3:14 PM
Feb 14, 2018
 |  BC Extra  |  Preclinical News

TGFB inhibition could treat checkpoint inhibitor-resistant cancer

In two studies published in Nature, scientists uncovered the role of transforming growth factor (TGF) beta in the tumor microenvironment, and suggested that blocking TGF beta could help treat cancers resistant to checkpoint inhibitor therapies.

In the first paper, researchers from the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY) evaluated treatment response to PD-L1 inhibitor Tecentriq atezolizumab in patients from the Phase II IMvigor210 trial to treat metastatic urothelial cancer. Non-responders had increased CD8+ T cell expression and fibroblast TGF beta signaling in the peritumoral stroma, which was associated with reduced overall survival (OS). The researchers identified this phenotype as an immune-excluded tumor microenvironment, in which T cells cannot penetrate the tumor but remain in the stroma.

Tecentriq is marketed by Genentech to treat locally advanced or metastatic urothelial cancer and non-small cell lung cancer (NSCLC).

In a mouse model exhibiting the patient immune-excluded tumor phenotype, combination therapy with an anti-TGF beta antibody and anti-PD-L1 therapy increased T cell penetration into tumors and decreased tumor growth compared with either treatment alone. The researchers found similar results in a mouse model of colon cancer.

In the second paper, researchers from the Institute for Research in Biomedicine and colleagues generated a mouse model of metastatic liver cancer derived from a colorectal cancer mouse model with high levels of stromal TGF beta signaling and T cell exclusion from tumors. Treatment with TGF beta receptor 1 (TGFBR1; ALK5) inhibitor galunisertib (LY2157299) plus an anti-PD-L1 antibody increased tumor T cell infiltration, decreased the number of metastases and increased survival compared with either treatment alone.

Galunisertib from Eli Lilly and Co. (NYSE:LLY) is in Phase Ib/II testing in combination with PD-1 inhibitor Opdivo nivolumab to treat advanced refractory solid tumors and recurrent or refractory NSCLC or hepatocellular carcinoma (HCC). Galunisertib is also in Phase Ib testing in combination with PD-L1 inhibitor Imfinzi durvalumab to treat recurrent or refractory metastatic pancreatic cancer.

Last year, Sanofi (Euronext:SAN; NYSE:SNY) said it is focusing on treating the 80% of cancer patients who do not respond to PD-1 or PD-L1 inhibitors and suggested that combination therapies could overcome therapeutic resistance. A Phase I trial is evaluating anti-TGF beta mAb SAR439459 in combination with anti-PD-1 mAb cemiplimab (REGN2810, SAR439684) to treat advanced solid tumors (see BioCentury Extra, Dec. 13, 2017).

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