論文

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, [89Zr]Zr-DFO-mCT3 (89Zr-mCT3), for non-invasive detection of GPC2 and [225Ac]Ac-macropa-mCT3 (225Ac-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, 225Ac-mCT3 induced tumor regression in a dose-dependent manner, with the maximal effect at 2.96 kBq (80 nCi). Because 225Ac-mCT3 does not downregulate GPC2, we assessed GPC2-CAR therapy with 225Ac-mCT3 (1.48 kBq [40 nCi]) and showed improved survival in mice with GPC2med but not GPC2high tumors. These findings establish 89Zr-mCT3 as a novel radiotracer for GPC2 monitoring and a predictive tool for CAR responses. 225Ac-mCT3 enhances GPC2-CAR therapy in tumors with medium antigen levels, offering a rationale for clinical development in NB and other pediatric tumors.