Development of third party grafts from pooled CD34- selected cryopreserved cord blood units for stem cell transplantation
Bibliographic record
Abstract
Umbilical cord blood (CB) is a valuable alternative source of stem cells for patients who do not have a compatible donor for allogeneic stem cell transplantation. Unfortunately, few banked cord blood units contain sufficient hematopoietic stem cells to transplant adult patients. Different approaches have been used to increase the number of infused HSC including the use of two or three HLA compatible CBUs, co-transplantation with related HLA haploidentical grafts to provide "third party" support, and cell expansion. These alternative approaches have the disadvantage of increasing the cost of graft procurement or relying on a related haploidentical donor that may not be available. I developed a method that aimed to increase the number of HSC available for transplantation by creating a third-party graft from pooled HLA-blind cryopreserved CBUs enriched for CD34+ cells. By using only CBUs rejected by the public cord blood bank, the cost of developing this mixed CBUs graft has been minimized. Over 60% of all collected CBUs do not qualify for public banking and could potentially be salvaged to create third-party grafts for clinical use. To pursue this project, it was necessary to establish a clinical grade research cord blood bank to ensure the availability of CBUs for experimental graft development. This project covered all aspects of cord blood banking from screening potential mothers, to CBU collection, processing, cryopreservation, and release of CBUs for transplantation. From October 2007 to December 2012, 2313 CBUs have been collected. Approximately 38% of the collected CBUs qualified for the Québec public cord blood bank and 1418 CBUs were retained. A small volume of CBUs did not qualified for any banking mainly due to a volume of less than 20 mL, CBUs being more than 96 hours post collection or positive bacteriology/serology testing. Some of the key accomplishments that permitted the successful creation of mixed cord blood grafts were the development of pooling methods to minimize the toxicity of the cryopreservative DMSO while simultaneously thawing and combining multiple CBUs. I also observed that passive transfer of anti-A and anti-B immunoglobulin-gamma could bind ABO-incompatible fetal leukocytes and potentially interfere with cell yields and function. The quality of mixed cord blood grafts was optimized by dilution of thawed CBUs to reduce DMSO concentration from 10% to 1% and selecting CBUs that had maternal-fetal ABO compatibility. Mixed cord blood grafts using from 12 to 45 CBUs were pooled with a mean nucleated cell recovery of 87% post-thawing and 73% post-centrifugation with a yield of CD34+ cells, sufficient for third party support in allogeneic cord blood transplantation. The safety and utility of using mixed cord blood grafts for allogeneic stem cell transplantation has been demonstrated in a clinical trial developed and conducted at the MUHC. Seven recipients with hematological cancers received, after myeloablative conditioning, a ≥ 4/6 HLA compatible CBU, followed by infusion of the third-party graft containing on average 2.5 x 105 CD34+ cell/kg. The median neutrophil engraftment time was 19.5 days. One patient had primary graft failure. All engrafted patients showed a 100% HLA-matched donor chimerism at first assessment on day +14. Six patients were alive at day +100 while one patient died at day +28 of disease relapse. All engrafted recipients developed grade I-III acute graft-versus-host-disease that responded promptly to treatment and no patients developed chronic GVHD.These results demonstrate that increasing the number of HSCs by using third-party cells from pooled HLA-blind CBUs to support a ≥ 4/6 HLA compatible CBU is safe, feasible, and results in rapid engraftment. Future studies are warranted to better understand the role of pooled third party units and factors involved in the homing of stem cells to their natural niche to facilitate the selection of units for engraftment.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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".