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Background Despite significant advances in immuno-oncology, many cancers remain resistant to treatment due to tumor heterogeneity, immune evasion, and insufficient immune activation. Allogeneic tumor cell vaccines offer a promising off-the-shelf strategy by presenting a broad repertoire of tumor-associated antigens; however, their clinical impact has been limited by weak immunogenicity and suboptimal activation of immune effector pathways.Bria-OTS+ is a novel, genetically engineered allogeneic tumor cell vaccine platform designed to overcome these limitations. It is genetically modified to express immune-stimulatory cytokines, co-stimulatory molecules, and a diverse library of HLA alleles to enhance antigen presentation and immune engagement. This multi-modal approach drives coordinated activation of dendritic cells, T cells, B cells, NK cells, and NKT cells, supporting both personalized and off-the-shelf immunotherapy applications.Bria-OTS+ represents a next-generation cancer vaccine that integrates classical adaptive immune memory with innate immune training. This reflects a paradigm shift in vaccine design, from focusing solely on adaptive immunity to actively engaging and educating both innate and adaptive compartments. By activating these immune pathways, Bria-OTS+ functions as a modular, immune-educating platform capable of overcoming resistance and inducing durable anti-tumor responses.Methods Bria-OTS+ cell lines targeting lung, breast, melanoma, and prostate cancers were genetically engineered to express immune-stimulatory cytokines (GM-CSF, IFN-α, IL-12, IL-7), co-stimulatory molecules (CD40, CD80, CD86), and diverse Class I and II HLA alleles to enable semi-allogeneic antigen presentation. These irradiated cells were co-cultured with healthy donor PBMCs in a multi-phase in vitro vaccination assay, including priming, resting, boosting, and effector phases. Immune activation was assessed by flow cytometry for cytokine production, activation markers, cytotoxicity, and proliferation of T cells, NK cells, NKT cells, and dendritic cells. Phenotypic and functional markers of memory and trained immunity were also evaluated.Results For each tumor type, we developed four distinct cell lines engineered to express GM-CSF, IFNα, IL-12, IL-7, CD80, CD86, CD40, and diverse HLA alleles. Bria-OTS+ cell lines elicited robust activation of CD4+ , CD8+ T cells and B-cells in vitro, along with NK, NKT and dendritic cells, leading to potent anti-tumor activity. Immune profiling demonstrated hallmarks of trained innate immunity and adaptive memory, supporting the potential for sustained, durable immune responses.Conclusions Bria-OTS+ drives coordinated activation of T cells and NK cells, enables HLA-matched precision therapy, and provides an off-the-shelf, cost-effective option through its allogeneic design. It also induces durable immune responses via trained innate immunity and adaptive memory.