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The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens. PBLs from patients with a mutated TP53 tumor were sorted for antigen-experienced T cells and in vitro stimulation (IVS) was performed with p53 neoantigens. The IVS cultures were stimulated with antigen-presenting cells expressing p53 neoantigens, enriched for 41BB/OX40 and grown with rapid expansion protocol. T-cell responses were not observed in the PBLs of 4 patients who did not have tumor-infiltrating lymphocyte (TIL) responses to mutated TP53. In contrast, 5 patients with TIL responses to mutated TP53 also had similar T-cell responses in their PBLs, indicating that the PBLs and TILs were congruent in p53 neoantigen reactivity. CD4+ and CD8+ T cells were specific for p53R175H, p53Y220C, or p53R248W neoantigens, including a 78% reactive T-cell culture against p53R175H and HLA-A*02:01. Tracking TCRB clonotypes (clonality, top ranked, and TP53 mutation-specific) supported the enrichment of p53 neoantigen-reactive T cells from PBLs. The same T-cell receptor (TCR) from the TIL was found in the IVS cultures in three cases and multiple unique TCRs were found in another patient. TP53 mutation-specific T cells also recognized tumor cell lines bearing the appropriate human leukocyte antigen restriction element and TP53 mutation, indicating these T cells could recognize processed and presented p53 neoantigens. PBL was a noninvasive source of T cells targeting TP53 mutations for cell therapy and can provide a window into intratumoral p53 neoantigen immune responses.See related commentary by Olivera et al., p. 1203. ©2020 American Association for Cancer Research.


Parisa Malekzadeh, Rami Yossef, Gal Cafri, Biman C Paria, Frank J Lowery, Mohammad Jafferji, Meghan L Good, Abraham Sachs, Amy R Copeland, Sanghyun P Kim, Scott Kivitz, Maria R Parkhurst, Paul F Robbins, Satyajit Ray, Liqiang Xi, Mark Raffeld, Zhiya Yu, Nicholas P Restifo, Robert P T Somerville, Steven A Rosenberg, Drew C Deniger. Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Mar 15;26(6):1267-1276

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PMID: 31996390

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