Trichosanthin Fused to Thermo-pH-Sensitive Polypeptides for Synergistic Cancer Immunotherapy

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Immunogenic cell death (ICD) is crucial for anti-tumor immune responses, involving dendritic cell maturation and cytotoxic T lymphocyte activation.
• Synergy between ICD and immune checkpoint blockade (ICB) therapy holds potential for improving cancer treatment outcomes.
• Existing ICD inducers have limitations in tumor penetration and retention.

Purpose of the Study:

• To develop a novel ICD inducer with enhanced tumor targeting and retention properties.
• To evaluate the efficacy of the novel inducer, TCS-ELP(HI), in combination with ICB therapy for cancer treatment.

Main Methods:

• Genetic fusion of trichosanthin (TCS) with a thermo-pH-sensitive elastin-like polypeptide (ELP(HI)) to create TCS-ELP(HI).
• Intratumoral injection of TCS-ELP(HI) to assess its depot formation, tumor cell uptake, lysosomal escape, penetration, and retention.
• Combination therapy studies involving TCS-ELP(HI) and immune checkpoint inhibitors in preclinical cancer models.

Main Results:

• TCS-ELP(HI) demonstrated thermo-pH-sensitive properties, leading to sustained release and improved tumor cell uptake and lysosomal escape compared to free TCS.
• Enhanced tumor penetration and retention of TCS-ELP(HI) were observed, resulting in boosted ICD and antitumor efficacy.
• The combination of TCS-ELP(HI) with an immune checkpoint inhibitor significantly improved therapeutic efficacy against primary and distant tumors.

Conclusions:

• TCS-ELP(HI) is a novel and effective ICD inducer with superior pharmacokinetic properties.
• The combination of TCS-ELP(HI) and ICB therapy represents a promising strategy for enhancing antitumor and antimetastasis efficacy.
• TCS-ELP(HI) holds significant potential for improving cancer immunotherapy outcomes.