Ambika P Jaswal, Anders Josefsson, Angel G Cortez, Abhinav Bhise, Bo Li, Chaim T Sneiderman, Sarah R Vincze, Michal Nisnboym, Joseph D Latoche, Kathryn E Day, Robert S Edinger, Itay Raphael, Lora H Rigatti, Wilson B Edwards, Gary Kohanbash, Jessie R Nedrow
{"title":"Targeting tumor-infiltrating immune cells for targeted alpha therapy in gliomas: Optimization of [225Ac]Ac-DOTA-αCD11b dosing through PET-imaging.","authors":"Ambika P Jaswal, Anders Josefsson, Angel G Cortez, Abhinav Bhise, Bo Li, Chaim T Sneiderman, Sarah R Vincze, Michal Nisnboym, Joseph D Latoche, Kathryn E Day, Robert S Edinger, Itay Raphael, Lora H Rigatti, Wilson B Edwards, Gary Kohanbash, Jessie R Nedrow","doi":"10.1158/1535-7163.MCT-24-0996","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3000,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1535-7163.MCT-24-0996","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.