Redirecting Polyclonal T Cells against Cancer with Soluble T-Cell Receptors.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Cancer cells present mutated peptides (pHLA) to T cells via TCR:CD3.
• Checkpoint therapy requires high neoantigen burden and reactive T cells.
• Many solid tumors have low neoantigen burden and resist current therapies.

Purpose of the Study:

• To introduce T-cell engagers (TCE) as a novel immunotherapy.
• To highlight TCEs' ability to target intracellular tumor antigens.
• To demonstrate TCE efficacy in low neoantigen burden tumors.

Main Methods:

• TCEs deconstruct the TCR:CD3 complex into bispecific proteins.
• TCEs redirect polyclonal T cells to cancer cells via a targeting domain (TCR).
• Tebentafusp, a TCR TCE targeting gp100 peptide-HLA*A02:01, was studied.

Main Results:

• Tebentafusp demonstrated a survival benefit in metastatic uveal melanoma (mUM).
• mUM is a solid tumor with low neoantigen burden and poor response to other treatments.
• TCR TCEs target a broad range of intra- and extracellular proteins.

Conclusions:

• TCR TCEs represent a promising immunotherapy approach, especially for tumors with low neoantigen burden.
• TCEs overcome limitations of checkpoint therapy by not requiring pre-existing neoantigen-specific T cells.
• TCR TCEs offer a wider therapeutic target pool than antibody-based treatments.