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

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.

• Authors: Winifred Lo, Maria Parkhurst, Paul F Robbins, Eric Tran, Yong-Chen Lu, Li Jia, Jared J Gartner, Anna Pasetto, Drew Deniger, Parisa Malekzadeh, Thomas E Shelton, Todd Prickett, Satyajit Ray, Scott Kivitz, Biman C Paria, Isaac Kriley, David S Schrump, Steven A Rosenberg
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 7 Issue 4 Pg. 534-543 (04 2019) ISSN: 2326-6074 [Electronic] United States
• PMID: 30709841 (Publication Type: Case Reports, Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• HLA-A Antigens
• Tumor Suppressor Protein p53

Topics

• Adult
• Antigens, Neoplasm (genetics, immunology)
• Colorectal Neoplasms (genetics, immunology, pathology)
• Female
• HLA-A Antigens (genetics)
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mutation
• Tumor Suppressor Protein p53 (genetics, immunology)