Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing...

Area of Science:

• Immunology
• Oncology
• Gene Therapy

Background:

• Effective gene therapy for human cancers requires T-cell receptors (TCRs) with potent antitumor activity.
• Identifying and engineering such TCRs is crucial for developing novel cancer treatments.

Purpose of the Study:

• To generate and evaluate TCRs reactive to melanoma antigens for cancer gene therapy.
• To assess the safety and efficacy of gene-engineered T cells in patients with metastatic melanoma.

Main Methods:

• Immunization of transgenic mice and high-throughput screening of human lymphocytes to identify anti-melanoma TCRs.
• Engineering TCR genes into retroviral vectors for transduction of autologous lymphocytes.
• Administering gene-engineered T cells to 36 patients with metastatic melanoma and monitoring treatment response and side effects.

Main Results:

• Gene-engineered T cells persisted in patients' blood one month post-infusion, with responders showing higher ex vivo antitumor reactivity.
• Objective cancer regressions were observed in 30% (human TCR) and 19% (mouse TCR) of patients.
• Adverse events included the destruction of normal melanocytes, leading to skin, eye, and ear damage, requiring steroid treatment for uveitis and hearing loss.

Conclusions:

• Highly reactive TCR-engineered T cells can mediate cancer regression in humans.
• These engineered T cells target cognate antigen-containing cells throughout the body, including normal melanocytes, highlighting a critical safety consideration for cancer gene therapy.