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Background Standard tumor-infiltrating lymphocyte (TIL) therapies use heterogeneous T cell populations that include both tumor-reactive and bystander cells. CD39 +CD103+ double-positive (DP) CD8+ T cells are a phenotypically exhausted yet highly enriched subset of tumor-reactive lymphocytes within solid tumors. Despite their exhaustion markers, these cells retain potent cytotoxic activity when expanded ex vivo. AGX-148 is a selected TIL product designed to selectively isolate and expand tumor-reactive CD8+ T cells.Methods This ongoing Phase I dose-escalation trial ( NCT05902520) is evaluating AGX-148 in adults with metastatic solid tumors that have progressed after standard and experimental therapies. Patients undergo tumor harvest, lymphodepleting chemotherapy, adoptive transfer of AGX-148 and high-dose IL-2 for one week, with subsequent low-dose IL-2 for 1, 2, or 3 weeks depending on cohort. Primary endpoints are safety and determination of the optimal biological dose; secondary endpoints include clinical response, T cell persistence, and immune correlates.Results AGX-148 manufacturing consistently yields billions of enriched tumor-reactive TIL. There have been no dose-limiting toxicities from AGX-148 encountered thus far. Toxicity has been as anticipated from lymphodepleting chemotherapy and IL-2. Clinical activity has been observed in solid tumors including melanoma, thyroid cancer, and oral head and neck squamous cell carcinoma with responses lasting over 600 days in some patients. TCR sequencing demonstrated long-term persistence of the infused product T cell clones in peripheral blood and metastatic tumor sites, confirming successful engraftment and tumor infiltration.Conclusions AGX-148 offers a novel, biomarker selection strategy enriching for tumor-reactive CD8 + T cells for adoptive transfer. Preliminary data show clinical responses with tolerability and sustained DP TIL persistence. These findings support continued clinical development of AGX-148 and highlight the therapeutic potential of targeting tumor-specific T cell subsets in solid tumors. Updated safety, efficacy, and correlative immune data will be presented.Trial Registration This trial is registered at ClinicalTrials.gov ( NCT05902520).Ethics Approval This clinical trial was approved by the Providence Institutional Review Board (Protocol #2023000082) and conducted under FDA IND#029-111. All participants provided written informed consent before study participation.