Pan-carcinoma sialyl-Tn-targeting expands CAR therapy to solid tumors

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Accurate tumor-specific markers are crucial for developing effective chimeric antigen receptor (CAR)-based therapies.
• Aberrant carbohydrate structures, such as the sialyl-Tn (STn) antigen, present promising tumor-specific targets due to their prevalence in epithelial cancers.
• Existing monoclonal antibodies (mAbs) against STn have faced limitations in clinical application due to specificity concerns.

Purpose of the Study:

• To develop a highly specific monoclonal antibody (mAb) targeting the sialyl-Tn (STn) antigen.
• To engineer CAR T-cells utilizing the AM52.1 mAb for cancer therapy.
• To evaluate the efficacy and specificity of AM52.1CAR T-cells in preclinical cancer models.

Main Methods:

• Development and characterization of the AM52.1 mAb for STn specificity.
• Assembly of the AM52.1 single-chain variable fragment (scFv) into a second-generation CAR scaffold.
• In vitro testing of AM52.1CAR T-cells against cancer cell lines and patient-derived organoids (PDOs).
• In vivo evaluation of AM52.1CAR T-cells in preclinical models of gastric, tubo-ovarian, and colorectal cancers.

Main Results:

• The AM52.1 mAb demonstrated unprecedented specificity for the STn antigen without reactivity to healthy tissues.
• AM52.1CAR T-cells effectively targeted and eliminated STn-expressing cancer cell lines and PDOs.
• AM52.1CAR T-cells showed robust control of gastric, tubo-ovarian tumors, and colorectal cancer mucinous peritoneal metastases in vivo.
• The engineered CAR T-cells successfully spared STn-negative cells, indicating high target specificity.

Conclusions:

• The AM52.1 mAb represents a highly specific tool for targeting the STn antigen in cancer.
• AM52.1CAR T-cell therapy holds significant therapeutic potential for various solid tumors expressing the STn antigen.
• This approach offers a promising strategy for managing complex solid tumors by leveraging specific post-translational modifications as therapeutic targets.