Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models. (2nd January 2018)

• Record Type: Journal Article
• Authors: Lewis, Katherine E.; Selby, Mark J.; Masters, Gregg; Valle, Jose; Dito, Gennaro; Curtis, Wendy R.; Garcia, Richard; Mink, Kathy A.; Waggie, Kimberly S.; Holdren, Matthew S.; Grosso, Joseph F.; Korman, Alan J.; Jure-Kunkel, Maria; Dillon, Stacey R.
• Is Part Of: Oncoimmunology. Volume 7:Number 1(2018)
• Publication Date: 2018-01-02
• Subjects: interleukin 21 -- IL-21 -- PD-1 -- CTLA-4 -- MC38 -- CT26 -- EMT-6 -- B16-F10 -- mouse tumor models; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2017.1377873
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Recent advances in cancer treatment with checkpoint blockade of receptors such as CTLA-4 and PD-1 have demonstrated that combinations of agents with complementary immunomodulatory effects have the potential to enhance antitumor activity as compared to single agents. We investigated the efficacy of immune-modulatory interleukin-21 (IL-21) combined with checkpoint blockade in several syngeneic mouse tumor models. After tumor establishment, mice were administered recombinant mouse IL-21 (mIL-21) alone or in combination with blocking monoclonal antibodies against mouse PD-1 or CTLA-4. In contrast to monotherapy, IL-21 enhanced antitumor activity of mCTLA-4 mAb in four models and anti-PD-1 mAb in two models, with evidence of synergy for one or both of the combination treatments in the EMT-6 and MC38 models. The enhanced efficacy was associated with increased intratumoral CD8+ T cell infiltrates, CD8+ T cell proliferation, and increased effector memory T cells, along with decreased frequency of central memory CD8+ T cells. In vivo depletion of CD8+ T cells abolished the antitumor activities observed for both combination and monotherapy treatments, further supporting a beneficial role for CD8+ T cells. In all studies, the combination therapies were well tolerated. These results support the hypothesis that the combination of recombinant human IL-21 with CTLA-4 or PD-1 monoclonal antibodies could lead to improved outcomes in cancer patients.