A Potent Tumor-Reactive p53-Specific Single-Chain TCR without On- or Off-Target Autoimmunity In Vivo

Area of Science:

• Immunology
• Oncology
• Genetic Engineering

Background:

• T-cell receptor (TCR) gene therapy shows promise for cancer immunotherapy.
• Inefficient TCR expression and mispairing can limit efficacy and safety.
• Targeting tumor antigens with engineered T cells is a key strategy.

Purpose of the Study:

• To evaluate the safety and therapeutic efficiency of an optimized single-chain TCR (scTCR) targeting p53.
• To assess scTCR efficacy in adoptive T-cell transfer (ACT) models mimicking human settings.
• To investigate potential on-target and off-target autoimmunity.

Main Methods:

• Developed transgenic mice expressing human p53 and HLA-A2.1.
• Utilized an optimized scTCR specific for the p53(264-272) peptide.
• Conducted adoptive T-cell transfer experiments in syngeneic and xenograft models.

Main Results:

• Optimized scTCR-redirected T cells showed no on-target or off-target autoimmunity.
• ACT resulted in complete tumor protection and long-lived antigen-specific memory T-cell response.
• Eradication of p53+A2.1+ tumor cells was achieved without self-directed toxicities.

Conclusions:

• The study demonstrates the safety and efficacy of a p53-specific scTCR for cancer immunotherapy.
• Optimized scTCRs can overcome limitations of traditional TCR gene therapy.
• These findings support p53scTCR as a viable option for treating p53-associated malignancies.