Novel theranostic agent for PET imaging and targeted radiopharmaceutical therapy of tumour-infiltrating immune cells in glioma,EBioMedicine

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Novel theranostic agent for PET imaging and targeted radiopharmaceutical therapy of tumour-infiltrating immune cells in glioma
EBioMedicine ( IF 9.7 ) Pub Date : 2021-09-13 , DOI: 10.1016/j.ebiom.2021.103571
Alexandra Foster ₁ , Shubhanchi Nigam ₂ , David S Tatum ₃ , Itay Raphael ₁ , Jide Xu ₃ , Rajeev Kumar ₁ , Elizabeth Plakseychuk ₄ , Joseph D Latoche ₄ , Sarah Vincze ₁ , Bo Li ₁ , Rajan Giri ₅ , Lauren H McCarl ₁ , Robert Edinger ₂ , Murat Ak ₂ , Vishal Peddagangireddy ₂ , Lesley M Foley ₆ , T Kevin Hitchens ₇ , Rivka R Colen ₂ , Ian F Pollack ₁ , Ashok Panigrahy ₂ , Darren Magda ₃ , Carolyn J Anderson ₈ , W Barry Edwards ₉ , Gary Kohanbash ₁₀

Affiliation

Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Lumiphore, Inc., 600 Bancroft Way Berkeley, CA 94710, USA.
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA.
Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh 15213, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Chemistry, University of Missouri, Columbia, MO, 65211 USA.
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA.
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Background

Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b⁺ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment.

Methods

Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT.

Findings

⁸⁹Zr/¹⁷⁷Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, ¹⁷⁷Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy.

Interpretation

⁸⁹Zr- and ¹⁷⁷Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses.

Funding

A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

中文翻译：

用于胶质瘤肿瘤浸润免疫细胞 PET 成像和靶向放射性药物治疗的新型治疗诊断剂

背景

恶性神经胶质瘤是致命的肿瘤，治疗选择很少。尽管免疫疗法可能是治疗神经胶质瘤的一种有前途的治疗策略，但一个重要的障碍是 CD11b ⁺肿瘤相关骨髓细胞 (TAMC)，这是一种异质神经胶质瘤浸润物，占神经胶质瘤细胞质量的 40%，抑制抗肿瘤 T 细胞功能并促进肿瘤进展。治疗诊断方法使用单分子进行靶向放射性药物治疗 (TRT) 和诊断成像；然而，针对肿瘤微环境的治疗诊断学的报道很少。