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PLT012, a humanized CD36-blocking antibody, is effective for unleashing anti-tumor immunity against liver cancer and liver metastasis

ABSTRACT: Tumor cells develop various strategies to evade immune surveillance, one of which is the modulation of the metabolic state of the tumor microenvironment (TME). In response to metabolic stress in the TME, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired anti-tumor immunity, as intratumoral regulatory T cells (Tregs) exhibit increased survival and suppressive activity, while CD8+ T cells become more susceptible to ferroptosis and exhaustion. Here, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkey. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust anti-tumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCCs). Notably, PLT012 also reprograms immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 effectively reprograms anti-tumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36.

ORGANISM(S): Mus musculus

PROVIDER: GSE291964 | GEO | 2025/04/11

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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PLT012, a humanized CD36-blocking antibody, is effective for unleashing anti-tumor immunity against liver cancer and liver metastasis

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