Abstract
To tackle the clinical challenge of noninvasively assessing immunotherapy efficacy in patients, here we used positron emission tomography (PET) with (68)Ga-grazytracer, which targets granzyme B, a crucial effector molecule secreted by activated CD8(+) T cells. In this phase 1/2 clinical trial (NCT05000372) involving a diverse cohort of 24 patients with solid tumors and lymphomas who received immunotherapies, including immune checkpoint inhibitors (either alone or with chemotherapies) and chimeric antigen receptor-T cell therapy, we examined the in vivo behaviors of (68)Ga-grazytracer. Primary endpoints were safety, biodistribution, granzyme B specificity, and the predictive utility of (68)Ga-grazytracer, while secondary endpoint was the relationship between (68)Ga-grazytracer uptake and tumor immune phenotype. (68)Ga-grazytracer exhibited a safe profile and specifically targeted granzyme B in patients. (68)Ga-grazytracer PET showed superior predictive value for short-term prognosis and progression-free survival than those of conventional assessment criteria, including RECIST 1.1 and PERCIST. Moreover, the uptake of (68)Ga-grazytracer in tumors was significantly higher in those with a "non-desert" immune phenotype than those with an immune "desert" phenotype, thereby meeting the primary and secondary endpoints of this trial. Collectively, we successfully visualized CD8(+) T cell effector function in humans using (68)Ga-grazytracer PET, offering insights for enhancing immunotherapy assessment, patient stratification and treatment planning.