Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer

Cancer Immunology Research - Tập 7 Số 4 - Trang 534-543 - 2019
Winifred Lo1,2, Maria R. Parkhurst2, Paul F. Robbins2, Eric Tran3, Yong‐Chen Lu2, Lee Jia2, Jared J. Gartner2, Anna Pasetto2, Drew C. Deniger2, Parisa Malekzadeh2, Thomas E. Shelton2, Todd D. Prickett2, Satyajit Ray2, Scott Kivitz2, Biman C. Paria2, Isaac Kriley1,2, David S. Schrump1, Steven A. Rosenberg2
11Thoracic and Gastrointestinal Oncology Branch, NCI, NIH, Bethesda, Maryland.
22Surgery Branch, NCI, NIH, Bethesda, Maryland.
33Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon.

Tóm tắt

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 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 such as 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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