Associate Professor Icahn School of Medicine at Mount Sinai, United States
Introduction: Preclinical models have been the backbone for drug development and learning about cancer biology. The inability to properly recapitulate the tumor niche and the difficulty to use primary cells have been great detrimental factors when translating results from the bench to the bedside. We have previously reported results of an ex-vivo 3D organoid cell model with biomimetic microenvironment that allowed prolonged cell survival of primary myeloma cells for up to 14 days in co-cultures and chemosensitivity results. We now present the effects different drug conditions have on both the plasma cells as well as the immune compartment found in primary patient samples.
Methods: After obtaining informed consent, we obtained bone marrow aspirate samples from patients with relapsed multiple myeloma. Using previously described technique, mononuclear cells were co-cultured cultured with stroma in a Matrigel scaffold. Each organoid containing 200,000 cells was plated on an individual well and nourished with enriched culture media. Batches of organoids from the same patient sample were exposed to three different chemotherapy agents (bortezomib 5 nM and 10nM, lenalidomide 50 µM and 100 µM, selinexor 10 µM and 30 µM) on day 5 of experiment and removed 72 hours later. Different timepoints prior to drug exposure (day 5), at the end of drug exposure (day 8), and six days later (day 14) were used to perform viability/proliferation assays with Alamar Blue and flow cytometry to assess different cellular compartments, specifically plasma cells and part of the immune repertoire (CD4, CD8, and NK cells).
Results: Primary cells from bone marrow aspirates remained viable for the duration of the experiment (14 days). Alamar blue showed proliferation in the control group while significant differences were seen in viability based on agent and concentration (Image 1). When looking at flow cytometry data, we see different impact in T cell and NK cell found in the tumor niche (Image 2, 3, 4, 5, 6).
Conclusions: While conventional preclinical models have been a cornerstone to drug development and advances in medicine, the current development of immunotherapies, including cellular therapy require a better physiological representation of the tumor niche. Organoid models from primary patient samples provide an environment that allows evaluation of different study conditions and its impact not just on the patient’s own myeloma cells, but their immune compartment as well. Additional studies to assess its application in T-cell redirecting therapy and other novel immunotherapies using this model is warranted to correlate with clinical outcomes.
