Targeting PD-1⁺ T cells with small-format immunocytokines enhances IL-12 antitumor activity

Area of Science:

• Immunology
• Cancer Therapeutics
• Biotechnology

Background:

• Immunostimulatory cytokines and immune checkpoint inhibitors are promising cancer therapies.
• Their clinical use is often limited by toxicity and reduced efficacy.

Purpose of the Study:

• To develop small-format immunocytokines (ICKs) by fusing interleukin-12 (IL-12) with nanobodies (Nbs) targeting PD-1 and PD-L1.
• To evaluate the in vitro and in vivo efficacy of these ICKs for cancer treatment.

Main Methods:

• Engineered ICKs incorporating IL-12 and anti-PD-1 or anti-PD-L1 nanobodies.
• Assessed in vitro immune cell tethering and T cell activity.
• Evaluated antitumor efficacy via intratumoral delivery of RNA vectors or recombinant proteins in mouse models.

Main Results:

• PD-1 and PD-L1 targeted ICKs enhanced IL-12 tethering and T cell activity in vitro.
• Intratumoral delivery of anti-PD-1 ICKs significantly boosted IL-12 mediated antitumor efficacy.
• Targeting intratumoral T cells via anti-PD-1 was more effective than PD-L1 tumor anchoring.

Conclusions:

• Targeting specific immune cells within the tumor microenvironment is crucial for effective IL-12 therapy.
• Anti-PD-1 immunocytokines show potential for enhanced cancer treatment.
• Developed human ICKs are active in human immune cells, suggesting clinical translation potential.