The impact of the large B-cell lymphoma tumor microenvironment on efficacy of CD19-directed CAR-T immunotherapy

Large B-cell lymphoma is an aggressive lymphoma subtype with poor outcomes in the relapsed and refractory setting. Despite considerable improvements in long-term survival with CD19 CAR-T immunotherapy, over half of patients do not achieve durable remissions. A deeper understanding of the mechanisms within the tumor microenvironment that drive treatment resistance is critical to informing the development of improved CAR-T therapies that can overcome immunosuppressive elements. In this review, we synthesize current knowledge on how histological, cellular, molecular and spatial features of the large B-cell lymphoma microenvironment influence clinical responses following CD19 CAR-T therapy and highlight key knowledge gaps in the field. We discuss data from clinical trials of emerging novel CAR-T engineering strategies aimed at reprogramming the immunosuppressive tumor microenvironment and underscore the growing need for advanced analytical approaches capable of integrating multimodal, high-dimensional datasets to comprehensively characterize this complex tumor ecosystem.