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1.
Cancer Res ; 81(7): 1788-1801, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33483371

ABSTRACT

CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell-specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens. SIGNIFICANCE: Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells.


Subject(s)
Antigens, CD1d/pharmacology , Clonal Anergy/drug effects , Galactosylceramides/pharmacology , Immunotherapy/methods , Natural Killer T-Cells/drug effects , Animals , Antigens, CD1d/chemistry , Antigens, CD1d/immunology , Clonal Anergy/immunology , Female , Galactosylceramides/chemistry , Humans , Immunoconjugates/pharmacology , Lymphocyte Activation/drug effects , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Mice, Knockout , Natural Killer T-Cells/immunology , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Tumor Cells, Cultured
2.
Clin Immunol ; 187: 76-84, 2018 02.
Article in English | MEDLINE | ID: mdl-29061445

ABSTRACT

NK cells represent a first line of immune defense, but are progressively dysregulated in multiple myeloma (MM) patients. To restore and facilitate their antitumor effect, NK cells are required in sufficient quantities and must be stimulated. We initially assessed the proportions of NKT and NK cells in 34 MM patients. The frequencies of both in PBMC populations correlated with those in BMMNCs irrespective of low BMMNC numbers. We then assessed the adjunctive effect of stimulating NKT cells with CD1d and α-GalCer complexes on the NK cells. The expression of NKG2D on CD56dimCD16+ NK cells and DNAM-1 on CD56brightCD16- NK cells increased after NKT cell activation. Apparently, NK cell-mediated anti-tumor effects were dependent on NKG2D and DNAM-1 ligands on myeloma cells. Thus, NK cell function in patients could be ameliorated, beyond the effect of immunosuppression, by NKT cell activation. This NKT-driven NK cell therapy could represent a potential new treatment modality.


Subject(s)
Killer Cells, Natural/immunology , Multiple Myeloma/immunology , Natural Killer T-Cells/immunology , Receptors, Antigen, T-Cell/immunology , Adult , Aged , Aged, 80 and over , Antigens, CD1d/pharmacology , Antigens, Differentiation, T-Lymphocyte/drug effects , Antigens, Differentiation, T-Lymphocyte/metabolism , Antineoplastic Agents/therapeutic use , Female , Galactosylceramides/pharmacology , Glucocorticoids/therapeutic use , Humans , Killer Cells, Natural/drug effects , Lymphocyte Activation , Male , Middle Aged , Multiple Myeloma/drug therapy , NK Cell Lectin-Like Receptor Subfamily K/drug effects , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Natural Killer T-Cells/drug effects
3.
Cancer Immunol Immunother ; 62(4): 747-60, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23242316

ABSTRACT

Despite the well-established antitumor activity of CD1d-restricted invariant natural killer T lymphocytes (iNKT), their use for cancer therapy has remained challenging. This appears to be due to their strong but short-lived activation followed by long-term anergy after a single administration of the CD1d agonist ligand alpha-galactosylceramide (αGC). As a promising alternative, we obtained sustained mouse iNKT cell responses associated with prolonged antitumor effects through repeated administrations of tumor-targeted recombinant sCD1d-antitumor scFv fusion proteins loaded with αGC. Here, we demonstrate that CD1d fusion proteins bound to tumor cells via the antibody fragment specific for a tumor-associated antigen, efficiently activate human iNKT cell lines leading to potent tumor cell lysis. The importance of CD1d tumor targeting was confirmed in tumor-bearing mice in which only the specific tumor-targeted CD1d fusion protein resulted in tumor inhibition of well-established aggressive tumor grafts. The therapeutic efficacy correlated with the repeated activation of iNKT and natural killer cells marked by their release of TH1 cytokines, despite the up-regulation of the co-inhibitory receptor PD-1. Our results demonstrate the superiority of providing the superagonist αGC loaded on recombinant CD1d proteins and support the use of αGC/sCD1d-antitumor fusion proteins to secure a sustained human and mouse iNKT cell activation, while targeting their cytotoxic activity and cytokine release to the tumor site.


Subject(s)
Antigens, CD1d/pharmacology , Immunoglobulin Fragments/pharmacology , Immunotherapy, Adoptive/methods , Natural Killer T-Cells/drug effects , Natural Killer T-Cells/immunology , Recombinant Fusion Proteins/pharmacology , Animals , Antigens, CD1d/immunology , Cell Line, Tumor , Female , Galactosylceramides/immunology , Humans , Immunoglobulin Fragments/immunology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Mice , Mice, Inbred C57BL , Recombinant Fusion Proteins/immunology
4.
Int J Mol Med ; 24(4): 481-6, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19724888

ABSTRACT

CD1d molecules on the cell surface play a critical role in the presentation of glycolipid antigens to natural killer T (NKT) cells. We previously showed that the human CD1d gene has 8 splice variants, one of which is a soluble form lacking the beta2-m and transmembrane domains. This study focused on soluble CD1d (sCD1d) by generating recombinant sCD1d proteins and assaying them in plasma using a newly established ELISA method. The amount of sCD1d proteins in plasma was significantly decreased in rheumatoid arthritis (RA) patients (55.2+/-13.3 years, mean +/-SD) compared with healthy donors (31.2+/-7.4 years). Plasma sCD1d protein levels correlated with the number of NKT cells (TCR V alpha 24+ V beta 11+CD3+) in peripheral blood mononuclear cells (r(2)=0.061). Furthermore, sCD1d proteins induced IFN-gamma production from NKT cells, but neither IL-4 nor IL-10. These findings suggest that the low plasma levels of sCD1d protein in RA patients reduce the number and thus activation of peripheral NKT cells. It is therefore hypothesized that sCD1d stimulates NKT cells and low plasma sCD1d levels in RA reflect a pathogenic mechanism associated with a decrease in NKT cells.


Subject(s)
Antigens, CD1d/blood , Antigens, CD1d/pharmacology , Antigens, CD1d/physiology , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/metabolism , Natural Killer T-Cells/immunology , Natural Killer T-Cells/metabolism , Adult , Aged , Antigens, CD1d/genetics , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , Immunoblotting , Immunoprecipitation , Interferon-gamma/metabolism , Interleukin-10/metabolism , Interleukin-4/metabolism , Male , Middle Aged , Natural Killer T-Cells/drug effects , Young Adult
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