Whole-body CD8⁺ T-cell PET imaging in patients with large B-cell lymphoma before and during CD19-directed CAR T-cell therapy: a phase 2 study.

Abstract

Chimeric antigen receptor T-cell therapy (CART) has revolutionized the treatment of patients with refractory/relapsed large B-cell lymphoma (R/R LBCL). Limited biopsy data indicate that a higher activated CD8⁺ T-cell density is associated with tumor response. However, tumor biopsies fail to capture the systemic kinetics of CD8⁺ T-cells. Therefore, we conducted an exploratory phase 2 single-arm trial utilizing a zirconium-89-labeled one-armed anti-CD8α antibody (⁸⁹ZED88082A) to enable whole-body imaging of CD8⁺ T-cells through positron emission tomography (PET) (NL9034; EUCTR2020-004749-35-NL). Imaging analysis was performed in 23 patients with R/R LBCL, encompassing 251 lesions before (pre-CART) and after infusion (post-CART). Primary endpoint was to determine the whole-body distribution of the tracer in normal and tumor tissues before and after CART. ⁸⁹ZED88082A uptake in normal tissues varied over time. Tumor uptake was heterogeneous between and within patients. At the lesion level, higher pre-CART ⁸⁹ZED88082A tumor uptake was associated with higher post-CART tumor uptake at day +2. As secondary endpoints, no tracer-related side effects occurred and above median pre-CART ⁸⁹ZED88082A tumor uptake was associated with a longer time to progression, while lesions that relapsed exhibited consistently low uptake. Exploratory analysis showed a 42% tumor volume reduction from pre-CART to post-CART day +7. In conclusion, ⁸⁹ZED88082A has the potential to detect lesions at risk for progression and worse patient outcome, emphasizing the critical role of a CD8-permissive tumor microenvironment.