Interleukin-21 combined with PD-1 or CTLA-4 blockade enhances antitumor immunity in mouse tumor models

Katherine E Lewis ¹, Mark J Selby ², Gregg Masters ³, Jose Valle ², Gennaro Dito ³, Wendy R Curtis ¹, Richard Garcia ¹, Kathy A Mink ¹, Kimberly S Waggie ¹, Matthew S Holdren ⁴, Joseph F Grosso ⁵, Alan J Korman ², Maria Jure-Kunkel ³, Stacey R Dillon ¹

Affiliations

¹ Oncology Discovery Research, Bristol-Myers Squibb, Seattle, WA.
² Oncology Discovery Research, Bristol-Myers Squibb, Redwood City, CA.
³ Oncology Translational Research, Bristol-Myers Squibb, Princeton, NJ.
⁴ Drug Safety Evaluation, Bristol-Myers Squibb, Mt. Vernon, IN.
⁵ Early Clinical Development, Bristol-Myers Squibb, Princeton, NJ.

PMID: 29296539
47 References
21 citations

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.

Keywords: B16-F10; CT26; CTLA-4; EMT-6; IL-21; MC38; PD-1; interleukin 21; mouse tumor models.

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