministry of Health, Labor and Welfare (Japan), The Japan Health Science Foundation, Yasuda Medical Foundation, Sagawa Foundation, and Kobayashi Institute for Innovative Cancer Chemotherapy.

² Address correspondence and reprint requests to Dr. Toshinori Nakayama, Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail address: tnakayama{at}faculty.chiba-u.jp

³ Abbreviations used in this paper: GalCer, -galactosylceramide; DC, dendritic cell; NSCLC, non-small cell lung cancer; DVT, deep vein thrombosis; MST, median survival time.

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