68Ga-grazytracer PET for noninvasive assessment of response to immunotherapy in solid tumors and lymphomas: a phase 1/2 clinical trial

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. Several approaches based on positron emission tomography (PET) are currently used to evaluate cancer response to immunotherapy. Here the authors report the results of a phase 1/2 trial evaluating a PET radiotracer, 68 Ga-grazytracer, for the imaging of granzyme B expression in patients treated with immune checkpoint inhibitors or CAR-T cell therapy.