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Background T cell therapies offer a promising, targeted approach for patients with relapsed/refractory (r/r) solid tumors. Patient-derived multi tumor-associated antigen-specific T cell (TAA-T) products targeting WT1, PRAME, and survivin have been safely administered to patients with r/r disease with disease stabilization but without objective clinical responses. The autologous patient-derived TAA-T products expressed multiple markers of exhaustion (PD1, CTLA4, and CD39), which may have limited anti-tumor potency in vivo. We hypothesized that treatment using healthy donor-derived off-the-shelf TAA-T products will be safe and elicit enhanced anti-tumor activity compared to patient-derived TAA-T in patients with r/r solid tumors.Methods TAA-T products were administered on a phase I dose escalation clinical trial ( NCT05238792) to patients with r/r pediatric solid tumors. Patients were eligible for a second dose in the absence of disease progression. Product selection was based on best overall match with antigen-specific activity mediated through a shared allele. Clinical and immunobiological studies were performed using radiologic studies, flow cytometric, multiplex, and IFNy ELISpot assays to assess immunologic and anti-tumor responses.Results TAA-T products were generated from 3 healthy donors with diverse HLA types, demonstrating polyfunctional phenotype and HLA-restricted antigen-specific activity. Six of 7 screened patients had a match identified in the TAA-T bank. TAA-T products administered over 2 dose levels to 6 patients (age range 18-66 years) with r/r solid tumors were well-tolerated with no dose limiting toxicities, both alone (n=3) and with lymphodepletion (n=3). Two patients achieved prolonged disease stabilization [(408 and 416 (ongoing) days]; there were no objective clinical responses ( figure 1). Preliminary correlative studies demonstrate an antigen spreading response to non-targeted antigens MAGE A3, MAGE A4, SSX-2, and SOX-2 and elevated levels of IL-8 in an otherwise quiescent circulating cytokine milieu.Conclusions Healthy donor-derived TAA-T products demonstrate evidence of safety in vivo in patients with high-risk, r/r solid tumors over 2 dose levels, including conditioning with lymphodepletion. Two of six (33%) patients experienced long periods of disease stabilization, both patients with minimal residual disease though disease status was not fully defined in the absence of biopsy. Correlative studies identified a small antigen spreading response that was muted in early time points for patients receiving lymphodepletion, suggesting the potential benefit of a combinatorial approach that may augment the immune milieu for a more potent anti-tumor response. Elevated IL-8 was correlated with disease progression in this patient population, representing a potential mechanism of therapeutic enhancement for future study using engineering strategies.Acknowledgements This work was supported by the Department of Defense Peer Reviewed Cancer Research Program Career Development Award (W81XWH2110259).Trial Registration Clinicaltrials.gov identifier NCT05238792Ethics Approval The study was approved by the Children’s National Hospital’s Institutional Review Board, approval number Pro00016539, IND 27716.Abstract 576 Figure 1Patients received partially HLA-matched TAA-T infusions safely with evidence of prolonged disease stabilization in patients with a history of rapidly progressive tumors. OS: osteosarcoma; WT: Wilms tumor; NB: neuroblastoma; Data censored June 30, 2025