Projects per year
Abstract
Studies were performed in immunocompetent, murine animal models, engrafted with modified melanoma cells to express the model antigen ovalbumin, a well-characterized Gallus gallus domesticus antigen. (i) Immune imaging was performed using technetium-99m (99mTc) radiolabeled anti-murine programmed death-ligand 1 (PD-L1) sdAbs upon vaccination with an mRNA vaccine, called Galsomes. (ii) In TRT-experiments, the melanoma cells also expressed the target antigen human CD20 (huCD20), to allow TRT with either β--emitter Lutetium-177 (177Lu) or α-emitter, Actinium-225 (225Ac) radiolabeled anti-huCD20 sdAbs. Additionally, various read-outs were performed on blood, tumor tissue and healthy organs to assess immune parameters.
(i) Immune imaging documented the dynamic expression of PD-L1 in a mouse melanoma model after Galsome vaccination. We showed the ability to generate serial high-resolution images allowing quantification of PD-L1 expression in peripheral organs and tumors. Ex vivo analysis using flow cytometry confirmed the results of the quantified images and showed that both non-immune and myeloid cells contributed to PD-L1 expression in the organs that were studied. (ii) TRT-experiments showed a delay in tumor growth in both α- and β--TRT which translated into a prolonged time to reach humane endpoint. Intriguingly, β--TRT induced protumoral, suppressive immune responses as opposed to α-TRT, which exhibited an increase in anti-tumoral immune activity. More specifically, β--TRT was characterized by increased interleukin (IL)-10 serum levels, increased the percentage of PD-L1pos and PD-L2pos myeloid cells in tumors with a marked increase in alternatively activated macrophages and decreased CD4pos T helper 1 (TH1)-cells. α-TRT was characterized by changes in various blood cytokine levels, a decrease in pro-tumoral alternatively activated macrophages and an increase in antitumoral macrophages and dendritic cells (DCs). We also showed that α-TRT increased the percentage of PD-L1pos immune cells in the tumor, providing a rationale for performing cotreatment with checkpoint blockade of the PD-1|PD-L1 axis. Combination of α-TRT with PDL1 blockade potentiated the therapeutic effect, however aggravated adverse events and a longterm toxicity study revealed severe kidney damage ensuing α-TRT.
To conclude, in this dissertation we documented immunological changes using 99mTc-labeled anti-PD-L1 sdAbs, marked by an increase in PD-L1 expression of lung and liver tissue upon administration of Galsomes, however the results obtained from tumor tissue remain ambiguous. As for immunological changes upon TRT, we documented a difference in response to α- and β--TRT. Whereas alterations in the TME upon α-TRT were more in favor of anti-tumoral immune responses, β--TRT induced an increase in immunosuppressive populations. Future perspectives for this thesis would be to optimize sdAb-based PD-L1 imaging as well as delve further into the immunological field when TRT is combined with promising immune and non-immune therapies and include upcomming immune checkpoint to these read-outs.
Original language | English |
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Award date | 17 Oct 2023 |
Publication status | Published - 2023 |
Fingerprint
Dive into the research topics of 'Radiolabeled single-domain antibodies as a means to evoke and monitor immunological responses in malignant lesions'. Together they form a unique fingerprint.Projects
- 1 Finished
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FWOSB80: Combining targeted radionuclide therapy and cancer immunotherapy to advance precision medicine through innovation.
Breckpot, K., Devoogdt, N., D'Huyvetter, M., Keyaerts, M. & Ertveldt, T.
1/11/19 → 31/10/23
Project: Fundamental
Research output
- 3 Article
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Nanobody-mediated SPECT/CT imaging reveals the spatiotemporal expression of programmed death-ligand 1 in response to a CD8+ T cell and iNKT cell activating mRNA vaccine
Ertveldt, T., Meulewaeter, S., De Vlaeminck, Y., Olarte, O., Broos, K., Van Calenbergh, S., Bourgeois, S., Deprez, J., Heremans, Y., Goyvaerts, C., Staels, W., De Smedt, S., Dewitte, H., Devoogdt, N., Keyaerts, M., Verbeke, R., Barbé, K., Lentacker, I. & Breckpot, K., 9 Oct 2023, In: Theranostics. 13, 15, p. 5483-5500 18 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile6 Citations (Scopus)47 Downloads (Pure) -
Targeted α-Therapy Using 225Ac Radiolabeled Single-Domain Antibodies Induces Antigen-Specific Immune Responses and Instills Immunomodulation Both Systemically and at the Tumor Microenvironment
Ertveldt, T., Krasniqi, A., Ceuppens, H., Puttemans, J., Dekempeneer, Y., De Jonghe, K., de Mey, W., Lecocq, Q., De Vlaeminck, Y., Awad, R. M., Goyvaerts, C., De Veirman, K., Morgenstern, A., Bruchertseifer, F., Keyaerts, M., Devoogdt, N., D'Huyvetter, M. & Breckpot, K., 1 May 2023, In: Journal of Nuclear Medicine. 64, 5, p. 751-758 8 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile12 Citations (Scopus)38 Downloads (Pure) -
Targeted radionuclide therapy with low and high-dose Lutetium-177 labeled single domain antibodies induces distinct immune signatures in a mouse melanoma model
Ertveldt, T., De Beck, L., De Ridder, K., Locy, H., De Mey, W., Goyvaerts, C., Lecocq, Q., Ceuppens, H., De Vlaeminck, Y., Awad, R. M., Keyaerts, M., Devoogdt, N., D'Huyvetter, M., Breckpot, K. & Krasniqi, A., Jul 2022, In: Molecular Cancer Therapeutics. 21, 7, p. 1136-1148 13 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile11 Citations (Scopus)69 Downloads (Pure)
Activities
- 1 Talk or presentation at a workshop/seminar
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Nanobody-mediated molecular imaging provides spatiotemporal insight in mRNA-vaccine-induced PD-L1 upregulation
Thomas Ertveldt (Speaker), Sofie Meulewaeter (Speaker), Ine Lentacker (Contributor), Rein Verbeke (Contributor), Stefaan De Smedt (Contributor), Oscar Javier Olarte Rodriguez (Contributor), Kurt Barbé (Contributor), Nick Devoogdt (Contributor), Marleen Keyaerts (Contributor), Heleen Dewitte (Contributor) & Karine Breckpot (Contributor)
19 Apr 2021Activity: Talk or presentation › Talk or presentation at a workshop/seminar
Prizes
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Alavi-Mandell Award
Ertveldt, Thomas (Recipient), 4 Apr 2024
Prize: Prize (including medals and awards)
File -
Marie-Louise Lottin Award
Ertveldt, Thomas (Recipient), Nov 2024
Prize: Prize (including medals and awards)
File