THE PROBLEM

Although immune checkpoint blockade (ICB) has emerged as promising cancer immunotherapy, many tumors fail to respond to ICB. This failed response is often driven by the activation of TGF-β1 in the tumor microenvironment (TME), which induces regulatory T cells and inhibits the function of effector CD8+ T cells to promote immune dysfunction. Due to the pleotropic, multifunctional nature of TGF-β1, has been a clinically challenging pathway to target as its systemic inhibition has numerous side effects, thus highlighting the need for new approaches that can inhibit TGF-β1 locally in the TME.

THE SOLUTION

Researchers at The Ohio State University, led by Dr. Zihai Li, have developed an antibody (PIIO-1) that binds to glycoprotein-A repetitions predominant (GARP) and inhibits the activation of GARP-bound latent TGFβ and downstream signaling. GARP is a cell surface, non-signaling, docking and activating receptor for latent TGFβ that is highly expressed in cancer cells and regulatory T cells. Blocking this signaling pathway has been shown to overcome tumor resistance to ICB via (i) a direct effect on tumor cells and (ii) modulation of the TME and increased immunosurveillance.

Treatment with the PIIO-1 antibody diminishes TGFβ signaling in the TME and significantly reduces metastasis. In models of breast cancer, they found that PIIO-1 therapy reduced lung metastases and presence of Treg cells, and augmented efficacy when combined with chemotherapy.

ADVANTAGES

• Improved efficacy of existing anti-cancer therapies: PIIO-1 improves response to PD-1 blockade in lung cancer models
• Promotes T cell function: PIIO-1 has single agent activity that is able to promote CD8+ T cell anti-cancer effector functions, as evidenced by reduction of exhausted T cells in the TME

APPLICATIONS

• Combination therapy with ICB for treatment of non-small cell lung cancer (NSCLC), bladder cancer, and triple negative breast cancer (TNBC)

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