Targeting GARP–TGF-β1 with livmoniplimab plus anti–PD-1 budigalimab to remodel the immunosuppressive tumor microenvironment.
Authors: Durga B. Dandamudi, Marion Refici, Myles Dillon, Ryan Duggan, Kevin Kolahi, Claire Sutherland, Catherine Tribouley, Tamar Uziel, Jack S.H. Chen
Journal: Journal of Clinical Oncology (2024)

2594 Background: Transforming growth factor (TGF)-β signaling has been shown to induce an immunosuppressive tumor microenvironment (TME) and promote tumor progression. Targeting key immune cells involved in this mechanism, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, by altering their function/depleting them is an important strategy in cancer therapeutics. Glycoprotein A repetitions predominant (GARP) is a membrane-bound receptor that complexes with latent TGF-β1 and plays a vital role in the immunosuppressive function of Tregs (1). In addition to Tregs, GARP–TGF-β1 is also expressed on other cells such as macrophages and tumor cells (2). Data from mouse models demonstrated that combined targeting of GARP–TGF-β1 and PD-1 improved antitumor effects compared with anti–PD-1 alone (3). Livmoniplimab (livmo), a first-in-class mAb, targets and stabilizes the GARP–TGF-β1 complex, sequestering TGF-β in its inactive form. Livmo is in clinical trials in combination with the anti–PD-1 mAb budigalimab (budi) (NCT03821935, NCT05822752). Methods: Recently, fresh human tumor-derived tissue culture platforms, which retain autologous TME and immune cell content, have emerged as powerful tools to address the gap between clinical data and preclinical models. To better understand the MOA of livmo + budi, we procured fresh tumors from patients (pts) undergoing surgical resection, minced and cultured them for 48h in the presence of livmo ± budi. The functional activity of livmo and budi was determined by assessing tumor cell viability, T-cell effector function, and modulation of immune-suppressive cells. Results: In tumor explant models from 10 pt samples from various indications (NSCLC: n=2; stomach cancer: n=3; HNSCC: n=2; pancreatic cancer: n=1; bladder cancer: n=1; RCC: n=1), treatment with livmo alone led to reduction of tumor cell viability, increase in T-cell effector function, and decrease in immune-suppressive myeloid cells. This effect was further enhanced in combination with budi. Specifically, within the immune cell components, livmo + budi treatment led to no change in the number of Tregs but a 40% reduction in MDSCs and macrophages, both of which depend on TGF-β1 for sustenance and survival. Furthermore, this decrease corresponded with a 50% increase in secretion of granzyme B/IFNγ antitumor T-cell effector functions. Conclusions: These data demonstrate that livmo induces decrease in tumor cell viability, increased antitumor immune cell activation, and remodeling of the immune-suppressive TME, which is further enhanced in combination with budi. These results support the hypothesis that pts would benefit from therapeutic intervention with livmo + budi. 1. Stockis et al. Mol Biosyst 2017;13:1925-35. 2. Zimmer et al. Front Immunol 2022;13:928450. 3. de Streel et al. Nat Commun 2020;11:4545.