A phase I study of loco-regional immunotherapy by transbronchial injection of α-galactosylceramide-pulsed antigen presenting cells in patients with lung cancer

Ishibashi, Fumihiro; Sakairi, Yuichi; Iwata, Takekazu; Moriya, Yasumitsu; Mizobuchi, Teruaki; Hoshino, Hidehisa; Yoshida, Shigetoshi; Hanaoka, Hideki; Yoshino, Ichiro; Motohashi, Shinichiro

doi:10.1016/j.clim.2020.108457

Cited by 8 publications

(8 citation statements)

References 26 publications

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“…In addition to enhancing the immunogenicity of the RBD-Fc protein, αGC-based glycolipids provide practical advantages in terms of the COVID-19 pandemic, as it enables a significant reduction in the antigen dose. Considering the facile manufacturing of the recombinant RBD-Fc protein and αGC-based glycolipids on a large scale, as well as the safety profile of αGC demonstrated in clinical trials, 73,74 our data support the continued development of RBD-Fc formulated with the iNKT glycolipid agonist as a candidate vaccine to prevent the COVID-19 disease.…”

Section: ■ Conclusionmentioning

confidence: 60%

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Wang

Zhang

et al. 2021

J. Med. Chem.

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The development of a safe and effective COVID-19 vaccine is of paramount importance to terminate the current pandemic. An adjuvant is crucial for improving the efficacy of the subunit COVID19 vaccine. α-Galactosylceramide (αGC) is a classical iNKT cell agonist which causes the rapid production of Th1- and Th2-associated cytokines; we, therefore, expect that the Th1- or Th2-skewing analogues of αGC can better enhance the immunogenicity of the receptor-binding domain in the spike protein of SARS-CoV-2 fused with the Fc region of human IgG (RBD-Fc). Herein, we developed a universal synthetic route to the Th1-biasing (α-C-GC) and Th2-biasing (OCH and C20:2) analogues. Immunization of mice demonstrated that αGC-adjuvanted RBD-Fc elicited a more potent humoral response than that observed with Alum and enabled the sparing of antigens. Remarkably, at a low dose of the RBD-Fc protein (2 μg), the Th2-biasing agonist C20:2 induced a significantly higher titer of the neutralizing antibody than that of Alum.

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Section: ■ Conclusionmentioning

confidence: 60%

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Wang

Zhang

et al. 2021

J. Med. Chem.

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“…They exhibit powerful cytotoxic activity mediated by perforin/granzyme B. In addition to their direct antitumor effect, iNKT cells also regulate the damaging activities of NK cells, CD8+ T cells, B cells and innate cells by release of a wide variety of pro-inflammatory cytokines ( 153 , 154 , 172 ).…”

Section: α-Galactosylceramide (α-Galcer)mentioning

confidence: 99%

“…Preclinical and clinical trials using α-GalCer have shown that this therapy is safe, exhibits durable activation, and increases the number of iNKT, NK, tumor-specific, CD4+, CD8+ T, and B cells ( 148 , 149 , 151 , 153 – 156 , 160 , 161 , 169 , 172 , 173 , 175 ). This activation is associated with increased serum levels of cytokines that stimulate the growth and function of T cells [IL-12 ( 150 , 175 ) and IL-2 receptors ( 175 )] and other factors that enhance natural killer cell activity (i.e., interferon gamma [IFN-γ] ( 150 , 155 , 156 , 158 , 161 , 163 , 172 ), CD16 ( 175 ), and tumor necrosis factor α [TNF-α]) and immune cell maturation (GMCSF) ( 164 ).…”

Section: α-Galactosylceramide (α-Galcer)mentioning

confidence: 99%

“…This activation is associated with increased serum levels of cytokines that stimulate the growth and function of T cells [IL-12 ( 150 , 175 ) and IL-2 receptors ( 175 )] and other factors that enhance natural killer cell activity (i.e., interferon gamma [IFN-γ] ( 150 , 155 , 156 , 158 , 161 , 163 , 172 ), CD16 ( 175 ), and tumor necrosis factor α [TNF-α]) and immune cell maturation (GMCSF) ( 164 ). In eleven out of twelve completed phase I-II clinical trials, tumor regression, stable disease, partial response or increased median survival time were observed in a subgroup of patients ( 153 , 157 , 159 , 160 , 162 – 169 ). These promising clinical findings are associated with the activation of natural killer cells, cytotoxic CD8+ T cells and CD4+ T cells, which are the most relevant immune responses to cancer ( 230 ).…”

Section: α-Galactosylceramide (α-Galcer)mentioning

confidence: 99%

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Targeting Sphingolipids for Cancer Therapy

et al. 2021

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Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outcomes of clinical trials have not been similar. The most effective drugs are fenretinide and α-galactosylceramide (α-GalCer). In contrast, minor adverse effects restricted to a few subjects and hepatic toxicity have been observed in clinical trials of ABC294640 and safingol, respectively. In the case of CNLs, SKI-II, fingolimod and sonepcizumab there are some limitations and absence of enough clinical studies to demonstrate a benefit. The effectiveness or lack of a major therapeutic effect of sphingolipid modulation by some drugs as a cancer therapy and other aspects related to their mechanism of action are discussed in this review.

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“…A new clinical study developed intranasal administration more effectively activate iNKT cells in the tumor microenvironment [36] . For patients with advanced or recurrent non-small cell lung cancer (NSCLC), 8 of 19 subjects were reaching disease stable [37] . The patients with head and neck squamous cell carcinoma were treated with intranasal injection of iNKT cells combined with α-GalCer pulsed DCs observed that infiltration of iNKT cells into tumor site, which is necessary for anti-tumor immune response [38] .…”

Section: Introductionmentioning

confidence: 99%

iNKT: A new avenue for CAR-based cancer immunotherapy

Liu

Wang

Chai

et al. 2022

Translational Oncology

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Highlights Invariant natural killer cells are rare but pleiotropic immunoregulatory and effector cells, which show powerful antitumor responses through direct killing, adjuvant effects, superior tumor infiltration and tumor-associated macrophages inhibition. iNKT cells are considered as an attractive platform for CAR-based cancer immunotherapy. Allogenic iNKT cells don't cause GvHD, which render CAR-iNKT a great potential to develop universal therapeutic product.

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A phase I study of loco-regional immunotherapy by transbronchial injection of α-galactosylceramide-pulsed antigen presenting cells in patients with lung cancer

Cited by 8 publications

References 26 publications

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

Targeting Sphingolipids for Cancer Therapy

iNKT: A new avenue for CAR-based cancer immunotherapy

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