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作者：Roxanne Nelson  
出處：WebMD醫學新聞

　　January 25, 2010 — 雖然這些是初步研究且繼續演變，研究者發現一種可以在幹細胞移植時更適當運用臍帶血的方法。根據線上發表於1月17日Nature Medicine期刊的研究，使用來自臍帶血的體外擴增幹細胞，可使移植時屬於緩解型態之高風險白血病患者的移植物迅速地成功生長。
　　
　　西雅圖Fred Hutchinson癌症研究中心的研究者，發展出一種用於人類CD34+臍帶血源祖細胞的臨床相關的Notch-調節體外擴增系統，可使臍帶血源祖細胞在Notch外配體的存在下於體外擴增，當它們在骨髓破壞準備處方後輸注，嗜中性白血球的恢復時間明顯縮短。
　　
　　經過平均1年的追蹤時間後，接受移植的10名病患有7人存活，沒有發病證據且持續完成捐贈者的移植物成功生長。
　　
　　研究者指出，這是首次提出體外擴增之造血源祖細胞的迅速造血移植物成功生長，本研究的初步結果首次發表於2008年的美國血液協會年會，當時由Medscape Oncology 報導。
　　
　　【令人鼓舞的初步研究】
　　第一作者、Fred Hutchinson臍帶血移植計畫主任Colleen Delaney醫師解釋，雖然這是初步研究且樣本數少，但是結果相當令人鼓舞。
　　
　　然而，雖然迄今顯示接受治療病患的嗜中性白血球移植物迅速成功生長，仍需要更多研究，她向Medscape Oncology表示，我們正計畫一個第2/3期的試驗，將包括更多病患且以隨機方式進行，我們明確地認為，體外擴增造血幹細胞/源祖細胞可以迅速地移植。
　　
　　她指出，下一步驟是在更大型的試驗顯示同樣的結果，他們也計畫在他們的機構內對更多病患使用此技術。
　　
　　作者們指出，臍帶血是有效且廣為使用於需要造血幹細胞移植之病患的來源，但是，捐贈者移植物成功生長的時間相對緩慢，平均而言，需花3週以上才可以達到適當的骨髓細胞數量，使病患容易發生感染。
　　
　　他們寫道，研究目標在於改善移植物成功生長的比率，使用體外生長激素-調節擴增方法增加細胞數量少有成功，且沒有明顯的臨床效果。
　　
　　Delaney醫師與其研究團隊檢視了Notch訊號路徑在調節體外擴增造血幹細胞/源祖細胞的角色，目標在發展一種增加細胞數量的方法，而可以迅速地使骨髓細胞移植物成功生長。
　　
　　之前的3個實驗型試驗中，研究者觀察老鼠骨髓接受培養的細胞移植之後10天，可測量的人類細胞移植物成功生長(定義是≧0.5% 人類CD45+細胞)，將之與接受未培養之臍帶血細胞老鼠沒有移植物成長加以比較。移植物成功生長包括超過95%的骨髓細胞，提醒研究者Notch-擴增臍帶血源祖細胞可在實驗設定中大幅地加速造血再增殖能力。
　　
　　【觀察發現較快的移植物成功生長】
　　現在的這個第1期試驗中，每位病患接受2單位骨髓破壞準備處方處置後的臍帶血，一單位是未添加的臍帶血細胞、另一單位包括了接受Notch-調節體外擴增的臍帶血源祖細胞。
　　
　　這個世代包括了10名高風險白血病患者，平均年紀27.5歲(範圍為3-43歲)，這些病患中，達到絕對嗜中性白血球數量超過100 cells/μL的天數中位數為9天，接受2單位未添加的臍帶血細胞的病患則是19天(P= .006)。
　　
　　雖然1名病患有初步的移植物排斥，作者們並未觀察到任何與輸注相關的毒性反應或其他安全考量。
　　
　　在發表的文獻中，相較於輸注2單位未添加的臍帶血細胞者，他們的確觀察到明顯地促進了骨髓移植物成功生長的比率，嗜中性白血球恢復的時間中位數也減少超過1週，在1週時的觀察發現，擴增的細胞促成了幾乎全部的初步骨髓移植物成功生長，他們寫道，這表示擴大的細胞移植物提升了迅速的骨髓恢復。
　　
　　可評估的8名病患中，7人在21天前即成功移植，與擴增的細胞移植物是否持續在體內無關，相反地，輸注2單位未添加的臍帶血細胞者，移植物成功生長的時間平均達4週，作者們指出，這些結果高度認為，對未添加的臍帶血，加入培養的細胞在促進移植物成功生長上有加速效果。
　　
　　所有可評估的病患都發生過急性等級2的移植物對抗宿主疾病(GVHD)；1位病患觀察到急性等級3的GVHD。所有人都對治療有反應，目前，3名病患診斷為慢性侷限性GVHD。
　　
　　【下一步？】
　　這個技術是否會促成幹細胞移植的大躍進，主要依賴更大型病患的更長期結果，不過，Delaney醫師對於他們的技術最後將成為主流且廣被使用感到樂觀；它的確可以減少移植物成功生長的時間。她表示，這是希望所在，使用這個方法將可提供臨床助益且將更廣為使用。
　　
　　國家健康研究中心支持本研究，研究者皆宣告沒有相關財務關係。
　　
　　Nat Med. 線上發表於2010年1月17日。


Expanded Umbilical Cord Blood Units Speed Engraftment During transplantation

By Roxanne Nelson
Medscape Medical News

January 25, 2010 — Although these results are early and continue to evolve, researchers have found a way to optimize umbilical cord blood for use in stem cell transplantation. According to data published online January?17 in Nature Medicine, the use of ex?vivo expanded stem cells from umbilical cord blood led to rapid engraftment in patients with high-risk acute leukemias who were in morphologic remission at the time of transplantation.

Researchers from the Fred Hutchinson Cancer Research Center in Seattle, Washington, developed a clinically relevant Notch-mediated ex?vivo expansion system for human CD34+ cord blood progenitors. The resulting cord blood progenitors expanded ex?vivo in the presence of Notch ligands, and when they were infused after a myeloablative preparative regimen for stem cell transplantation, the time to neutrophil recovery was substantially reduced.

After an average follow-up time of 1 year, 7 of the 10 patients who underwent transplantation were alive, with no evidence of disease and with sustained complete donor engraftment.

This is the first demonstration of rapid hematopoietic engraftment derived from ex?vivo expanded hematopoietic progenitors, the researchers note. Preliminary results from the study were first presented at the 2008 annual meeting of the American Society of Hematology, and were reported at that time by Medscape Oncology.

Research Early But Encouraging

Although this is still early research with a very small cohort, the results are encouraging, explained lead author Colleen Delaney, MD, MSc, director of the Cord Blood Transplant Program at Fred Hutchinson.

However, even though rapid neutrophil engraftment has been shown in the patients treated to date, more data are needed. "We are planning a phase?2/3 trial that will involve a much larger group of patients in a randomized fashion," she told Medscape Oncology. "We have definitively shown that ex?vivo expanded hematopoietic stem/progenitor cells can rapidly engraft."

The next step, she added, is to demonstrate these same findings in a larger trial. They are also planning on using this technique in more patients at their institution.

Cord blood is an effective and widely used source of stem cells for patients needing hematopoietic stem cell transplantation, the authors note, but the time to donor engraftment is relatively slow. On average, it takes more than 3 weeks to achieve an adequate number of myeloid cells, leaving the patient susceptible to infection.

Investigations aimed at improving the rate of engraftment using ex?vivo cytokine-mediated expansion methods to generate increased numbers of cells have been less than successful, and have not demonstrated significant clinical effects, they write.

Dr. Delaney and her team examined the role of the Notch signaling pathway in the regulation of ex?vivo expansion of hematopoietic stem/progenitor cells, with the goal of developing a method of increasing cell numbers that is capable of providing rapid myeloid engraftment.

In 3 previous experimental trials, the researchers observed measurable human cell engraftment (defined as ?0.5% human CD45+ cells) 10 days after transplantation in the marrow of mice who had received cultured cells. This was compared with no engraftment in mice who received noncultured cord blood cells. This engraftment consisted of more than 95% myeloid cells, and indicated to the researchers the ability of Notch-expanded cord blood progenitors to substantially accelerate hematopoietic repopulation in an experimental setting.

Faster Engraftment Observed

In the current phase?1 trial, each patient received 2 units of cord blood after a myeloablative preparative regimen. One unit was unmanipulated cord blood cells, and the second contained cord blood progenitors that had undergone Notch-mediated ex?vivo expansion.

The cohort consisted of 10 patients with high-risk leukemias who had a median age of 27.5 years (range, 3 to 43 years). Among this group, the median time to achieve an absolute neutrophil count of more than 100 cells/μL was 9 days, compared with 19 days in patients undergoing a double unmanipulated cord blood transplant (P?= .006).

Although 1 patient experienced primary graft rejection, the authors did not observe any toxic effects related to the infusion or other safety concerns.

They did observe substantially enhanced rates of myeloid engraftment, and the median time to neutrophil recovery was decreased by more than 1 week, compared with neutrophil recovery after infusion of 2 unmanipulated units, as reported in published literature. The expanded cells contributed almost exclusively to the initial myeloid engraftment that was observed at 1 week. This demonstrated "an enhanced capacity of the expanded cell graft to provide rapid myeloid recovery," they write.

Of the evaluable 8 patients, 7 of whom were engrafted before day?21, this was independent of whether the expanded cell graft persisted in?vivo. Conversely, the average time to engraftment is approximately 4 weeks in a double unmanipulated cord blood transplant. These results, note the authors, are "highly suggestive of a facilitating effect of the cultured cells in promoting engraftment from the unmanipulated cord blood unit."

All evaluable patients experienced acute grade?2 graft-vs-host disease (GVHD); acute grade?3 GVHD was observed in 1 patient. All responded to treatment and, at this time, 3 patients have been diagnosed with chronic limited GVHD.

Next Step Forward?

Whether or not this technique will be the next leap forward in advancing stem cell transplantation largely depends on longer-term patient outcomes in larger populations. However, Dr. Delaney is optimistic that their technique will eventually become more mainstream and widely used; it does appear to cut down on the engraftment time. "That is the hope," she said, "that the use of this methodology will provide clinical benefit and will be more widely available."

The study was supported by the National Institutes of Health. The researchers have disclosed no relevant financial relationships.

Nat Med. Published online January?17, 2010.