RT Journal Article
SR Electronic
T1 Targeted α-Therapy Using <sup>225</sup>Ac Radiolabeled Single-Domain Antibodies Induces Antigen-Specific Immune Responses and Instills Immunomodulation Both Systemically and at the Tumor Microenvironment
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 751
OP 758
DO 10.2967/jnumed.122.264752
VO 64
IS 5
A1 Ertveldt, Thomas
A1 Krasniqi, Ahmet
A1 Ceuppens, Hannelore
A1 Puttemans, Janik
A1 Dekempeneer, Yana
A1 Jonghe, Kevin De
A1 Mey, Wout de
A1 Lecocq, Quentin
A1 Vlaeminck, Yannick De
A1 Awad, Robin Maximilian
A1 Goyvaerts, Cleo
A1 Veirman, Kim De
A1 Morgenstern, Alfred
A1 Bruchertseifer, Frank
A1 Keyaerts, Marleen
A1 Devoogdt, Nick
A1 D’Huyvetter, Matthias
A1 Breckpot, Karine
YR 2023
UL http://jnm.snmjournals.org/content/64/5/751.abstract
AB Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle–emitting radionuclides (α-TRT) is an intensely investigated treatment approach as the short range of α-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of α-TRT is lacking in literature. Methods: Using flow cytometry of tumors, splenocyte restimulation, and multiplex analysis of blood serum, we studied 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 α-TRT and increased blood levels of various cytokines such as interferon-γ, C-C motif chemokine ligand 5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-1. Peripheral antitumoral T-cell responses were detected on α-TRT. At the tumor site, α-TRT modulated the cold tumor microenvironment (TME) to a more hospitable and hot habitat for antitumoral immune cells, characterized by a decrease in protumoral alternatively activated macrophages and an increase in antitumoral macrophages and dendritic cells. We also showed that α-TRT increased the percentage of programmed death-ligand 1 (PD-L1)–positive (PD-L1pos) immune cells in the TME. To circumvent this immunosuppressive countermeasure we applied immune checkpoint blockade of the programmed cell death protein 1–PD-L1 axis. Combination of α-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 α-TRT. Conclusion: These data suggest that α-TRT alters the TME and induces systemic antitumoral immune responses, which explains why immune checkpoint blockade enhances the therapeutic effect of α-TRT. However, further optimization is warranted to avoid adverse events.