A Folate Receptor β-Targeted TLR7 Agonist Significantly Augments Checkpoint Inhibitor Potencies by Reprogramming...

Area of Science:

• Immunology
• Oncology
• Drug Development

Background:

• Immune checkpoint inhibitors (ICIs) show promise for solid tumors.
• Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) can limit ICI efficacy.
• Targeting myeloid cells may overcome resistance to ICIs.

Purpose of the Study:

• To develop a targeted therapy to reprogram TAMs and MDSCs.
• To enhance the potency of ICIs by modulating the tumor microenvironment (TME).
• To assess the safety and efficacy of the novel therapeutic conjugate.

Main Methods:

• A folate-TLR7 conjugate was designed to target folate receptor β (FRβ)-expressing myeloid cells.
• The conjugate was administered to tumor models to assess its effect on myeloid cell repolarization and TME.
• The efficacy of the conjugate in combination with anti-PD-1 and anti-CTLA-4 antibodies was evaluated.
• Toxicity in healthy tissues was assessed.

Main Results:

• The folate-TLR7 conjugate successfully reprogrammed FRβ-expressing TAMs and MDSCs.
• Treatment induced a global shift in the TME towards an inflammatory state.
• Repolarization of myeloid cells significantly enhanced the efficacy of anti-PD-1 and anti-CTLA-4 inhibitors.
• No significant toxicity was observed in healthy tissues.

Conclusions:

• Reprogramming TAMs and MDSCs to a tumoricidal phenotype can augment ICI efficacy.
• The folate-TLR7 conjugate offers a promising strategy to enhance cancer immunotherapy.
• This approach demonstrates potential for improving treatment outcomes in solid tumors without adverse effects.