Spatial remodeling of the tumor microenvironment by IL-18-armored CD19 CAR T cells is associated with durable remission in relapsed or refractory lymphoma

Patients with relapsed or refractory B-cell lymphoma who experience disease progression after CD19-directed CAR T-cell therapy have poor outcomes and few effective treatment options. Subsequent therapies provide only modest benefit, with complete remission (CR) rates near 20% and limited durability. huCART19-IL18, an IL-18-secreting CD19 CAR T-cell product, produced an overall response rate of 81% and a CR rate of 52% after prior anti-CD19 CAR T failure in a phase I trial, but the spatial determinants of durable response within the tumor microenvironment (TME) remain incompletely defined. We performed multimodal spatial profiling of paired pre- and post-huCART19-IL18 lymph node biopsies from 11 patients (6 with CR, 5 without CR) enrolled in the phase I study. GeoMx whole-transcriptome atlas and protein profiling were integrated with CosMx 6000-plex single-cell spatial imaging to map transcriptional and cellular remodeling across tumor, myeloid, and lymphoid compartments. CoPro, a computational framework for detecting coordinated progression of cell states in space, was applied to identify spatially coordinated gene expression programs within and between myeloid and T-cell compartments. Post-infusion samples from responders showed increased T-cell and NK-cell infiltration, frequent tertiary lymphoid structures, and induction of interferon (IFN)- and tumor necrosis factor-responsive chemokine and immune effector programs, including enhanced antigen presentation, together with coordinated loss of B-cell identity and signaling. These changes localized to regions enriched for CAR T cells, effector memory CD4⁺ and CD8⁺ T cells, and IFN-polarized macrophages, consistent with IL-18-driven recruitment and reprogramming of myeloid and T-cell compartments. Pre-infusion TMEs in responders showed baseline myeloid chemokine signatures associated with clinical response. CoPro revealed that myeloid functional heterogeneity is organized along spatial gradients that are independent of lineage identity and coordinated with T-cell effector programs in CAR T-infiltrated regions. These findings support a model in which IL-18 armoring promotes spatially organized remodeling of the TME through coordinated myeloid and T-cell activation associated with durable remission after CD19 CAR T failure, nominating myeloid recruitment, antigen presentation, and T-cell exhaustion programs as critical biomarkers and rational engineering targets for next-generation armored CAR T strategies in lymphoma.