On March 26, 2018 Polaris Group reported that its lead product ADI‑PEG 20 modulates PD-L1 expression via stimulating the release of IFN-α and -ß in several tumor cell lines and the combination of ADI‑PEG 20 and PD-1/PD-L1 blockade abrogated tumorigenesis in a murine model according to research presented by a group from Barts Cancer Institute, London at the 2018 Cancer Immunotherapy Keystone Symposia held in Montreal, Canada (Press release, Polaris Pharmaceuticals, MAR 26, 2018, View Source [SID1234526245]). These findings suggest that ADI‑PEG 20 could potentially enhance the anti-tumor activity of checkpoint inhibitors.

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Anti-PD1/anti-PD-L1 agents belong to a group of drugs called checkpoint inhibitors and work by disrupting the interaction between PD-1 on immune cells and PD-L1 on cancer cells, thereby unleashing the body’s own immune system to fight cancers. ADI‑PEG 20 converts the amino acid arginine in body’s circulation to citrulline and ammonia. Normal cells are able to synthesize arginine through the urea cycle. Certain cancer cells are deficient in argininosuccinate synthetase (ASS1), a key enzyme in the urea cycle, thereby rendered entirely dependent on arginine in the circulation for their survival and growth. These ASS1-deficient cancer cells are more sensitive to arginine depletion by ADI‑PEG 20.

In several mesothelioma and uveal melanoma cell lines, overexpression of ASS1 by transfection or prolonged treatment with ADI-PEG 20 was found to induce type I interferon genes and PD-L1 gene expression. In addition, the researchers also noted a statistically significant correlation between constitutive expressions of ASS1 and PD-L1 genes in primary mesothelioma and uveal melanoma tumor samples. Finally the combination of PD-1/PD-L1 blockade with ADI‑PEG 20 abrogated tumorigenesis in an immunocompetent ASS1 negative and PD-L1 negative fibrosarcoma murine model in which PD-1/PD-L1 inhibition alone had limited efficacy.

"The immunometabolic link between ADI‑PEG 20 and PD-1/PD-L1 is very intriguing," said John Bomalaski, M.D., Executive Vice President, Medical Affairs at Polaris Pharmaceuticals, Inc. "To explore this in the clinic, we are currently conducting a clinical study combining ADI‑PEG 20 with Pembrolizumab, a PD-1 inhibitor, in solid tumors to investigate the potential of combining ADI‑PEG 20 with checkpoint inhibitors."

About ADI‑PEG 20

ADI‑PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI‑PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI‑PEG 20.