CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses

• Published in: Cancer Immunology, Immunotherapy Vol. 62; no. 4; pp. 747 - 760
• Main Authors: Corgnac, Stéphanie, Perret, Rachel, Derré, Laurent, Zhang, Lianjun, Stirnemann, Kathrin, Zauderer, Maurice, Speiser, Daniel E., Mach, Jean-Pierre, Romero, Pedro, Donda, Alena
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.04.2013; Springer Nature B.V
• Subjects: Animals; Antibodies; Antigens; Antigens, CD1d - immunology; Antigens, CD1d - pharmacology; Cancer; Cancer Research; Cell Line, Tumor; Cells; Cloning; Cytokines; Female; Galactosylceramides - immunology; Humans; Immunoglobulin Fragments - immunology; Immunoglobulin Fragments - pharmacology; Immunology; Immunotherapy; Immunotherapy, Adoptive - methods; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Ligands; Lymphocytes; Medical research; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - immunology; Oncology; Original; Original Article; Proteins; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacology; Switzerland; CD1d; Cancer immunotherapy; Fusion protein; iNKT cells; Tumor targeting
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-012-1381-7

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.