LY3200882

While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy.

P1, N=223, Active, not recruiting, Eli Lilly and Company | Trial completion date: Aug 2024 --> Aug 2025

P1, N=223, Active, not recruiting, Eli Lilly and Company | Trial completion date: Aug 2023 --> Aug 2024

We demonstrated that pretreatment with a TGFβR1 inhibitor (LY3200882) significantly augmented the efficacy of CAR-T therapy and improved overall survival of mice bearing large established tumors...Based on these results, we next evaluated TGFβ-resistant CAR-T cells in vivo and demonstrated that blocking TGFβ-signaling through TGFβR2 knockout augmented the efficacy of CAR-T cells in a large immunosuppressive GBM tumor model in syngeneic mice. Conclusions Collectively, our results indicate that inhibiting the TGFβ pathway either in TME or CAR T cells is essential for enhancing CAR-T cell efficacy in GBM.

LY3200882 (LY), a selective transforming growth factor-β (TGF-β) inhibitor, is encapsulated in the ROS-responsive nanogel and dispersed uniformly with regorafenib (REG) in a thermosensitive hydrogel (Gel/(REG+NG/LY)). LY contributed to preventing the epithelial-mesenchymal transition and immune escape of tumor cells induced by elevated TGF-?. In subcutaneous and orthotopic colorectal tumor-bearing mouse models, Gel/(REG+NG/LY) effectively inhibited tumor growth and liver metastasis by increasing the tumor infiltration of CD8 T cells, reducing the recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, and promoting the polarization of macrophages from M2 to M1 type, indicating the significant potential in improving the prognosis of advanced cancer patients.

Notably, the synergistic effect of LY and siPD-L1 remarkably enhanced the tumor antigen presentation and immunosuppressive microenvironment remodeling, thus efficiently inhibiting the TNBC growth, metastasis, and recurrence. Therefore, the programmed site-specific delivery nanosystem is a promising drug delivery platform for boosting anti-tumor immunotherapy efficacy for TNBC.

These data shed new light on the role of TGFβ in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFβR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.