Generation of circulating tumor cell derived organoids through enrichment by leukapheresis - A novel drug screening system in metastatic prostate cancer

Prostate cancer (PCa) is the most common malignancy in men worldwide. 20-40% of
patients will have recurrent (metastatic) disease within 10 years after primary
treatment. The last decade many novel treatment options have been developed for
patients with metastatic PCa. At this moment selecting the best treatment and
determining the optimal treatment sequence for individual metastatic PCa
patients remains an important issue as few biomarkers exist that predict
treatment response. Therefore, our search for novel predictive biomarkers
needs to continue. A potential advance would be culturing tumor cell using
so-called *organoids* as these could be used to perform *ex vivo* drug
screening for individual patients potentially enabling more tailored treatment
choices. Moreover, systematic exploration of ex vivo drug sensitivity enables
the search for novel biomarkers which is essential for further realization of
more tailored patient management. Obtaining such cultures in metastatic PCa
patients is challenging as metastases are frequently confined to bone, making
it hard to retrieve sufficient material. Circulating tumor cells (CTCs) could
potentially serve as a more accessible source which can be even obtained
repeatedly at different stages during disease progression. Recently,
investigators have determined that the number of input cells is the main driver
of successfully culturing organoids and that at least 300 CTCs are needed.
However, CTCs have a low abundance in blood of generally 1 CTC/ml. To obtain
the minimally required number of 300 CTCs for organoid generation,
leukapheresis (LA) is a conceivable method to increase the CTC yield from
blood. In this study we aim to generate CTC-derived organoids using CTC
enrichment by leukapheresis in metastatic PCa patients. Organoid cultures from
CTCs have the ability to transform the treatment of metastatic PCa patients and
could help to decipher the biology of this complex disease.

The primary objective of this study is to establish the success rate of
culturing organoids from CTCs obtained by LA. Secondary objectives include to
assess the fraction of metastatic PCa patients who have * 300 viable CTCs
obtained by LA, the exploration of the potential of cultured organoids to
represent realistic disease models, the exploration of the presence of novel
molecular biomarker predictive of response and exploration of drug sensitivity
in organoids compared to therapy response of the matching patient in the
clinic.

Prospective, observational study

All patients are asked to undergo a single LA procedure which will take 3-5
hours. A volume of 10 L peripheral blood will be processed with the use of an
Optia Spectra Cell Separator. Patients do not benefit from this study. The most
common adverse events to be expected are pain or bruising at the venipuncture
site (1-5%), apprehension or fainting associated with venipuncture (1-5%),
fluid imbalance (0.01-0.1%) and citrate anticoagulant infusion-related symptoms
resulting in tingling or buzzing around the mouth or fingers (20-50%). All
patients will receive intravenous calcium to prevent this. The risk of adverse
events associated with LA is considered negligible.