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Roche scientists uncover cancer's resistance mechanism to PD-L1, PD-1 blockers

Roche Holding AG scientists have discovered a mechanism that cancer cells use to resist attack from body's immune cells, suggesting a way to make immuno-oncology drugs more effective.

The research found that TGF-ß, a protein known to suppress immune responses, helps certain tumors fortify themselves against the immune system's T cells.

The study, released at the ESMO Immuno Oncology Congress 2017, could spur more research to increase the efficacy of the class of cancer drugs targeting PD-L1 and PD-1 proteins, which enable cancer to elude T cells.

As of now, the PD-L1 and PD-1 inhibitors, such as Roche's Tecentriq, Merck & Co. Inc.'s Keytruda and Bristol-Myers Squibb Co.'s Opdivo, induce immune response only in a subset of patients.

The IMvigor210 biomarker study investigated tumor response to the anti-PD-L1 inhibitor Tecentriq in 300 patients with bladder cancer.

This study found two drivers of efficacy and one driver of resistance. In terms of efficacy, tumors with the highest number of mutations were the most responsive to immunotherapy. Tumors that had T cells present in the tumor microenvironment were also more responsive to immunotherapy.

Regarding resistance, tumors with high expression of the cytokine TGF-ß tended to be unresponsive to immunotherapy.

Nearly 50% of bladder cancers were what the scientists called T cell excluded tumors, meaning the cancer cells blocked entry of the T cells by building an outer layer.

The study's lead author, Sanjeev Mariathasan, said these tumors may secrete a factor that builds a velcro-like layer around the tumor where the T cells get stuck.

A link was found between the high expression of TGF-ß and the nonresponders, suggesting that the protein may be a factor behind the tumor's defense against T cells.

Researchers thereafter tested the theory in a mouse model with a similar kind of tumor resistance by treating it with a combination of anti-TGF-ß and anti-PD-L1 agents.

The study showed positive results — as TGF-ß activity was reduced, the T cell penetrated the tumor and it shrunk in size.

"The 'T cell excluded' phenotype is common in other cancers such as lung, pancreatic and colorectal, so this combination therapy could be tested in a wider group," said Mariathasan, also a senior scientist at Roche unit Genentech.

The TGF-ß blockade was also found to be synergistic with PD-1/PD-L1 inhibitors in another mouse model with breast cancer.

While drugs targeting TGF-ß have failed previously, the combination can be used for patients in whom TGF-ß is the dominant resistance mechanism, according to Ignacio Melero, a senior researcher at Centre for Applied Medical Research in Spain.

Researchers highlighted the need for a clinical trial evaluating a combination of PD-1/PD-L1 and TGF-ß blockers in bladder cancer patients with high TGF-ß signature.