Targeting tumor-infiltrating immune cells for targeted alpha therapy in gliomas: Optimization of [225Ac]Ac-DOTA-αCD11b dosing through PET-imaging.

Myeloid cells are key mediators of immunosuppression and treatment resistance in primary brain tumors including glioblastoma (GBM). This study aims to eradicate CD11b+ immunosuppressive cells at the tumor site to enhance overall survival in a model of GBM using an α-emitting radiopharmaceutical therapy (αRPT) targeted to tumor-associated myeloid cells (TAMCs) as a monotherapy or in combination with immune checkpoint inhibitors (ICI). An anti-CD11b (αCD11b) antibody was modified for radiolabeling with diagnostic (89Zr) or therapeutic (225Ac) radioisotopes. Initial PET-imaging and biodistribution studies using 89Zr-αCD11b found an antibody concentration of ~5 mg/kg of αCD11b (100-µg) was effective to saturate on-target/off-site sinks, such as the spleen, but effective at increasing tumor accumulation. The estimated maximum tolerable activity (eMTA) of 225Ac-αCD11b was determined by biodistribution and dosimetry studies, including the free in vivo generated decay daughters. The dose limiting tissue was the bone marrow and an eMTA (~0.55 kBq, 100-µg) was determined. The therapeutic efficacy of 225Ac-αCD11b was evaluated by survival studies, as both a monotherapy and in combination with ICI. Combinational therapy resulted in increased survival in the GBM model as compared to the monotherapy and controls; in addition, long-term survival was observed in 50% of the mice receiving combinational therapy as well as a single mouse receiving 225Ac-αCD11b alone. No long-term surviving mice were observed in the control groups. Long-term surviving mice were rechallenged, and potential antitumor immunity was observed, as no tumors developed over 120-days post-rechallenge. Overall, these results validate the preclinical relevance of CD11b-targeted image-guided αRPT.