Data from Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor

• DOI: 10.1158/2326-6066.c.6548573
• Publication Date: 2024-03-12T19:52:28Z
• Authors: Anna Pasetto; Alena Gros; Paul F. Robbins; Drew C. Deniger; Todd D. Prickett; Rodrigo Matus-Nic...; Daniel C. Douek; Bryan Howie; Harlan Robins; Maria R. Parkhurst; Jared Gartner; Katarzyna Trebska...; Jessica S. Crystal; Steven A. Rosenberg

<div>Abstract<p>Adoptive transfer of T cells with engineered T-cell receptor (TCR) genes that target tumor-specific antigens can mediate cancer regression. Accumulating evidence suggests that the clinical success of many immunotherapies is mediated by T cells targeting mutated neoantigens unique to the patient. We hypothesized that the most frequent TCR clonotypes infiltrating the tumor were reactive against tumor antigens. To test this hypothesis, we developed a multistep strategy that involved TCRB deep sequencing of the CD8⁺PD-1⁺ T-cell subset, matching of TCRA–TCRB pairs by pairSEQ and single-cell RT-PCR, followed by testing of the TCRs for tumor-antigen specificity. Analysis of 12 fresh metastatic melanomas revealed that in 11 samples, up to 5 tumor-reactive TCRs were present in the 5 most frequently occurring clonotypes, which included reactivity against neoantigens. These data show the feasibility of developing a rapid, personalized TCR-gene therapy approach that targets the unique set of antigens presented by the autologous tumor without the need to identify their immunologic reactivity. <i>Cancer Immunol Res; 4(9); 734–43. ©2016 AACR</i>.</p></div>