Abstract LB413: Peripheral blood as the sole source for cancer neoantigen and reactive T cell discovery

Abstract Neoantigen-targeted T-cell therapies require invasive tumor biopsies to identify neoantigens and reactive T cells, limiting their applicability and potentially underestimating tumor heterogeneity. We propose a novel strategy relying solely on peripheral blood to identify non-synonymous mutations via cell-free DNA whole-exome sequencing and isolate neoantigen-specific CD4+ and CD8+ T cells based on PD-1 and CD39 co-expression. Our method successfully identified most neoantigens and increased the number of T-cell reactivities detected by standard biopsy-based techniques in an initial cohort of eight metastatic cancer patients. Critically, our approach uncovered additional neoantigens missed by tumor biopsy analysis, highlighting the potential for broader neoantigen targeting using liquid biopsies. Analysis of a larger cohort of 69 metastatic cancer patients revealed that approximately half could be eligible for our blood-only approach. This proof-of-concept study demonstrates the potential of using peripheral blood as a surrogate or complement for tumor biopsies to develop neoantigen-reactive T-cell therapies against a broader spectrum of neoantigens. Citation Format: Andrea Garcia Garijo, Immaculada Creus-González, Pierre Levy, Ana Belen Moreno-Cárdenas, Maria Lozano-Rabella, Carlos Alberto Fajardo, Ricardo Pujol-Borrell, Albert Marín, Johanna Kusnick, Jared Gartner, Anna Yuste-Estevanez, Alma Calahorro, Jose Fernandez, Rebeca Sanz, Thomas B. Watkins, Vladimir Galvao, Eva Muñoz-Couselo, Javier Ros, Elena Elez, Mafalfa Oliveira, Cristina Saura, Irene Braña, Ana Oaknin, Ramon Alemany, Josep Tabernero, Raquel Perez-Lopez, Alexander M. Frankell, Elena Garralda, Rodrigo De Almeida Toledo, Alena Gros. Peripheral blood as the sole source for cancer neoantigen and reactive T cell discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB413.