TLY012

In summary, the combination of anti-PD-1 and TLY012 prevented the growth of PDAC in an immunocompetent mouse model while increasing tumor-infiltrating CD8+ T cells, decreasing circulating T-regulatory cells and altering plasma cytokine expression of CCL5, interferon-gamma, and IL-3 to promote proinflammatory, antitumor effects. Combining TLY012 and anti-mouse PD-1 modifies immune cell and cytokine levels to induce a more proinflammatory immune environment that contributes to decreased PDAC tumor growth.

We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications.

Taken together, the preclinical efficacy of ONC201 and TLY012 represents a novel therapeutic option for further testing in pancreatic cancer patients. This combination showed marked efficacy in tumor cells that are both sensitive and resistant to the pro-apoptotic effects of ONC201, providing rationale to further investigate the combination of ONC201 plus TLY012 in patients with pancreatic cancer.