T-cell receptor recognizing POLE P286R–HLA-A*11:01 complex (POLE P286R-TCR)

The T-cell receptor (TCR) recognizing the POLE P286R–HLA-A*11:01 complex is a specialized immune receptor designed for adoptive cell therapy against ultramutated cancers. The POLE P286R mutation is a highly recurrent hotspot mutation in the DNA polymerase epsilon gene, leading to a massive accumulation of somatic mutations and the generation of potent neoantigens (Shinbrot et al., 2014, Nature Genetics). This specific TCR is engineered to recognize a peptide fragment containing the P286R substitution when presented by the Human Leukocyte Antigen (HLA) allele A*11:01 (He et al., 2021, Nature Communications). By targeting a neoantigen that is entirely absent from healthy tissues, this TCR-T approach aims to provide high specificity and potent anti-tumor activity with minimal risk of autoimmunity. The interaction between the TCR and the peptide-HLA complex triggers T-cell activation, resulting in the release of cytotoxic molecules like perforin and granzymes to kill the tumor cell. It is primarily being investigated for the treatment of POLE-mutated endometrial and colorectal carcinomas, which are characterized by high immunogenicity (Van Gool et al., 2015, Clinical Cancer Research). This therapeutic strategy represents a personalized medicine approach, requiring patients to possess both the specific POLE mutation and the matching HLA-A*11:01 genotype. Clinical development of such TCRs is part of a broader effort to harness neoantigen-specific T cells for the treatment of solid tumors with high mutational loads (Parkhurst et al., 2019, Journal of Clinical Oncology).

Other names

POLE P286R-specific T-cell receptorHLA-A*11:01-restricted POLE P286R TCRPOLE-mutant specific TCRTCR recognizing AVVREAAKL-HLA-A*11:01

The TCR-engineered T cells recognize the POLE P286R neoantigen peptide (typically the 9-mer AVVREAAKL) presented by the HLA-A*11:01 molecule on the surface of tumor cells. This binding event triggers the TCR signaling complex, leading to T-cell activation, proliferation, and the directed release of cytotoxic granules containing perforin and granzymes, which induce apoptosis in the target tumor cell (He et al., 2021, Nature Communications).