Hematologic Malignancy
Conditions
Keywords
3D organoid technique
Brief summary
The objective of this project is to compare chemosensitivity between chemotherapy combinations in bone marrow aspirates using 3D organoid models. The investigators overarching hypothesis is that 3D organoids are ideal to test chemosensitivity in real time, to provide personalized medicine and guidance in the setting of relapsed hematologic malignancy and potentially other cancers.
Detailed description
Optimize the novel 3D organoid technique already used to recreate hematologic tumors. Optimize cell viability of hematologic cancer organoids to extend available time in culture by screening cell culture media cytokines and 3D extracellular matrix composition. Evaluate hematologic tumor composition at different time points to confirm accurate tumor representation and identify genetic expression characteristics, unique mutations, and tumor-stroma interaction. These aspects of tumor interaction with its stromal microenviroment will provide critical knowledge to better understand its biology. Evaluate chemosensitivity on patient derived 3D organoids. Using marrow aspirate from participants with hematologic malignancies, evaluate live/kill rates of hematologic cancer cells after being exposed to established regimen combinations after 24 and 36 hours of exposure at pre-determined concentrations. Using participant samples, evaluate differences in gene expression and cell markers of the hematologic cancer cells that remained alive after chemotherapy exposure to better understand mechanisms of resistance. Validate the predictive value of the 3D organoid chemotherapy sensitivity results compared with retrospective data of the donor's responses to the treatment used at that time point. This will compare in vivo/ex vivo responses and facilitate future personalized medicine.
Interventions
OTHERAncillary-Correlative - Creation of three-dimensional myeloma organoids using marrow aspirates
Bone marrow aspirates will be collected from participants with hematologic malignancy being evaluated for relapsed disease to create three-dimensional constructs using a three-dimensional bioprinting methodology for automated organoid biofabrication.
Sponsors
Wake Forest University Health Sciences
National Cancer Institute (NCI)
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with suspected or confirmed hematologic malignancy undergoing a bone marrow biopsy as part of their care. * The ability to understand and willingness to sign an IRB approved informed consent document.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Live/Dead Myeloma Cells Using Bioprinting Technology | Up to 5 days | Bone marrow aspirates (around 3-7 ml) will be collected from participants with confirmed or suspected hematologic malignancy being evaluated with a bone marrow biopsy. The samples will be used to create 3D organoid constructs using a 3D bioprinting technology for automated organoid biofabrication using hyaluronic acid and gelatin-based hydrogel. The 3D organoid constructs allow extended time to simulate the protective environment cancer cells use to survive in bone marrow. Organoids will be assessed at 1, 3, and 5 days for viability of myeloma cells. Based on live/dead cells using fluorescent imaging, the hydrogel composition will be modified to allow the optimal media for cell survival ex vivo. |
| Tumor-Stroma Interactions | Up to 5 days | To assess the interaction of myeloma cells with stromal cells in a 3D organoid model, plasma and myeloma cells will be labeled using differing colors of Vybrant Multicolor Cell Labeling Kit to allow visualization of the cells' nuceli. By confocal microscope, slides will be evaluated for Vybrant-labeled hematologic malignant cells or healthy plasma cells (different colors) to identify preferential cell interactions. These aspects of tumor interaction with its stromal microenvironment will provide critical knowledge to better understand its biology. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Reduced Hematologic Malignant Myeloma Cells | Up to 3 days | After 24 hours of incubation, chemotherapy agents will be added at prepared concentrations that fall within the prescribed therapeutic ranges. A maximum of 15 combinations for each donor will be allowed for testing after which the efficacy of the treatments will be assessed qualitatively (live/dead straining) and quantitatively and quantitatively (automated segmentation and quantification of live/dead staining, mitochondrial metabolism/ATP activity, and ratio of Annexin V staining versus Ki67 staining \[apoptosis versus proliferation\]). These metrics will capture the reduction in hematologic malignant cell population. |
| Comparison of Cell Viability | 24 and 36 hours | Using myeloma patients' marrow aspirate, evaluate live/kill rates of myeloma cells after being exposed to established regimen combinations after 24 and 36 hours of exposure at pre-determined concentrations. |
| Organoid Responses Compared to Clinical Response | Up to 3 months | The response to each chemotherapy agent from obtained three-dimensional organoids will be compared to actual clinical responses of each participant through retrospective chart review to obtain regimen used to treat disease and the level of measurable disease in serum at different time points of treatment. The time points would include time of marrow biopsy, after 2 cycles of treatment and after 4 cycles of treatment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTimothy Pardee, MD, PhD
Wake Forest University Health Sciences
Outcome results
None listed