Safe eradication of large established tumors using neovasculature-targeted tumor necrosis factor-based therapies

Area of Science:

• Oncology
• Immunotherapy
• Biotechnology

Background:

• Systemic toxicities of tumor necrosis factor (TNF) limit its use as an anticancer agent.
• Activity-on-Target cytokines (AcTakines) are engineered immunocytokines designed for improved therapeutic index.
• Targeting specific tumor markers is often required for localized cytokine therapy.

Purpose of the Study:

• To develop a novel TNF-based AcTakine for selective tumor neovasculature activation.
• To evaluate the efficacy and safety of CD13-targeted AcTakines in preclinical cancer models.
• To explore combination therapies involving AcTakines for enhanced tumor elimination.

Main Methods:

• Development of a TNF-based AcTakine engineered to target the CD13 antigen.
• In vivo administration of AcTakines in tumor-bearing animal models.
• Assessment of tumor neovasculature activation, immune cell infiltration, and tumor regression.
• Evaluation of systemic toxicity and therapeutic index.

Main Results:

• A TNF-AcTakine targeted to CD13 selectively activated tumor neovasculature with no detectable in vivo toxicity.
• Upregulation of adhesion markers facilitated enhanced T-cell infiltration.
• CAR T cells and combination therapy with a CD8-targeted type I interferon AcTakine controlled or eliminated solid tumors.
• Co-treatment with a CD13-targeted type II interferon AcTakine rapidly destroyed tumor neovasculature, leading to complete regression of large tumors.

Conclusions:

• CD13-targeted AcTakines represent a safe and effective strategy for cancer therapy.
• This approach enables broad-spectrum tumor elimination without the need for specific tumor markers.
• AcTakine-based therapies hold promise for overcoming limitations of traditional cytokine-based treatments.