The FDA granted an orphan drug designation to PLT012 (Pilatus Biosciences) for the treatment of patients with liver and intrahepatic bile duct cancer (HCC/ICCA). According to experts, the agent has shown potential against multiple tumors that have unmet needs and is set to advance to its first US investigational new drug application submission as well as first patient dosing in 2025.1
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Initially, primary liver cancer occurs in either the liver or the intrahepatic bile ducts. The 2 most common types of liver and intrahepatic bile duct cancer are HCC, which consists of approximately 80% to 90% of cases, and intrahepatic cholangiocarcinoma (ICCA), which consists of about 10% to 15% of cases. Metabolic reprogramming plays a significant role in the promotion of tumor progression, by modifying the tumor microenvironment (TME) to support HCC/ICCA tumor growth and immune evasion.1
Further the most common first-line systemic therapies for HCC include a combination of a PD-L1 inhibitor and a VEGF inhibitor, or a combination of a PD-L1 inhibitor and a CTLA-4 inhibitor. Multiple lines of treatment will be required for most patients because the recurrence rate of has previously been reported to be as high as 88%. For second-line treatments, options mostly consist of multiple tyrosine kinase receptor inhibitors, with the incidence of a second HCC recurrence being approximately 50%-70%. If the patient is able to tolerate a second-line therapy with a different mechanism of action than those previously received, additional lines of treatment may be administered.1
PLT012 is a humanized anti-CD36 antibody that disarms immunosuppressive cell populations while simultaneously amplifying effector T cell functions. It has shown potential against multiple tumors with unmet medical needs. As a monotherapy, PLT012 has demonstrated anti-tumor efficacy in multiple immune tumor models with a significant augmentation in GzmB-expressing CD8+ T cells and reductions in both intratumoral Tregs and pro-tumorigenic macrophage.1,2
“PLT012 leverages metabolic checkpoint targeting to reprogram the TME, offering a unique therapeutic approach. This designation highlights the promising scientific discoveries and results we have achieved in addressing the underserved area. It further motivates us to…bring this promising treatment to patients with limited options,” Ping-Chih Ho, PhD, chair of the Scientific Advisory Board and co-founder of Pilatus Biosciences, said in a news release.1
In a study, PLT012 demonstrated its ability to block CD36-mediated metabolic alterations in Tregs and CD8+ tumor-infiltrating lymphocytes. For this study, investigators evaluated assessed the efficacy of PLT012 in liver metastases. This was evaluated using a concurrent MC38 liver metastasis murine model, and the mechanism of action was further confirmed using human liver metastasis samples on an ex vivo culture platform.2
Results of the in silico analysis in one of the cohorts to assess PLT012’s mechanism of action revealed that liver metastases exhibit similar TME features as HCC, including elevated fatty acid signatures, increased Treg percentages, and a decreased CD8+ cell infiltration, regardless of the primary tumor type. Administering PLT-12 in an MC38 syngeneic mouse model with liver metastasis had significantly reduced tumor growth in both liver metastases and subcutaneous tumors. According to the investigators, this was alongside a decreased M2 macrophage population, reduced Treg population, and increased CD8+ T cell population, which was consistent with other ex vivo observations of PLT012 in human liver metastatic samples.2
Further, the authors emphasized that PLT012 further reduced liver metastasis-dependent ICI resistance while resensitizing subcutaneous tumors to anti-PD1 treatment. These findings support the potential of using immunometabolic targeting in cancer immunotherapy, noted the investigators.2
"We are honored to receive [an] orphan drug designation for PLT012, a milestone that reflects our dedication to addressing the urgent need for innovative therapies in HCC/ICCA," said Raven Lin, PhD, MBA, CEO and co-founder of Pilatus Biosciences, in the news release.1
REFERENCES
1. PR Newswire. Pilatus Biosciences Inc. secures FDA orphan drug designation for PLT012: a breakthrough in liver and intrahepatic bile duct cancer treatment. News release. December 10, 2024. Accessed December 11, 2024. https://www.prnewswire.com/news-releases/pilatus-biosciences-inc-secures-fda-orphan-drug-designation-for-plt012-a-breakthrough-in-liver-and-intrahepatic-bile-duct-cancer-treatment-302328383.html
2. Yu YR, Tzeng SF, Hsiao HW, Lin YH, Tsai CH, Ho PC. 1346 PLT012: a first-in-class antibody targeting CD36, revolutionizing immunotherapy by unleashing anti-tumor immunity through metabolic reprogramming in the tumor microenvironment. JITC. 12(Suppl 2):A1503-A1503. doi:10.1136/jitc-2024-SITC2024.1346