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For many of you this question may sound strange. A few years ago, like many of you I’d answer – YES, we really need it, no doubt! Recently I’ve changed my opinion and I don’t think we need it. I don’t think we need to spend a lot of time and waste money on searching for the magic “expansion elixir”.
Hundreds of articles have proposed pre-clinical and clinical protocols for so-called “hematopoietic stem cells (HSCs) expansion” and some RegenMed startup companies started to commercialize it. I think it’s worthless to continue to do that.
Ok, now I’ll tell you why I think so and how I came to this conclusion.
1. As soon as clinical trials started we realize that unlike preclinical data we actually can not achieve expansion of engraftable long-term HSCs
The most convincing evidence came from results of a recent trial in the Fred Hutchinson Cancer Research Center. We can expand different progenitors, maybe short-term HSC, but not long-term HSC. The authors didn’t observe any “stem cell activity” from expanded cord blood sample in patients a few months after transplant.
…virtually all expanded CD34+/CD38- cells were multipotent and myeloid primed progenitors with very very few true HSC. Those very few expanded HSC, the authors were not able to detect a few months after transplant in 8 out of 10 patients. 2 patients with some signs of expanded long-term HSC engraftment were under observation for 240 and 180 days. But in one of them they were not able to detect signs of multilineage engraftment at the time point of 1 year and second patient didn’t possess engraftment in T-cells.
2. In order to achieve significant clinical improvement we don’t need a lot of HSCs but we need a lot of progenitors
Bone marrow transplant (BMT) patients are struggling with neutropenia, delayed neutrophil recovery and thrombocytopenia in the first month after the procedure. Toxic myeloablative treatment and absence of neutrophils makes them very sensitive to infections and prone to sepsis. So, the first thing that we need is earlier and rapid neutrophil recovery! Long-term engraftable HSCs are not going to make neutrophils in the first month after transplant, but donor’s progenitors will do it and allow the patient to survive. Multipotent or myeloid or granulocytic progenitors – doesn’t matter, but we need a lot of them. Fortunately it’s much easier to expand them than HSCs.
For illustration of the importance of progenitors for hematopoiesis recovery from irradiation and survival I’d like to refer you to the earlier study of Koichi Akashi.
To identify the principal components of the hematopoietic system that are radioprotective, we transplanted lethally irradiated mice with purified progenitors: common myeloid progenitors (CMPs), megakaryocyte/erythrocyte-restricted progenitors (MEPs), or granulocyte/monocyte-restricted progenitors (GMPs). CMPs and MEPs but not GMPs protected mice in a dose-dependent manner, suggesting that erythrocytes, platelets, or both are the critical effectors of radioprotection.
All animals radioprotected for 30 days subsequently survived for at least 6 months post-transplant, and showed only host-derived hematopoiesis after 30 days. These findings suggest that rare hematopoietic stem cells survive myeloablation that can eventually repopulate irradiated hosts if myeloerythroid-restricted progenitors transiently rescue ablated animals through the critical window of bone marrow failure.
3. T-cells alone, without engraftable HSCs can induce graft-versus-tumor effect and eradicate neoplasm
T-cell therapy (donor leukocyte infusion (DLI) or adoptive T-cell or CAR’s) in leukemia clinic achieved significant progress in the last few years and got close to the point when one can ask: “Can it replace HSCs transplant?” If you think about it, why do we need donor’s HSCs at all? If conditioning regimen is not killing all host normal HSCs, if donor’s (or autologous CAR’s) T-cells can efficiently induce graft-versus-leukemia effect and eradicate leukemic stem cells, we don’t need BMT. I believe that in the future, at least for some indications, cellular immunotherapy alone or with a few normal fresh HSCs will be efficient enough to eradicate leukemia.
As a clinical example I’d like to refer you to some observations, which indicate that clinically significant graft-versus-leukemia effect can be achieved without sustained donor engraftment.
4. Methods for HSCs engraftment improvement will be more clinically sufficient than chasing for increasing of HSCs number through expansion
The problem is not as much in low number of HSCs in fresh cord blood sample as in their low rate of homing to bone marrow niche and engraftment. Would you agree that manipulating HSCs by migration, homing and engraftment after transplantation is an easier and more efficient way to improve the clinical outcome compared to HSCs expansion ex vivo? I believe so, because there are a number of smart approaches for increasing engraftment of HSCs in preclinical development and different stages of clinical trials.
Especially, I like approaches dedicated to the improvement of homing of transplanted HSCs and niche manipulations.
5. Cost, scalability and commercialization
Have you ever thought about how much money and human resources you may spend for clinical “HSCs expansion manufacturing”? You should include in counting: 2-4 weeks of large-scale cell culture (medium, supplements, labware) in GMP facility, technicians work and “product release tests”. Long ex vivo manipulations, risk of cell product contamination and safety tests, included in strict “release criteria” will make it hard to go smoothly through FDA (or other regulatory agency) approval. But if you work with approved substances (such as PTH for instance) in order to increase homing or engraftment of fresh HSCs, you will get easier and quicker approval.
Concluding remark:
I just shared some of my thoughts on “necessity of HSCs expansion for clinical use”. I think that we should re-direct our efforts to:
- – manipulations of migration and engraftment (niche interaction) of fresh HSCs;
- different progenitor populations expansion;
- cytotoxic T-cell and NK-cell therapy for graft-versus-tumor effect induction.
We probably should stop writing proposals for “HSCs expansion magic”.
I’d be happy to hear any critical comment and to discuss this further. I hope to hear the opinion of bone marrow transplant physicians on this problem, especially.
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