Ex Vivo Graft Purging and Expansion of Autologous Mobilized Peripheral Blood Progenitor Cell (PBPC) Products from Patients with Multiple Myeloma (MM).
Bibliographic record
Abstract
Abstract Introduction: Autologous PBPC transplantation has become the treatment of choice for selected MM patients. Autografts are often contaminated with MM cells which could be a source of post-transplant relapse. We elected to develop a graft manipulation procedure to purge tumor cells from the autograft without compromising its normal reconstituting activity. Previous studies have shown that bortezomib (Velcade, Millenium Pharmaceuticals, Inc., Cambridge, MA) can kill CD138+ MM cells, with little effect on CD138− B cells. However, the anti-CD20 monoclonal antibody, rituximab (Rituxan, Genentech, Inc., San Francisco, CA) has been shown to kill CD138− B cells, the putative MM “stem cells” population. Therefore we investigated whether an optimized combination of bortezomib and rituximab might effectively eradicate tumor cells from PBPC products. Previous studies1 have also suggested that tumor cells can also be selectively purged by ex vivo culture while expanding the normal hematopoietic progenitors. Thus, we incorporated an ex vivo culture step to optimize MM cell depletion and expansion of the reconstituting normal progenitors. Methods: CD138+ cells were depleted from the thawed PBPC of MM patients using the midiMACS device (Miltenyi Inc, Auburn, CA). The CD138− cells were treated for 24 hrs with 10 or 20 μg/ml rituximab followed by 20nM or 80nM bortezomib for 16hrs. Cells were then washed and ex vivo-expanded using an allogeneic normal marrow donor-derived mesenchymal stem cell (MSC) co-culture technique as previously reported.2 At the end of culture, cells were evaluated for total viable cells, expression of CD138, CD20, CD19, CD34, CD45 by flow cytometry and colony-forming cell (CFC) content in methylcellulose assays (StemCell Technologies, Vancouver, BC). Results: CD138+, CD138−/CD20+ or CD138−/CD20+/CD19+ cells were depleted in the MM PBPC products from patients when treated with bortezomib (20nM) and rituximab (20 μg/ml) followed by ex vivo culture.(Fig 1) Compared with input control, TNC increased by 6–72 fold and absolute numbers of CD34+ cells increased by approximately 3–9 fold. (See representative data Fig 2) Conclusion: Treating CD138-depleted MM PBPC products with bortezomib, rituximab and 2 weeks of ex vivo culture depleted CD138+ malignant plasma cells and CD138− B cells (MM “stem cells”). An estimated >4 log tumor depletion from a mobilized PBPC product was achieved, while the use of ex vivo expansion culture not only preserved but increased the number of normal hematopoietic progenitors. Further refinements of this procedure are in progress and will be tested clinically. Figure Figure Figure Figure
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".