Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity

Area of Science:

• Immunology
• Cancer Biology
• Biotechnology

Background:

• Programmed cell death protein 1 (PD-1) signaling limits T cell immunity, but anti-PD-1 therapy efficacy is restricted in advanced cancers.
• Anti-PD-1 therapy efficacy is dependent on Interleukin-2 (IL-2) signaling, suggesting IL-2 deficiency limits effector T cell expansion.

Purpose of the Study:

• To engineer a novel therapeutic agent that selectively delivers IL-2 to PD-1-expressing CD8+ tumor-infiltrating lymphocytes (TILs).
• To evaluate the efficacy and toxicity of the engineered agent compared to existing treatments.

Main Methods:

• Engineered a low-affinity IL-2 molecule paired with anti-PD-1 (PD-1-laIL-2) to enhance avidity to PD-1+CD8+ TILs while reducing affinity for peripheral regulatory T cells.
• Assessed tumor control and toxicity in preclinical models.
• Investigated the mechanistic effects of PD-1-laIL-2 on T cell expansion and function, particularly focusing on dysfunctional TILs.

Main Results:

• PD-1-laIL-2 demonstrated superior tumor control and reduced toxicity compared to single-agent or combined treatments.
• The therapy effectively expanded dysfunctional and tumor-specific CD8+ T cells.
• PD-1+TIM3+ TILs were identified as the dominant tumor-specific T cells responding to PD-1-laIL-2 therapy.

Conclusions:

• PD-1-laIL-2 represents a unique strategy to target and reactivate tumor-specific TILs, leading to tumor regression.
• This approach offers enhanced efficacy and lower toxicity for cancer immunotherapy.