AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models
| Autor: | Abi Vainstein, Arik A. Zur, Ella Sorani, Giles F. Whalen, Jenny Middleton, Chris Pickford, Melanie S. Glossop, Robert Old, Oliver Schulz, Sascha A. Kristian, Irit Carmi-Levy, Amber Charlemagne, Mike Westby, Rinat Tabakman, Kim Wigglesworth, Stephen M. Shaw |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
medicine.medical_treatment T cell Abscopal effect lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Immune system Antigen Cancer immunotherapy Checkpoint inhibition Cancer vaccine Genetics medicine lcsh:QH573-671 Antigen-presenting cell Melanoma 030304 developmental biology 0303 health sciences biology alpha-Gal lcsh:Cytology Chemistry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Tumor antigen Complement-dependent cytotoxicity anti-Gal medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis AGI-134 Cancer research biology.protein anti-PD-1 Immunotherapy Antibody Primary Research Intratumoral injection |
| Zdroj: | Cancer Cell International, Vol 19, Iss 1, Pp 1-19 (2019) Cancer Cell International |
| ISSN: | 1475-2867 |
| Popis: | BackgroundTreatments that generate T cell-mediated immunity to a patient’s unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galα1-3Galβ1-4GlcNAc (α-Gal) in situ leading to opsonization with pre-existing natural anti-α-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity.MethodsVarious immunological effects of coating tumor cells with α-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI-134 mediated complement dependent cytotoxicity (CDC) in cancer cells. The anti-tumoral activity of AGI-134 alone or in combination with an anti-programmed death-1 (anti-PD-1) antibody was tested in melanoma models in anti-Gal expressing galactosyltransferase knockout (α1,3GT−/−) mice. CDC and phagocytosis data were analyzed by one-way ANOVA, ADCC results by paired t-test, distal tumor growth by Mantel–Cox test, C5a data by Mann–Whitney test, and single tumor regression by repeated measures analysis.ResultsIn vitro, α-Gal labelling of tumor cells via AGI-134 incorporation into the cell membrane leads to anti-Gal binding and complement activation. Through the effects of complement and ADCC, tumor cells are lysed and tumor antigen uptake by APCs increased. Antigen associated with lysed cells is cross-presented by CD8α+ dendritic cells leading to activation of antigen-specific CD8+ T cells. In B16-F10 or JB/RH melanoma models in α1,3GT−/−mice, intratumoral AGI-134 administration leads to primary tumor regression and has a robust abscopal effect, i.e., it protects from the development of distal, uninjected lesions. Combinations of AGI-134 and anti-PD-1 antibody shows a synergistic benefit in protection from secondary tumor growth.ConclusionsWe have identified AGI-134 as an immunotherapeutic drug candidate, which could be an excellent combination partner for anti-PD-1 therapy, by facilitating tumor antigen processing and increasing the repertoire of tumor-specific T cells prior to anti-PD-1 treatment. |
| Databáze: | OpenAIRE |
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