TCR-engineered T cells targeting a shared β-catenin mutation eradicate solid tumors.

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Recurrent driver mutations in cancer can produce neoantigens recognized by T cells.
• The CTNNB1 gene mutation (S37F) leads to a gain-of-function in beta-catenin, implicated in over 7,000 US cancer cases annually.
• Identifying specific neoantigens and developing targeted immunotherapies are crucial for cancer treatment.

Purpose of the Study:

• To identify and characterize neoantigens derived from the CTNNB1 S37F mutation.
• To develop T cell receptor (TCR)-engineered T cells targeting these neoantigens for cancer immunotherapy.
• To evaluate the efficacy of CTNNB1-S37F-specific TCR-T cells in preclinical cancer models.

Main Methods:

• Identification of CTNNB1 S37F-derived neopeptides presented by HLA-A*02:01 and HLA-A*24:02 molecules.
• Isolation of T cell receptors (TCRs) specific for the identified neopeptides from healthy donor T cells.
• In vitro and in vivo testing of TCR-engineered T cells against cancer cell lines, organoids, and patient-derived xenografts.

Main Results:

• Two neopeptides encoded by the CTNNB1 S37F mutation were identified, presented on common HLA alleles.
• TCRs specific for CTNNB1-S37F neoantigens were successfully isolated.
• Engineered T cells demonstrated potent killing of CTNNB1 S37F-positive cancer cells and organoids in vitro.
• Tumor eradication was achieved in mouse models, including melanoma and endometrial adenocarcinoma xenografts.

Conclusions:

• CTNNB1 S37F-specific neoantigens can be targeted by TCR-engineered T cells.
• TCR-T cell therapy targeting CTNNB1 S37F represents a potential new strategy for solid cancer immunotherapy.
• This approach holds promise for treating cancers driven by CTNNB1 gain-of-function mutations.