Dissection of exhaustion trajectories of immune cells under tumor selection pressure in the tumor microenvironment (TME) elucidates the underlying machinery in anti‐tumor immunity, which still lacks easy‐to‐use models to decipher. Herein, gelatin methacryloyl (GelMA)–poly (ethylene oxide) (PEO) based 3D hydrogel microspheroids are constructed with non‐immunogenicity and controllable macroporous structure to establish a tumor‐immune cell coculture (3D‐HyGTIC) system. In 3D‐HyGTIC system, when immune cells embarked, stepwise up‐regulation of main immune checkpoints (ICs) molecules is observed with compromised cytokine production in CD8+ T cells, the trajectory of which is in lineage correlation with in vivo grafted tumors. Reinvigoration of CD8+ T cells is more obvious with the addition of an anti‐PD‐1 regimen at the early time point, which is recapitulated during the coculture of patient‐derived tumor fragments (PDTF) and autologous T cells. Moreover, the upregulation of LAG‐3 on CD8+ T cells after anti‐PD‐1 treatment is uncovered. Sequential addition of anti‐LAG‐3 successfully rescues the otherwise failed reactivation of CD8+ T cells. Therefore, the 3D‐HyGTIC system is not only inclined to mimic the early differentiation trajectories of tumor‐infiltrating CD8+ T cells but also may facilitate an evaluation of the efficacy of IC blockades and guide the designing of combination immunotherapy.
e14523 Background: Adenosine and TGF-β are two key immune suppressors in tumor microenvironment (TME) that cause broad immune suppression resulting in resistance to current CPI immunotherapies. Cancer cells, and other cell types within TME, frequently express TGFβ, which inhibits CD8+ T and Th1 cells and promotes epithelial–mesenchymal transition. We have designed a bi-specific targeting molecules blocking the two inhibitory pathways, aiming to create an immune-friendly TME. Methods: We have created a bifunctional antibody–ligand trap called ES014 that comprises an antibody targeting CD39 fused to a TGFβ receptor II ectodomain sequence. ES014 molecule could simultaneously disable CD39 to prevent extracellular ATP from degradation and neutralize autocrine/paracrine TGFβ in the vicinity of target cells. The immunological function of ES014 was studied in series of in vitro immuno-assays. The in vivo efficacy of ES014 was investigated in human PBMC engrafted models. The effects of ES014 on immune cells were also analyzed using malignant pleural effusions (MPE) collected from lung cancer patients. The pharmacokinetics (PK), pharmacodynamics (PD) and safety profile were assessed in cynomolgus monkeys after intravenous administration of ES014. Results: The bispecific antibody, ES014 exhibited synergistic effects in T cell activation and suppression of Treg differentiation. ES014 activates dendritic cells, macrophages and natural killer cells by maintaining extracellular ATP level and neutralizing the immune-suppressive effects of TGFβ. Interestingly, ES014 demonstrated a unique mechanism by protecting effector T cells from activation induced cell death (AICD), which was not observed with TGFβ receptor or anti-CD39 antibody alone, or the combination of the two. The ES014 molecule is effective in inhibiting tumor progression in a PD-1 antibody-unresponsive in vivo model. Treatment of ES014 in malignant pleural effusions (MPE) collected from lung cancer patients led to the switch of M2 to M1 macrophage as indicated by increased CD86 expression and decreased CD163 expression on CD11b+ cells. Importantly, more CD8+ T cells were maintained with ES014 treatment in MPE as compared to control, resulting in significant reduction of cancer number. ES014 was well tolerated in cynomolgus monkeys, and a phase I clinical study is ongoing to investigate the safety, tolerability, PK, PD and preliminary clinical activity of ES014 in patients with advanced solid tumors. Conclusions: ES014 is a first-in-class molecule that simultaneously targeting CD39 and TGFβ. ES014 counteracts TGFβ-mediated differentiation of Tregs and adenosine-induced immune tolerance, and protected effector T cells from AICD. Treatment of ES014 resulted in significant anti-tumor effects in ex vivo and in vivo efficacy models. A single agent activity of ES014 is therefore expected in clinical trials.
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