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Cancer Immunol Res. 2019 Feb 1. pii: canimm.0686.2018. doi: 10.1158/2326-6066.CIR-18-0686. [Epub ahead of print]

Immunologic recognition of a shared p53 mutated neoantigen in a patient with metastatic colorectal cancer.

Author information

1
Surgery Branch, National Cancer Institute.
2
Surgery Branch, National Cancer Institute Maria_Parkhurst@nih.gov.
3
Providence Cancer Institute, Earle A. Chiles Research Institute.
4
Surgery Branch, National Institutes of Health.
5
Bioinformatics core, National Institutes of Health.
6
SB, NCI/NIH.
7
Laboratory Medicine, Karolinska Institutet.
8
Surgery, National Cancer Institute.
9
General Surgery, Allegheny General Hospital.
10
Thoracic and Oncologic Surgery Branch, CCR/NCI, NIH, National Institutes of Health.

Abstract

Adoptive cell therapy (ACT) with T cells targeting neoantigens can mediate durable responses in patients with metastatic cancer. Cell therapies targeting common shared antigens for epithelial cancers are not yet broadly available. Here we report the identification and characterization in one patient of T cell receptors (TCRs) recognizing mutated p53 p.R175H, which is shared among a subset of patients with cancer. Tumor-infiltrating lymphocytes (TILs) were screened for recognition of mutated neoantigens in a patient with metastatic colorectal cancer. HLA-A*0201 restricted recognition of mutated p53 p.R175H was identified, and the minimal peptide epitope was HMTEVVRHC. Reactive T cells were isolated by tetramer sorting, and three TCRs were identified. These TCRs mediated recognition of commercially available ovarian cancer, uterine carcinoma, and myeloma cell lines, as well as an NIH patient-derived esophageal adenocarcinoma line that endogenously expressed p53 p.R175H and HLA-A*0201. They also mediated recognition of p53 p.R175H+ colon, breast, and leukemia cell lines after transduction with a retrovirus encoding HLA-A*0201. This work demonstrates that common shared mutated epitopes like those found in p53 can elicit immunogenic responses and that the application of ACT may be extended to patients with any cancer histology that expresses both HLA-A*0201 and the p53 p.R175H mutation.

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