Abstract C067: Developing TCR-based precision immunotherapies for EGFR-mutant NSCLC

Abstract EGFR-mutant non-small cell lung cancer (NSCLC) remains largely refractory to immune checkpoint inhibitors (ICIs), and universally develop resistance to EGFR tyrosine kinase inhibitors (TKIs), leaving a major unmet clinical need. To address this challenge, we performed multi-omics profiling of NSCLC (>200 patients, Weill Cornell cohort) and identified EGFR-L858R as a recurrent, fitness-constrained, and naturally presented neoantigen across common HLA alleles (HLA-A*11:01, HLA-A*03:01 and HLA-A*68:01). This discovery provides a compelling rationale for the development of mutation-directed immunotherapies. We engineered an LNP-mRNA vaccine encoding EGFR-L858R, which elicited strong polyfunctional CD8+ T cells in immunocompetent mice. Overlapping mutant peptide library screens, RMA-S stabilization, and targeted immunopeptidomics defined a naturally processed 9-mer L858R neoepitope presented by H2-Kb MHC class I, providing direct mechanistic evidence of in vivo presentation. In an EGFR mutant genetically engineered mouse model, the LNP-mRNA vaccine suppressed tumor growth in a subset of mice, with responders characterized by high L858R antigen specific T cell infiltration into tumors, whereas non-responders harbored immunosuppressive tumor associated macrophages (TAM) signatures and low tumor MHC I expression. These mechanistic insights are informing rational combinations that augment antigen presentation and modulate the myeloid compartment to overcome resistance. Building on these mechanisms, we developed TCR-engineered T cells and TCR-mimic CAR-T cells recognizing L858R presented by HLA-A*11:01, HLA-A*03:01 and HLA-A*68:01. These next generation therapies are being evaluated in EGFR-mutant patient-derived organoids, xenografts and humanized mouse models with matched HLA backgrounds to enable preclinical-to-clinical translation. Together, this work establishes EGFR-L858R as a shared, druggable neoantigen and demonstrates an integrated platform for mutation-specific immunotherapy, spanning neoantigen discovery, mRNA vaccination, and TCR-engineered cell therapy development. These findings define a translational path toward precision immunotherapies for EGFR-mutant NSCLC, a population historically resistant to current immuno-oncology approaches. Citation Format: Yongfeng He, Zhen Tian, Joshua Lau, Anca Apavaloaei, Xiaojun Zhu, Mitchell Cheung, Arshdeep Singh, Greenbaum Benjamin, Taha Merghoub, Margie Clapper, Nasser K. Altorki, Xinbo Yang, Shaoyi Jiang, Vivek Mittal. Developing TCR-based precision immunotherapies for EGFR-mutant NSCLC [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C067.