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Abstract
Introduction: Targeted radionuclide therapy (TRT) is a systemic treatment with radiolabeled cancer-specific probes purposed to selectively hit diseased cells. As radioactive labels, beta--emitters, such as 90Yttrium and 177Lutetium, are studied to cause irreparable DNA damage. Beta--TRT using camelid single domain antibodies (sdAbs) is studied at the VUB, showing high potential in controlling tumor growth. Recently, immune activation after beta--TRT was reported. Therefore, we studied stimulation of CD8+ T cells and upregulation of inhibitory immune checkpoints after sdAb-mediated beta--TRT.
Materials and methods: C57BL/6 mice were inoculated with B16-melanoma cells expressing human CD20 and ovalbumin. After engraftment, mice received fractionated treatment with non-targeting sdAb or anti-CD20 sdAbs, labeled with the radionuclide 177Lutetium. Different readouts were evaluated: (1) tumor volume, measured by caliper, (2) gene expression profiling of the tumor microenvironment (TME), evaluated using RT-qPCR, (3) immune cell composition of the TME, evaluated using flow cytometry and (4) systemic immune responses, evaluated by stimulation of CD8+ splenocytes with tumor antigens.
Results: A reduced tumor progression was observed upon treatment of CD20+ melanoma-bearing mice. Despite this tumor control, we were not able to document immune activation. Gene expression and flow cytometry analysis did not reveal changes in CD8+ T cells or the inhibitory immune checkpoint PD-1/PD-L1 in the TME. Moreover, CD8+ splenocytes did not show specificity for the antigen ovalbumin, which serves as a surrogate tumor antigen.
Conclusion: Although beta--TRT with 90Yttrium coupled to a tumor-targeting alkylphosphocholine in a model non-Hodgkin Lymphoma was shown to induce immune responses, we were not able to show similar immune activation with 177Lutetium-coupled anti-CD20 sdAbs in a melanoma model. Further research to confirm and study the reason for these contradicting results is required.
Materials and methods: C57BL/6 mice were inoculated with B16-melanoma cells expressing human CD20 and ovalbumin. After engraftment, mice received fractionated treatment with non-targeting sdAb or anti-CD20 sdAbs, labeled with the radionuclide 177Lutetium. Different readouts were evaluated: (1) tumor volume, measured by caliper, (2) gene expression profiling of the tumor microenvironment (TME), evaluated using RT-qPCR, (3) immune cell composition of the TME, evaluated using flow cytometry and (4) systemic immune responses, evaluated by stimulation of CD8+ splenocytes with tumor antigens.
Results: A reduced tumor progression was observed upon treatment of CD20+ melanoma-bearing mice. Despite this tumor control, we were not able to document immune activation. Gene expression and flow cytometry analysis did not reveal changes in CD8+ T cells or the inhibitory immune checkpoint PD-1/PD-L1 in the TME. Moreover, CD8+ splenocytes did not show specificity for the antigen ovalbumin, which serves as a surrogate tumor antigen.
Conclusion: Although beta--TRT with 90Yttrium coupled to a tumor-targeting alkylphosphocholine in a model non-Hodgkin Lymphoma was shown to induce immune responses, we were not able to show similar immune activation with 177Lutetium-coupled anti-CD20 sdAbs in a melanoma model. Further research to confirm and study the reason for these contradicting results is required.
| Original language | English |
|---|---|
| Pages | page 79 |
| Number of pages | 1 |
| Publication status | Published - 7 Feb 2020 |
| Event | BACR Annual Meeting 2020: Cancer metastasis: From bedside to bench - Vrije Universiteit Brussel, Campus Jette, Brussels, Belgium Duration: 7 Feb 2020 → 7 Feb 2020 Conference number: 26th https://www.bacr.be/program/ |
Conference
| Conference | BACR Annual Meeting 2020 |
|---|---|
| Country/Territory | Belgium |
| City | Brussels |
| Period | 7/02/20 → 7/02/20 |
| Internet address |
Keywords
- Targeted Radionuclide Therapy
- Lutetium-177
- tumor microenvironment
- Single domain antibodies
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Dive into the research topics of 'Investigating immune activation upon beta targeted radionuclide therapy using anti-CD20 single domain antibody fragments in melanoma'. Together they form a unique fingerprint.Projects
- 6 Finished
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FWOSB80: Combining targeted radionuclide therapy and cancer immunotherapy to advance precision medicine through innovation.
Breckpot, K. (Administrative Promotor), Devoogdt, N. (Co-Promotor), D'Huyvetter, M. (Co-Promotor), Keyaerts, M. (Co-Promotor) & Ertveldt, T. (Mandate)
1/11/19 → 31/10/23
Project: Fundamental
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SRP50: SRP-Onderzoekszwaartepunt: Exploiting Peptides: Protein Binders, Modulators and Inhibitors for Imaging and Therapy [Exploit-PeptIT]
Ballet, S. (Administrative Promotor), Caveliers, V. (Co-Promotor), Hernot, S. (Co-Promotor), Versées, W. (Co-Promotor), Vinken, M. (Co-Promotor), Muyldermans, S. (Co-Promotor), Devoogdt, N. (Co-Promotor), Bridoux, J. (Collaborator) & Martin, C. (Collaborator)
1/03/19 → 30/09/25
Project: Fundamental
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SRP62: SRP-Groeifinanciering: Single-domain antibody fragment (SdAb)-based TArgeted Radionuclide Therapy: STaRT programme
Keyaerts, M. (Administrative Promotor), D'Huyvetter, M. (Co-Promotor) & Neyns, B. (Co-Promotor)
1/03/19 → 30/09/24
Project: Fundamental
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