Natural killer T (NKT) cells are a unique subset of lymphocytes that present a mixed T-NK phenotype. Our hypothesis is that Natural killer T cells may decrease the tumor burden and improve overall survival. The purpose of this study is to determine whether Natural killer T (NKT) cells are effective and safe in the treatment of patients with unresectable advanced solid tumor.

Start Date01 Nov 2015

Sponsor / Collaborator

Tsinghua University

[+2]

100 Clinical Results associated with Natural killer T cell(Tsinghua University)

100 Translational Medicine associated with Natural killer T cell(Tsinghua University)

100 Patents (Medical) associated with Natural killer T cell(Tsinghua University)

Literatures (Medical) associated with Natural killer T cell(Tsinghua University)

01 Aug 2018·Acta BiomaterialiaQ1 · ENGINEERING & TECHNOLOGY

α-Galactosylceramide and peptide-based nano-vaccine synergistically induced a strong tumor suppressive effect in melanoma

Q1 · ENGINEERING & TECHNOLOGY

Article

Author: Helena F. Florindo ; Julia E. Vela Ramirez ; Mire Zloh ; Manuela Gaspar ; Teresa S. Barata ; Liane I.F. Moura ; Vanessa Sainz ; Steve Brocchini ; Nicholas A. Peppas ; Ana I. Matos ; Ana S. Viana ; Angela M. Wagner ; Ronit Satchi-Fainaro ; Carina Peres

α-Galactosylceramide (GalCer) is a glycolipid widely known as an activator of Natural killer T (NKT) cells, constituting a promising adjuvant against cancer, including melanoma. However, limited clinical outcomes have been obtained so far. This study evaluated the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II melanoma-associated peptide antigens and the Toll-Like Receptor (TLR) ligands CpG and monophosphoryl lipid A (MPLA), which we intended to maximize following their co-delivery by a nanoparticle (NP). This is expected to improve GalCer capture by dendritic cells (DCs) and subsequent presentation to NKT cells, simultaneously inducing an anti-tumor specific T-cell mediated immunity. The combination of GalCer with melanoma peptides and TLR ligands successfully restrained tumor growth. The tumor volume in these animals was 5-fold lower than the ones presented by mice immunized with NPs not containing GalCer. However, tumor growth was controlled at similar levels by GalCer entrapped or in its soluble form, when mixed with antigens and TLR ligands. Those two groups showed an improved infiltration of T lymphocytes into the tumor, but only GalCer-loaded nano-vaccine induced a prominent and enhanced infiltration of NKT and NK cells. In addition, splenocytes of these animals secreted levels of IFN-γ and IL-4 at least 1.5-fold and 2-fold higher, respectively, than those treated with the mixture of antigens and adjuvants in solution. Overall, the combined delivery of the NKT agonist with TLR ligands and melanoma antigens via this multivalent nano-vaccine displayed a synergistic anti-tumor immune-mediated efficacy in B16F10 melanoma mouse model.STATEMENT OF SIGNIFICANCECombination of α-galactosylceramide (GalCer), a Natural Killer T (NKT) cell agonist, with melanoma-associated antigens presented by MHC class I (Melan-A:26) and MHC class II (gp100:44) molecules, and Toll-like Receptor (TLR) ligands (MPLA and CpG), within nanoparticle matrix induced a prominent anti-tumor immune response able to restrict melanoma growth. An enhanced infiltration of NKT and NK cells into tumor site was only achieved when the combination GalCer, antigens and TLR ligands were co-delivered by the nanovaccine.

12 Sep 2011·Clinical and Experimental ImmunologyQ3 · MEDICINE

Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice

Q3 · MEDICINE

Article

Author: Tohn, R ; Blumenfeld, H J ; Liu, Y ; Delovitch, T L ; Haeryfar, S M M ; Savage, P B

SummaryBecause invariant natural killer T (iNK T) cells link innate and adaptive immunity, the structure-dependent design of iNK T cell agonists may have therapeutic value as vaccines for many indications, including autoimmune disease. Previously, we showed that treatment of non-obese diabetic (NOD) mice with the iNK T cell activating prototypic glycolipid α-galactosylceramide (α-GalCer) protects them from type 1 diabetes (T1D). However, α-GalCer is a strong agonist that can hyperactivate iNK T cells, elicit several side effects and has shown only limited success in clinical trials. Here, we used a structure-guided design approach to identify an iNK T cell agonist that optimally protects from T1D with minimal side effects. Analyses of the kinetics and function of a panel of synthetic α-GalCer fatty acyl chain derivatives (C8:0-C16:0) were performed in NOD mice. C16:0 elicited the highest protection from insulitis and T1D, which was associated with a higher frequency and survival of iNK T cells and enhanced activity of tolerogenic dendritic cells (DCs) in draining pancreatic lymph nodes (PLN), inability to transactivate NK cells and a more rapid kinetics of induction and recovery of iNK T cells from anergy. We conclude that the length and structure of the acyl chain of α-GalCer regulates the level of protection against T1D in mice, and propose that the extent of this protection depends on the relative capacity of the acyl chain to accommodate an endogenous spacer lipid of appropriate length and structure. Thus, our findings with the α-GalCer C16:0 derivative suggest strongly that it be considered as a lead glycolipid candidate in clinical trials of T1D.

PLoS ONEQ3 · CROSS-FIELD

Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis

Q3 · CROSS-FIELD

ArticleOA

Author: Marcos A. Cenedeze ; Alexandre C. Keller ; Niels O. S. Câmara ; Maria Fernanda Soares ; Alvaro Pacheco-Silva ; Bruna N. Buscariollo ; Paul B. Savage ; Cassiano Donizetti-Oliveira ; Rafael L. Pereira ; Vanessa O. Reis ; Patricia Semedo

A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis (FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T (iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin(ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1α, IL-1β, IL-17, TNF-α, and chemokines, such as RANTES and eotaxin. In addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-β analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-β could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-β, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-β through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. In conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM-induced glomerulosclerosis and may provide an alternative approach to disease management.

100 Deals associated with Natural killer T cell(Tsinghua University)

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	CN	The First Hospital of Tsinghua University	01 Nov 2015
Colorectal Cancer	Phase 2	CN	Tsinghua University	01 Nov 2015
Colorectal Cancer	Phase 2	CN	Shanghai Public Health Clinical Center	01 Nov 2015
Hepatocellular Carcinoma	Phase 2	CN	The First Hospital of Tsinghua University	01 Nov 2015
Hepatocellular Carcinoma	Phase 2	CN	Tsinghua University	01 Nov 2015
Hepatocellular Carcinoma	Phase 2	CN	Shanghai Public Health Clinical Center	01 Nov 2015
Non-Small Cell Lung Cancer	Phase 2	CN	The First Hospital of Tsinghua University	01 Nov 2015
Stomach Cancer	Phase 2	CN	Shanghai Public Health Clinical Center	01 Nov 2015
Stomach Cancer	Phase 2	CN	The First Hospital of Tsinghua University	01 Nov 2015
Stomach Cancer	Phase 2	CN	Tsinghua University	01 Nov 2015

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