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Pre-clinical evaluation of theranostic [177Lu]Lu-PSMA617 prostate cancer treatment in combination with adjuvant agonistic OX40-targeting

University of British Columbia

Prostate cancer represents a significant disease burden worldwide. While recent advancements in diagnostics and therapy have increased both overall and progress-free survival in PCa, relapses are common, and progression to the metastatic phenotype continues to block therapeutic efforts, often leading to fatal outcomes in spite of multimodal therapy. Consequently, more potent treatment options are the subject of dynamic pre-clinical and clinical research. A substantial part of this research focuses on combination treatment strategies, such as therapy using theranostic targeted radioligands combined with immunotherapeutics. We proposed co-targeting of OX40, a T-cell surface antigen using an agonistic antibody OX86, in combination with a lutetium-177-labelled, PSMA antigen-binding radiopharmaceutical [¹⁷⁷Lu]Lu-(DKFZ)-PSMA617. Based on promising results from pre-clinical and clinical trials, we hypothesized that the combined treatment would have greater therapeutic effect than either treatment alone. First we isolated four clones of a doxycycline (Tet-On)-inducible cell line, deriving from a commonly used TRAMP-C2 cell line. Next, we conducted imaging and biodistribution studies and were able to prove inducibility of PSMA protein-expression upon induction, in a non-immunogenic model. Induction was visualized in PET/CT scans as increased [¹⁸F]DCFPyL uptake in the inoculated tumour region, and evident from the dosimetry analysis of gamma-counted organ samples ex vivo, whereas tumour tissue tracer uptake amounted to up to 26% ID/g. Cells derived from excised tumours were viable in an immunocompetent model, which facilitated experiments aimed at comparing therapeutic efficacy of the proposed combination treatment. In the adapted therapy studies, tumour growth inhibition was achieved in both iv treatment groups ([¹⁷⁷Lu]Lu-PSMA617 alone and in combination with OX86 antibody). Growth dynamics of untreated tumours showed a high degree of variability, which negatively impacted the interpretative value of the results. However, underlying processes causing such non-uniformity of results were delineated in another set of experiments - the pilot autoradiography (betaimaging) and tissue architecture imaging studies concluding this thesis, identifying pronounced intra- and intertumoural heterogeneity. To conclude, successful induction of PSMA-expression and the viability of used clones in immunocompetent models hold promise of applying this system as a gene-reporting tool, and further subcloning of the cell populations can pave a way for expanded therapy studies.

Text

2020-09-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75828

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/