816 NT-I7 and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that favors anti-tumor efficacy in combination with checkpoint inhibitors

• Published in: Journal for immunotherapy of cancer 2023-11, Vol.11 (Suppl 1), p.A914-A914
• Main Authors: Lee, Minji, Ferrando-Martinez, Sara, Im, Sun-Kyoung, Baek, Seungtae, Ji, Mankyu, Kim, Miyoung, Lee, Eunju, Ji, Seung Taek, Kim, Daeun, Lee, Jun-Young, Choi, Donghoon
• Format: Article
• Language: English
• Subjects: Cytokines; Immunotherapy; Lymphatic system; Lymphocytes; Regular and Young Investigator Award Abstracts; Tumors
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.0816

BackgroundNT-I7 (efineptakin alfa; rhIL-7-hyFc) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. NT-I7 promotes extensive infiltration of CD8+ T cells to the tumor, concurrently increasing absolute numbers of PD-1+ CD8+ T cells in mice.1 2 Moreover, it expands central memory CD8+ T cells in tumors and tumor-draining lymph nodes. The hIL-2/TCB2 complex inhibits tumor growth by preferential activation of CD122 (IL-2Rβ)high CD8+ T cells and NK cells, without stimulating Treg. Both cytokines belong to the common gamma-chain cytokine family and induce antitumor effects. We investigated the synergistic antitumor efficacy and mechanisms of NT-I7 in combination with hIL-2/TCB2c, with or without PD-1 inhibitor.MethodsMC38 and/or CT26 tumor-bearing mice were administered a single dose of 10 mg/kg NT-I7 intramuscularly (IM) and 0.9 mg/kg hIL-2/TCB2c intravenously (IV). Anti-PD-1 monoclonal antibody was administered intraperitoneally three times with three-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumor and tumor-draining lymph nodes (TDLN) by flow cytometry.ResultsOur data demonstrated that the combination of NT-I7 and hIL-2/TCB2c synergistically inhibits tumor growth and generates an immune-stimulatory tumor microenvironment (TME). This TME was characterized by an increased infiltration of tumor-specific CD8+ T cells, and a decreased frequency of CD11b+ MDSCs and CD39high TIM-3+ Treg cells, known to be highly immunosuppressive. Most importantly, NT-I7 increased infiltration of CD62L+Ly108+ early progenitor population of exhausted CD8+ T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+ T cells. IL-2/TCB2c treatment induces differentiation of CD62L+Ly108+ TPEX rapidly into CD101+ terminally differentiated subsets. Remarkably, our study demonstrated that NT-I7 significantly enhances the proliferation rate of CD8+ TPEX as well as memory T cells in the tumor-draining lymph nodes (TDLNs), positively correlated with the abundance of TPEX within the tumor. These findings strongly suggest that the expansion of TPEX, following NT-I7 administration, originates from the TDLNs. Moreover, the addition of PD-1 blockade further enhances the therapeutic efficacy of NT-I7 plus hIL-2/TCB2c, leading to complete regression of tumors.ConclusionsNT-I7 drama