Phase I study of α-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer

Uchida, Tetsuro; Horiguchi, Susumu; Tanaka, Yuriko; Yamamoto, Heizaburo; Kunii, Naoki; Motohashi, Shinichiro; Taniguchi, Masaru; Nakayama, Toshinori; Okamoto, Yoshitaka

doi:10.1007/s00262-007-0373-5

Cited by 153 publications

(134 citation statements)

References 33 publications

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“…We detected lower but significant NKT cell immune responses in the PBMCs, suggesting the systemic induction of NKT cell-dependent responses even when a small number of ␣GalCer-pulsed IL-2/GM-CSF-cultured PBMCs were injected locally (43). Although confirmation is needed, we did observe one partial response case in this trial (43).…”

Section: Discussionmentioning

confidence: 68%

“…This route could offer an advantage for inducing the local immune responses more efficiently because the injected cells would quickly migrate to the ipsilateral regional lymph nodes (44). We detected lower but significant NKT cell immune responses in the PBMCs, suggesting the systemic induction of NKT cell-dependent responses even when a small number of ␣GalCer-pulsed IL-2/GM-CSF-cultured PBMCs were injected locally (43). Although confirmation is needed, we did observe one partial response case in this trial (43).…”

Section: Discussionmentioning

confidence: 75%

“…Immunotherapy that targeted on the NKT cell immune system has been undertaken at several institutes, and at present, there is no report of obvious tumor regression under the RECIST criteria after NKT cell immunotherapy including ␣GalCer-pulsed DC or in vitro-expanded NKT cell (25,31,41,42). We have recently performed a phase I clinical trial of the administration of a small number of ␣GalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 ϫ 10 8 ) in patients with advanced head and neck cancer (43). In this trial, ␣GalCer-pulsed IL-2/GM-CSF-cultured PBMCs were injected via the nasal submucosa.…”

Section: Discussionmentioning

confidence: 99%

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

Motohashi

Nagato

Kunii

et al. 2009

The Journal of Immunology

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

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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

Motohashi

Nagato

Kunii

et al. 2009

The Journal of Immunology

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205

162

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“…In addition, based on our previous study of postinfarct heart failure [17], αGC administration may attenuate also LV remodeling and reduce mortality after MI. To date, several clinical trials (Phase I/II) using activated iNKT cells by αGC have been conducted in patients with cancer [45][46][47][48][49]. No severe adverse events were observed in these trials.…”

Section: Clinical Implicationmentioning

confidence: 99%

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

Homma¹,

Kinugawa²,

Takahashi³

et al. 2013

Journal of Molecular and Cellular Cardiology

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“…10−12 KRN7000 (1), 13 a synthetic α-GalCer (1, Figure 1) derived from the structural modification on the ceramide part of agelasphin-9b, presented convincing effects on the treatment of liver tumors, 14,15 metastatic cancers, 16,17 parasitic infections, 11,18 and autoimmune diseases. 19,20 The action mechanism of KRN7000 has been suggested in approximately three sequential steps.…”

mentioning

confidence: 99%

Synthesis and Biological Activities of 5-Thio-α-GalCers

Wang

Zhou

et al. 2015

ACS Med. Chem. Lett.

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NKT cells, a unique subset of T cells that recognizes glycolipid antigens presented by CD1d molecules, are believed to produce key cytokines of both Th1 and Th2 T cells and are thus involved in the control of several types of immune response. As an active glycolipid antigen having α-galactosyl ceramide core structure, KRN7000 showed promising immunostimulation activity and was selected as an anticancer drug candidate for further clinical application. In this report, three new KRN7000 structural analogues were designed and synthesized, in which the ring oxygen of the galactopyranose residue is replaced by a sulfur atom along with the variation on the lipid chain. Their abilities for stimulating mouse NKT cells to produce IFN-γ and IL-4 were evaluated both in vivo and in vitro. KEYWORDS: KRN7000, 5-thio-α-GalCer, iNKT cells, antitumor activity I nvariant natural killer T (iNKT) cells are a specialized subset of T cells that play an important role in tumor immunity and preventing autoimmunity.1−4 The anti-infective activity of iNKT cells can be triggered by various viruses, bacteria, and parasites. 5,6 When stimulated by glycolipid antigens such as marine natural product agelasphin-9b, 7 the iNKT cells could rapidly release T helper 1 (Th1) cytokines (e.g., IFN-γ, TNF-α, IF-2) and Th2 cytokines (e.g., IL-4, IL-10).8,9 Th1-biased cytokines are believed to be concerned with the antitumor, antibacterial, and antiviral activities, whereas the release of Th2-biased cytokines may relieve some autoimmune diseases.10−12 KRN7000 (1), 13 a synthetic α-GalCer (1, Figure 1) derived from the structural modification on the ceramide part of agelasphin-9b, presented convincing effects on the treatment of liver tumors, 14,15 metastatic cancers, 16,17 parasitic infections, 11,18 and autoimmune diseases. 19,20 The action mechanism of KRN7000 has been suggested in approximately three sequential steps. First, KRN7000 is combined with the CD1d protein to form a glycolipid−protein complex. Second, the KRN7000/CD1d complex is recognized by the T cell receptor (TCR) on the surface of NKT cells to form a three-molecule complex. Lastly, it stimulates NKT cells to release Th1 and Th2 cytokines rapidly. 21 Because of the mutual repulsion of Th1 and Th2 cytokines, the simultaneous high level production of both cytokines weaken the therapeutic effectiveness of KRN7000. 22Therefore, some KRN7000 derivatives modifying on either sugar or ceramide moieties were synthesized and expected to selectively control the release of Th1 and Th2 cytokines. 23−27For example, KRN7000 analogue with a longer acyl tail (2, Figure 1) exhibited a greater ability for activation of B cells and induced IL-2 from mouse NKT cells, and IL-4 and IFN-γ from human Vα24i NKT cells in vitro, 28,29 while the analogue with a relative shorter chain (3, Figure 1) influenced cytokine release toward Th2 bias with an immunomodulatory response. 30 In consideration of the intrinsic instability of O-glycosides in vivo, both C-bridged glycoside (α-C-GalCer) 31−33 and S-bridged ...

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Phase I study of α-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer

Abstract: The administration of alpha-GalCer-pulsed APCs into the nasal submucosa was found to be safe and induce anti-tumor activity in some patients.

Cited by 153 publications

References 33 publications

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

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

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

Synthesis and Biological Activities of 5-Thio-α-GalCers

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