CELL INTELLIGENCE · 肿瘤细胞治疗研究

Chimeric antigen receptor (CAR) efficacy depends on the presence of surface antigen. While antigen levels in leukemias can be measured in the blood or bone marrow, expression in solid tumors is often inferred from archival tissues or remains undetermined. Neuroblastoma (NB) is an aggressive pediatric solid tumor for which we have co-developed a CAR targeting glypican 2 (GPC2). Here, we developed a radiotheranostic platform comprising an antibody-based positron emission tomography (immunoPET) agent, [ 89 Zr]Zr-DFO-mCT3 ( 89 Zr-mCT3), for non-invasive detection of GPC2 and [ 225 Ac]Ac-macropa-mCT3 ( 225 Ac-mCT3) for alpha-particle therapy. In orthotopic NB models with variable GPC2 levels, immunoPET accurately detected tumors with positive versus low/negative GPC2 status, which correlated with in vivo response to CAR. As a therapeutic agent, 225 Ac-mCT3 induced tumor regression in a dose-dependent manner, with the maximal effect at 2.96 kBq (80 nCi). Because 225 Ac-mCT3 does not downregulate GPC2, we assessed GPC2-CAR therapy with 225 Ac-mCT3 (1.48 kBq [40 nCi]) and showed improved survival in mice with GPC2 med but not GPC2 high tumors. These findings establish 89 Zr-mCT3 as a novel radiotracer for GPC2 monitoring and a predictive tool for CAR responses. 225 Ac-mCT3 enhances GPC2-CAR therapy in tumors with medium antigen levels, offering a rationale for clinical development in NB and other pediatric tumors.