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- W2954656030 abstract "Background: ICOS is a member of the CD28 superfamily mainly expressed on activated T cells. An up-regulation of ICOS+ T cells is observed in patients treated with ipilimumab. These findings prompt further studies examining the synergy between CTLA-4 blockade and ICOS stimulation in generating optimal anti-tumor T cell immunity. Methods: Peripheral blood mononuclear cells (PBMC) were collected from French patients with metastatic melanoma and treated with ipilimumab at baseline (V1) and after 1-2 ipilimumab infusion and restimulated in vitro with anti-CD3 plus anti-human non-depleting agonist ICOS IgG4 isotype antibodies. T cell proliferation and cytokine secretion was determined after 24 and 48h incubation. For in vivo experiments, C57Bl/6 and BALB/c mice were inoculated subcutaneously with MC38 and CT26 tumor cell lines respectively. Mice received intraperitoneal injections of anti-CTLA4 or its isotype control along with anti-mouse ICOS or corresponding isotype at D7, D10 and D13 with tumor growth assessments three times a week. Results: PBMC collected from patients that respond to anti-CTLA-4 mAb exhibited stronger activation of T cells at baseline compared to patients with poor benefit. Treatment with a non-depleting agonist ICOS IgG4 mAb was able to rescue T cell activation in PBMC from patients with poor benefit. Furthermore, ICOS IgG4 with concurrent TCR engagement favored IL-10 secretion in patients that do not develop colitis during ipilimumab treatment suggesting that these patients may be protected from colitis due to a stronger capacity to secrete IL-10 after ipilimumab blockade particularly when ICOS is stimulated. In both mouse tumor models, combination with agonist non-depleting ICOS mAb increased the anti-CTLA-4 tumor activity without any colitis development. Conclusion: This study provides evidence in mice and in humans that non-depleting agonistic ICOS mAb may increase anti-CTLA-4 tumor activity particularly in patients that do not benefit from anti-CTLA-4 alone without exacerbation of colitis. Citation Format: Clelia Coutzac, Jean Jouniaux, Aurore Vozy, Marc Ballas, Sara Brett, Sapna Yadavilli, Eric Angevin, Axel Hoos, Nathalie Chaput. Agonistic T cell non depleting ICOS antibody strongly enhances anti-tumor activity with CTLA4 blocking monoclonal antibody without exacerbating colitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2268." @default.
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- W2954656030 date "2019-07-01" @default.
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- W2954656030 title "Abstract 2268: Agonistic T cell non depleting ICOS antibody strongly enhances anti-tumor activity with CTLA4 blocking monoclonal antibody without exacerbating colitis" @default.
- W2954656030 doi "https://doi.org/10.1158/1538-7445.sabcs18-2268" @default.
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