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.