The use of a patient’s own immune or tumor cells, manipulated ex vivo, enables Ag- or patient-specific immunotherapy. Despite some clinical successes, there remain significant barriers to efficacy, broad patient population applicability, and safety. Immunotherapies that target specific tumor Ags, such as chimeric Ag receptor T cells and some dendritic cell vaccines, can mount robust immune responses against immunodominant Ags, but evolving tumor heterogeneity and antigenic downregulation can drive resistance. In contrast, whole tumor cell vaccines and tumor lysate-loaded dendritic cell vaccines target the patient’s unique tumor antigenic repertoire without prior neoantigen selection; however, efficacy can be weak when lower-affinity clones dominate the T cell pool. Chimeric Ag receptor T cell and tumor-infiltrating lymphocyte therapies additionally face challenges related to genetic modification, T cell exhaustion, and immunotoxicity. In this review, we highlight some engineering approaches and opportunities to these challenges among four classes of autologous cell therapies.

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