rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors.

Background: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8 ⁺ T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1 ⁺ CD8 ⁺ T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rβ) ^high CD8 ⁺ T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8 ⁺ cells within the tumor and the tumor-draining lymph nodes (tdLN).
Methods: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-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 tumors and tdLNs by flow cytometry.
Results: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8 ⁺ T cells, and a decreased frequency of CD39 ^high TIM-3 ⁺ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L ⁺ Ly108 ⁺ early progenitor population of exhausted CD8 ⁺ T cells (T _PEX ), which may retain long-term proliferation capacity and replenish functional effector CD8 ⁺ T cells. hIL-2/TCB2c induces differentiation of CD62L ⁺ Ly108 ⁺ T _PEX rapidly into CD101 ⁺ terminally differentiated subsets (terminally exhausted T cell (T _{EX term} )). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of T _PEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors.
Conclusions: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8 ⁺ T cells, whereas hIL-2/TCB2c promotes their differentiation into T _{EX term} . Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.
Competing Interests: Competing interests: ML, S-KI, SB, MJ, MK, EJL, STJ, SF-M, AW and DC are currently employed by NeoImmuneTech. J-YL and DK work for Selecxine.
(© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)