DSG2-Directed CAR-T Cells Safely and Universally Eliminate Solid Tumors.

Area of Science:

• Oncology
• Immunotherapy
• Cellular Therapy

Background:

• CAR-T cell therapy is effective against hematologic cancers but faces challenges in solid tumors due to a lack of specific targets.
• Epithelial cancers often overexpress cell-surface proteins not found on healthy tissues, presenting potential therapeutic targets.
• Desmoglein 2 (DSG2) is a transmembrane protein overexpressed on many epithelial cancers, with normal expression restricted to cell junctions.

Purpose of the Study:

• To develop and evaluate DSG2-directed CAR-T cells for targeting epithelial-derived solid tumors.
• To assess the safety and efficacy of DSG2-targeted CAR-T cells in preclinical models of various solid cancers.
• To explore DSG2 as a novel, junctionally-restricted antigen for solid tumor immunotherapy.

Main Methods:

• Generation of DSG2-specific CAR-T cells (αDSG2).
• In vitro testing of αDSG2 CAR-T cells against diverse solid tumor cell lines.
• In vivo efficacy studies using patient-derived and cell-derived solid tumors in mouse models.
• Toxicity assessment in transgenic mice expressing human DSG2.

Main Results:

• αDSG2 CAR-T cells demonstrated universal recognition and lysis of various solid tumor cell lines in vitro.
• Significant elimination of colon, pancreatic, lung, prostate, breast, and liver tumors in vivo.
• No observed toxicity in transgenic mice receiving αDSG2 CAR-T cells, indicating a favorable safety profile.
• DSG2 was confirmed as a safe and effective target for solid tumor treatment.

Conclusions:

• DSG2-directed CAR-T cells exhibit potent and safe antitumor activity against a broad spectrum of solid tumors.
• Targeting junctionally-restricted antigens like DSG2 represents a promising strategy for solid tumor immunotherapy.
• This approach offers a new therapeutic avenue for overcoming limitations of current CAR-T cell therapies in solid malignancies.