Thesis
Investigations towards a rational combination of 177Lu-PSMA with immunotherapy
- Abstract:
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PSMA (prostate-specific membrane antigen)-targeted radioligand therapy (PRLT) with 177Lu-labelled ligands has proven to be effective for the treatment of metastasised castration-resistant prostate cancer (PC) patients. Nevertheless, one-third of patients are non-responders although their tumours express sufficient PSMA. Suppression of an anti-tumour immune response could explain the resistance and murine transcriptomic studies have shown conversion of an immune-suppressive tumour microenvironment to a responsive one after PRLT. Elevation of IDO1(indoleamine-pyrrole 2,3-dioxygenase)-expression, known to confer radioresistance, was noted.
To assess the benefit of the combination of PRLT with the IDO1-inhibitor epacadostat, the cytotoxicity of epacadostat on RM1-PGLS PC cells was tested with a viability assay before the combination was evaluated in immunocompetent male C57BL/6 mice bearing RM1-PGLS murine PC allografts. Groups of mice were treated with epacadostat (7.5 mg/d, over 5 d), PRLT (41.9±3.9 MBq or 59.4±2.9 MBq), or the combination thereof (and untreated controls). Furthermore, the modulation of IDO1 expression after PRLT (and external beam radiation therapy) should be reconfirmed by NanoString analysis. To study the role of CD8+ T cells in PRLT, a CD8+ T cell-depleted xenograft mouse model was generated through anti-CD8-antibody injections.
In viability assays, epacadostat showed low chemotoxicity in RM1-PGLS cells (IC50 w/o medium exchange 415±227 uM, w/ exchange 233±135 uM). In the survival study, no additional benefit for the combination could be detected (median overall survivals, combination: 15 days, PRLT: 14 days, epacadostat: 13 days, untreated: 10 days) with the applied design regimen. Although IDO1 upregulation could not be reconfirmed, modulation of other relevant pathways, especially senescence, was detected shortly after PRLT.
The CD8+ T cell depletion model could successfully be created with significantly reduced effector cell frequencies in the tumours (P=0.0039, t-test) for at least 13 days.
In conclusion, the obtained results will support finding rational combinations of PRLT with immunotherapy.
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Authors
Contributors
- Institution:
- University of Oxford
- Division:
- MSD
- Department:
- Oncology
- Role:
- Supervisor
- ORCID:
- 0000-0003-4672-5683
- DOI:
- Type of award:
- MSc
- Level of award:
- Masters
- Awarding institution:
- University of Oxford
- Language:
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English
- Keywords:
- Subjects:
- Deposit date:
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2024-05-02
- ARK identifier:
Terms of use
- Copyright holder:
- Kramer, C
- Copyright date:
- 2023
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