Promising potential of [
      <sup>177</sup>Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using
      a syngeneic breast cancer model

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Abstract

Purpose

It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [ ¹⁷⁷Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy .

Methods

In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [ ¹⁷⁷Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [ ¹⁷⁷Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment.

Results

[ ¹⁷⁷Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [ ¹⁷⁷Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [ ¹⁷⁷Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls.

Conclusion

Application of [ ¹⁷⁷Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

Electronic supplementary material

The online version of this article (10.1007/s00259-020-05054-9) contains supplementary material, which is available to authorized users.

Related collections

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Author and article information

Contributors

Patrycja Guzik: patrycja.guzik@psi.ch

Klaudia Siwowska: klaudiasiwowska@gmail.com

Hsin-Yu Fang: hy.fang11@gmail.com

Susan Cohrs: susan.cohrs@psi.ch

Peter Bernhardt: peter.bernhardt@gu.se

Roger Schibli: roger.schibli@psi.ch

Cristina Müller:

ORCID: http://orcid.org/0000-0001-9357-9688

cristina.mueller@psi.ch

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur J Nucl Med Mol Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 19 October 2020

Publication date PMC-release: 19 October 2020

Publication date (Print): 2021

Volume: 48

Issue: 4

Pages: 984-994

Affiliations

[1 ]GRID grid.5991.4, ISNI 0000 0001 1090 7501, Center for Radiopharmaceutical Sciences ETH-PSI-USZ, , Paul Scherrer Institute, ; 5232 Villigen-PSI, Switzerland

[2 ]GRID grid.8761.8, ISNI 0000 0000 9919 9582, Department of Radiation Physics, The Sahlgrenska Academy, , University of Gothenburg, ; SE-413 45 Gothenburg, Sweden

[3 ]GRID grid.1649.a, ISNI 000000009445082X, Department of Medical Physics and Medical Bioengineering, , Sahlgrenska University Hospital, ; SE-413 45 Gothenburg, Sweden

[4 ]GRID grid.5801.c, ISNI 0000 0001 2156 2780, Department of Chemistry and Applied Biosciences, , ETH Zurich, ; 8093 Zurich, Switzerland

Author information

Cristina Müller http://orcid.org/0000-0001-9357-9688

Article

Publisher ID: 5054

DOI: 10.1007/s00259-020-05054-9

PMC ID: 8041666

PubMed ID: 33078260

SO-VID: 43113fb7-df25-459d-b81c-f2f7f9fa08eb

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 20 June 2020

Date accepted : 22 September 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;

Award ID: 310030_156803

Award ID: 310030_188978

Funded by: Swiss Government Excellence Scholarship

Funded by: Swedish Cancer Society

Award ID: 2018/577

Award Recipient : Peter Bernhardt

Funded by: Swedish Research Council

Award ID: 2018-05098-3

Award Recipient : Peter Bernhardt

Funded by: King Gustav V Jubilee Clinic Cancer Research Foundation

Award ID: 2018:200

Award Recipient : Peter Bernhardt

Custom metadata

ScienceOpen disciplines: Radiology & Imaging

Keywords: folate receptor,immunotherapy,nf9006 breast tumor cells,ctla-4,[177lu]lu-dota-folate

Data availability:

ScienceOpen disciplines: Radiology & Imaging

Keywords: folate receptor, immunotherapy, nf9006 breast tumor cells, ctla-4, [177lu]lu-dota-folate