Targeted a-Therapy Using 225Ac Radiolabeled Single-Domain Antibodies Induces Antigen-Specific Immune Responses and Instills Immunomodulation Both Systemically and at the Tumor Microenvironment

被引：12

作者：

Ertveldt, Thomas ^{[1
]}

Krasniqi, Ahmet ^{[2
]}

Ceuppens, Hannelore ^{[1
]}

Puttemans, Janik ^{[2
]}

Dekempeneer, Yana ^{[2
]}

De Jonghe, Kevin ^{[2
]}

de Mey, Wout ^{[1
]}

Lecocq, Quentin ^{[1
]}

De Vlaeminck, Yannick ^{[1
]}

Awad, Robin Maximilian ^{[1
]}

Goyvaerts, Cleo ^{[1
]}

De Veirman, Kim ^{[3
]}

Morgenstern, Alfred ^{[4
]}

Bruchertseifer, Frank ^{[4
]}

Keyaerts, Marleen ^{[2
,5
]}

Devoogdt, Nick ^{[2
]}

D'Huyvetter, Matthias ^{[2
]}

Breckpot, Karine ^{[1
]}

机构：

[1] Vrije Univ Brussel, Dept Biomed Sci, Lab Mol & Cellular Therapy, Brussels, Belgium

[2] Vrije Univ Brussel, Dept Med Imaging, In Vivo Cellular & Mol Imaging Lab, Brussels, Belgium

[3] Vrije Univ Brussel, Myeloma Ctr Brussels, Dept Hematol & Immunol, Brussels, Belgium

[4] Karlsruhe Inst, European Commiss, Joint Res Ctr, Directorate Nucl Safety & Secur, Karlsruhe, Germany

[5] UZ Brussel, Dept Nucl Med, Brussels, Belgium

来源：

JOURNAL OF NUCLEAR MEDICINE | 2023年 / 64卷 / 05期

关键词：

actinium-225; immunology; oncology; single-domain anti-body; radionuclide therapy; RADIONUCLIDE THERAPY; RADIOIMMUNOTHERAPY; SAFETY;

D O I：

10.2967/jnumed.122.264752

中图分类号：

R8 [特种医学]; R445 [影像诊断学];

学科分类号：

1002 ; 100207 ; 1009 ;

摘要：

Targeted radionuclide therapy (TRT) using targeting moieties labeled with a-particle-emitting radionuclides (a-TRT) is an intensely investi-gated treatment approach as the short range of a-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of a-TRT is lacking in literature. Methods: Using flow cytometry of tumors, sple-nocyte restimulation, and multiplex analysis of blood serum, we stud-ied immunologic responses ensuing from TRT with an antihuman CD20 single-domain antibody radiolabeled with 225Ac in a human CD20 and ovalbumin expressing B16-melanoma model. Results: Tumor growth was delayed with a-TRT and increased blood levels of various cytokines such as interferon-g, C-C motif chemokine ligand 5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-1. Peripheral antitumoral T-cell responses were detected on a-TRT. At the tumor site, a-TRT modulated the cold tumor microenvironment (TME) to a more hospitable and hot habitat for antitumoral immune cells, characterized by a decrease in protu-moral alternatively activated macrophages and an increase in antitu-moral macrophages and dendritic cells. We also showed that a-TRT increased the percentage of programmed death-ligand 1 (PD-L1)- positive (PD-L1pos) immune cells in the TME. To circumvent this im-munosuppressive countermeasure we applied immune checkpoint blockade of the programmed cell death protein 1-PD-L1 axis. Combi-nation of a-TRT with PD-L1 blockade potentiated the therapeutic effect, however, the combination aggravated adverse events. A long-term toxicity study revealed severe kidney damage ensuing from a-TRT. Conclusion: These data suggest that a-TRT alters the TME and induces systemic antitumoral immune responses, which explains why immune checkpoint blockade enhances the therapeutic effect of a-TRT. However, further optimization is warranted to avoid adverse events.

引用

页码：751 / 758

页数：8