Dual-Targeting Approach to Tumor Immunotherapy: Insights into M7824's Anti-PD-L1 and TGFβ Mechanisms

The M7824 (MSB0011359C) bifunctional fusion protein, which targets both the programmed death ligand 1 (PD-L1) and transforming growth factor β (TGFβ) pathways, has been developed to address tumor immune evasion. This novel agent is a human IgG1 monoclonal antibody against PD-L1, fused to the extracellular domain of the human TGFβ receptor II, designed to block both PD-L1 and TGFβ pathways concurrently.

In preclinical evaluations, M7824 showed significant antitumor efficacy across various syngeneic tumor models. It demonstrated superior antitumor effects when compared to anti-PD-L1 or TGFβ trap monotherapy in orthotopic and intramuscular models, and it also inhibited spontaneous metastases in certain models. M7824 was found to extend survival, provide long-term protective antitumor immunity, and induce unique activation of both adaptive and innate immune systems. This activation included increased tumor infiltration and cytotoxicity of CD8+ T cells, enhanced presence of antigen-specific CD8+ T cells in the spleen, and elevated tumor-infiltrated natural killer (NK) cells, among other immune responses.

Mechanistic studies indicated that the simultaneous activation of the adaptive and innate immune systems contributed to M7824's antitumor activity. Depletion of CD8+ T cells and NK cells significantly reduced M7824's tumor regression effects, whereas CD4+ T cells and antibody-dependent cellular cytotoxicity were less critical.

Toxicologic evaluation in cynomolgus monkeys showed that M7824 was well tolerated with only minor hematologic effects. Moreover, the antitumor activity of M7824 could be further enhanced when combined with radiotherapy or chemotherapy, resulting in more effective tumor growth inhibition and increased frequency of tumor antigen-specific IFN-γ-producing CD8+ T cells.

The preclinical data support the potential of M7824 to provide potent and synergistic antitumor effects through the dual blockade of PD-L1 and TGFβ pathways. Phase 1 clinical trials for M7824 in patients with solid tumors are currently underway.

The research was presented by Yan Lan and colleagues at the American Association for Cancer Research Annual Meeting in 2017.