Parent’s Guide to Cord Blood, September 2022
Frances Verter PhD
The pros and cons of cord blood transplants are well-established. The biggest advantage of cord blood over adult sources of stem cells, either from bone marrow or peripheral blood, is that cord blood transplants do not require precise HLA matching1. This makes transplants accessible to patients from racially diverse backgrounds who cannot find matching adult donors. Cord blood transplants also yield better long-term outcomes, in terms of risks for relapse or graft versus host disease (GvHD)2,3. However, cord blood transplants have struggled to overcome two disadvantages that pose obstacles to their broad acceptance. One is that most of the cord blood units (CBU) in public banks are not big enough to provide a sufficient cell dose for adult patients4. The other is that cord blood engrafts more slowly than bone marrow, and this delay in immune reconstitution leads to treatment related mortality (TRM)5.
ExCellThera is a biotechnology company based in Montréal that is dedicated to making cord blood transplants available to more patients by lowering the starting cell dose that can be safely used in therapy. ExCellThera has developed an expanded cord blood product called ECT-001 that is based culturing cord blood with the small molecule UM171. The ExCellThera ECT-001 product is made from a single CBU but consist of two parts; the CD34+ cell fraction of the CBU is expanded for 7 days in the presence of UM171, then it is combined with the remaining CD34- cell fraction of the CBU and they are transplanted together. ExCellThera has been testing their ECT-001 product in patients since 2016, and published the results of their phase 2 clinical trial in The Lancet in 20206.
It is important to emphasize that the ExCellThera clinical trials have not been designed to achieve the fastest possible engraftment, but to push the envelope of the smallest possible starting dose that can be clinically successful after expansion.
In summer of 2022, ExCellThera has published a paper which analyzed how their cell expansion technology could increase the number of United States patients receiving cord blood transplants7. The first part of their analysis looked only at the size of units in the current Be The Match® cord blood inventory that can be used, either for a single cord blood transplant, a double cord blood transplant, or an ExCellThera transplant. The number of CBU which are big enough depends on the patient weight, and the analysis was performed for the three patient weights 50, 70, and 100 kg. The results in Table 1 demonstrate that, for larger patients, the ExCellThera expansion technology increases the number of patients that have big enough CBU over 10-fold.
The specific minimum doses for each of these transplant types are as follows: The guidelines for a single unit cord blood transplant call for a minimum dose of 25 million (25M) total nucleated cells (TNC) per kg of patient weight as well as 0.15 million CD34+ cells per kg of patient weight8. Alternatively, a double cord blood transplant requires two CBU that both meet a threshold of 15M TNC/kg and 0.10M CD34+/kg. And finally, the ExCellThera expansion would enable patients to be treated with a single CBU holding 15M TNC/kg and 0.05 CD34+/kg.
The same paper also performed a second analysis to determine how ExCellThera technology could help real world patients to gain access to transplants. This was a retrospective analysis that incorporated both patient weight and patient HLA type for the 58,971 adult searches in the US national registry Be The Match® over the five years from August 2015 to August 2020. Each patient had a measured HLA type, a measured body weight, and a self-reported ethnic identity. For the purposes of the study, the inventory had to provide the patient with both a big enough CBU plus an HLA match that was 5 out of 8 or higher. The results in Table 2 show an increase in matched CBU for all ethnic types, but the most dramatic improvement is for African Americans.
It has been reported that many factors contribute to racial disparities in access to advanced medical care9,10. Over the past decade, Be The Match® and the US public banks have worked very hard to increase the inclusion of racially and ethnically diverse cord blood donors, so that by 2021 they represented 51% of the inventory11,12. Thanks to this emphasis on recruiting diverse donors, we can say that Be The Match® has a match (an HLA match) for at least 80% of all ethnic groups13,14. But having a match is only half the challenge, the other half is having a big enough CBU for an adult patient. In 2014, only 24% of adult African Americans could find a qualifying CBU, and by 2021 that percentage had risen to 53%13,7. Now, with the additional boost of ExCellThera expansion, it is possible to increase that percentage to 78%.
ExCellThera’s product ECT-001 has received the FDA Orphan Drug designation, the FDA Regenerative Medicine Advanced Therapy (RMAT) designation, and ExCellThera has submitted a Drug Master File for UM171 to the FDA15-17. The process of obtaining FDA approval for a cell-based product is notoriously slow, but ExCellThera is making progress down that pipeline, which hopefully brings improved transplant access closer for patients.
- Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, Loberiza FR, Champlin RE, Klein JP, Horowitz MH, Wagner JE. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. The Lancet 2007; 369(9577):1947-1954.
- Milano F, Gooley T, Wood B, … Delaney C. Cord-Blood Transplantation in Patients with Minimal Residual Disease. NEJM 2016; 375:944-953.
- Ando T, Tachibana T, Tanaka M, … Nakajima H. Impact of graft sources on immune reconstitution and survival outcomes following allogeneic stem cell transplantation. Blood Advances 2020; 4(2):408–419.
- Verter F. RAND Corporation report on Public Cord Blood Banking Industry. Parent’s Guide to Cord Blood Foundation News Nov. 2017
- Milano F, Rezvani AR, Kurtzberg J, … Delaney C. No Engraftment Advantage after Single or Double Umbilical Cord Blood Transplant (CBT) with the Addition of a Non-HLA Matched Off-the-Shelf Expanded Cord Blood Unit Compared to Conventional CBT: Results of a Randomized Trial. Blood 2019; 134(S1):146.
- Cohen S, Roy J, Lachance S, … Sauvageau G. Hematopoietic stem cell transplantation using single UM171-expanded cord blood: a single-arm, phase 1–2 safety and feasibility study. The Lancet 2020; 7(2):e134-e145.
- Dumont-Lagacé M, Feghaly A, Meunier MC, Finney M, Van’t Hof W, Frenet EM, Sauvageau G, Cohen S. UM171 Expansion of Cord Blood Improves Donor Availability and HLA Matching For All Patients, Including Minorities. Transplantation and Cellular Therapy 2022; 28(7):410.e1-410.e5.
- Politikos I, Davis E, Nhaissi M, …. American Society for Transplantation and Cellular Therapy Cord Blood Special Interest Group. Guidelines for Cord Blood Unit Selection. BBMT 2020; 26(12):2190-2196.
- American Medical Association. Reducing disparities in health care. Accessed 2022-09-01
- Barker JN, Boughan K, Dahi PB, … Politikos I. Racial disparities in access to HLA-matched unrelated donor transplants: a prospective 1312-patient analysis. Blood Advances 2019; 3(7):939–944.
- United States Census Bureau. Quick Facts. Accessed 2022-08-23
- HRSA Blood Stem Cell. Data >> Donation and Transplant Statistics >> Donor Registry Data >> Diversity of Cord Blood Units on the Registry. Last Updated April 2022
- Gragert L, Eapen M, Williams E, … Maiers M. HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U.S. Registry. NEJM 2014; 371:339-48.
- Verter F. Be The Match® has a matching stem cell donor for most US patients. Parent’s Guide to Cord Blood Foundation News Oct. 2014
- ExCellThera. ExCellThera receives FDA orphan drug designation for ECT-001 for the prevention of graft-versus-host disease. Press Release Announced 2018-12-17
- ExCellThera. ExCellThera’s lead technology, ECT-001, receives Regenerative Medicine Advanced Therapy (RMAT) designation. GlobeNewswire Announced 2019-04-23
- ExCellThera. ExCellThera announces submission of Drug Master File for UM171. Press Release Announced 2022-06-17
Source: Parent’s Guide to Cord Blood