Experimental Mesothelioma Therapy May Boost Tumor Immune Surveillance

Experimental Mesothelioma Therapy May Boost Tumor Immune Surveillance

ADI-PEG 20, a drug that depletes arginine from the body, is under clinical trials for a number of cancers, including mesothelioma, due to its strong anti-cancer activity. But a new study suggests that ADI-PEG 20 also can boost tumor immune surveillance, suggesting that the therapy may reach its full potential when combined with immunotherapy agents.

The findings were presented recently by Polaris, the drug’s manufacturer, at the 2016 American Association for Cancer Research Tumor Immunology and Immunotherapy conference, held Oct. 20-23 in Boston.

Cancer cells often carry a metabolic defect that renders them unable to synthesize arginine. But because arginine is essential to synthesize proteins and for cell survival, these cells become highly dependent on external sources of this aminoacid.

ADI-PEG 20 is an arginine deaminase developed to deplete the extra source of arginine supply, causing the cancer cells to die without affecting the healthy cells.

Several cancers have been reported to have a high degree of arginine dependency, and potentially can be treated with ADI-PEG 20. The drug already has been tested in more than 20 clinical trials globally for a number of cancers, including pancreatic cancer, mesothelioma, hepatocellular carcinoma, non-small cell lung cancer, melanoma and acute myeloid leukemia.

Based on positive data from those clinical trials, the U.S. Food and Drug Administration and European Medicines Agency already have granted orphan drug designation to ADI-PEG 20 for the treatment of mesothelioma and hepatocellular carcinoma.

Now, to investigate the potential of ADI-PEG 20 on immune cells, researchers have treated healthy immune cells with ADI-PEG 20 under resting and activation conditions. Results have shown that under activation conditions ADI-PEG 20 treatments can boost T-cell activation, while moderating T-cell exhaustion.

In addition, ADI-PEG 20 treatment reduced the number of regulatory T-cells, which are immune cells that suppress the function of tumor-killing cells.

The effect of ADI-PEG 20 on the immune system was tested subsequently in vivo in a melanoma mouse model that is poorly immunogenic (has low levels of infiltrating immune cells in the tumor). Analysis of the tumor of ADI-PEG 20-treated mice revealed that the drug enhanced immune cell infiltration in five out of six mice.

The findings thus suggest that ADI-PEG 20 can improve tumor immunogenicity and work in cooperation with immunotherapies, such as immune checkpoint inhibitors, to inhibit tumor growth.

“We are excited about the discovery of ADI-PEG 20’s ability to regulate cellular immune response, thereby expanding its mechanism of action for its anti-tumor activity. We are conducting further research to assess which combinations of ADI-PEG 20 with PD1/PD-L1 blockers will further enhance these drugs’ anti-tumor efficacy,” John Bomalaski, MD, executive vice president of Medical Affairs at Polaris Pharmaceuticals, said in a press release.


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