Journal
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Volume 48, Issue 4, Pages 984-994Publisher
SPRINGER
DOI: 10.1007/s00259-020-05054-9
Keywords
Folate receptor; Immunotherapy; NF9006 breast tumor cells; CTLA-4; [Lu-177]Lu-DOTA-folate
Funding
- Lib4RI - Library for the Research Institutes within the ETH Domain: Eawag, Empa, PSI WSL
- Swiss National Science Foundation [310030_156803, 310030_188978]
- Swiss Government Excellence Scholarship
- Swedish Cancer Society [2018/577]
- Swedish Research Council [2018-050983]
- King Gustav V Jubilee Clinic Cancer Research Foundation [2018:200]
- Swiss National Science Foundation (SNF) [310030_188978] Funding Source: Swiss National Science Foundation (SNF)
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The study showed that [Lu-177]Lu-DOTA-folate has a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy, sensitizing tumors to the treatment and significantly improving the median survival time of mice, indicating potential for future clinical translation of folate radioconjugates.
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 [Lu-177]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 [Lu-177]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [Lu-177]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 x 200 mu g; 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 [Lu-177]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [Lu-177]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). [Lu-177]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 [Lu-177]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.
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