A remarkable progress of cancer immunotherapy in a recent decade, including immune checkpoint blockades (ICB), has shed a new light on the medical treatment of cancer patients. These successes of immunotherapies affirm the notion that modulation of immune-related environment, although not directly targeting a tumor cell, might lead to a better efficacy for cancer treatment. Interleukine-7 (IL-7), a member of the common γ chain family cytokine, plays important roles in the development and homeostasis of lymphocytes in both mouse and human, in particular T lymphocytes. Positive effects of recombinant IL-7 on anti-tumor activity in preclinical models have placed IL-7 as a strong candidate for a novel immunotherapeutic agent in clinics; however, a short half-life of recombinant protein has remained a challenge. Here, we investigated anti-tumor effects in mice of the long-acting form of recombinant human IL-7 fused with hybrid Fc (IL-7-hyFc) in syngeneic tumor models. A dramatic inhibition of tumor growth was achieved when IL-7-hyFc is given in a single subcutaneous injection with palpable tumor burdens. IL-7-hyFc administration significantly enhanced the expression level of CXCR3 on T cells and the frequency of CD8+ tumor-infiltrating lymphocytes (TILs). Of interest, the fraction of PD-1+CD8+ TILs was decreased by IL-7-hyFc, with the cell surface level of PD-1 being diminished. Therefore, IL-7-hyFc is able to expand tumor antigen specific CD8+ effector T cells, resulting in the enhanced infiltration and functional recuperation of TILs. Nonetheless, the tumor growth inhibition by IL-7-hyFc was not observed in mice with large tumor burdens. To increase the therapeutic efficacy of IL-7-hyFc in this model, we combined single injection of the conventional chemotherapeutics cyclophosphamide (CTX) with a moderate dose in which CTX confers immunogenic tumor cell death without severely depleting immune compartment. The combinatorial treatment with IL-7-hyFc and CTX augmented the infiltration of CD8+ TILs, leading to an increased survival in a large established tumor model. In sum, IL-7-hyFc confers the effective anti-tumor responses through reconstructing CD8+ T lymphocytes; this activity was limited when the tumor burden was high but restored along with combination with the chemotherapeutics. Thus, these results imply that IL-7-hyFc can be applied to various cancer immunotherapy regimens as monotherapy or a combination partner with conventional and other immunotherapy, like ICB.
Citation Format: Ji-Hae Kim, Donghoon Choi, Man Kyu Ji, Seat-byeul Jo, Han Wook Park, Yeon Kyung Oh, Youngmin Kim, Hyekang Kim, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Seung-Woo Lee. Preclinical evaluation of the anti-tumor activity of Fc-fused interleukin-7 in both monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1731.