In this issue of the journal, Kindwall‐Keller and Ballen present a targeted overview of the advantages, disadvantages, and milestones of cord blood transplantation over the past 30 years.1 First they highlight the advantages of cord blood as a source of donor cells for hematopoietic transplantation, including off the shelf availability, increased tolerance for HLA mismatching, lower incidence of acute and chronic GvHD, lower risk of infectious disease transmission, and improved protection against leukemic relapse in high risk patient populations. They also make several important points about the limitations of cord blood in transplantation, highlighting slower engraftment, delayed immune reconstitution, and cost amongst others. Overall, the report is somewhat pessimistic about the overall outlook of this novel graft source.

More than 4 decades ago, Hal Broxmeyer showed that cord blood (CB), the baby's blood left over in the placenta after birth and usually discarded as medical waste, was enriched for hematopoietic stem and progenitor cells (HSCs).2 He further demonstrated that CB cells had a higher proliferative capacity and higher ratios of stem to progenitor cells compared with adult bone marrow (BM) confirming the old saying that “younger is better.” Broxmeyer led a group of investigators in NYC to develop techniques to collect and cryopreserve CB with the goal of performing a transplant in which CB was substituted for BM as the source of HSCs. The first transplant, performed by Eliane Gluckman in Paris, France, in 1988 using HLA‐identical sibling CB to treat a 5‐year‐old boy with Fanconi anemia, was a success.3 What an amazing phenomenon of nature, allowing recycling of otherwise discarded material to potentially save lives!

Subsequent CB transplants between siblings demonstrated a 10‐fold decrease in the incidence of acute Graft‐vs‐Host Disease (GvHD),4 and this led to the hypothesis that CB could substitute for BM as a donor for HSC transplant (HSCT) without complete HLA matching. Pablo Rubinstein and colleagues set up the first unrelated donor CB bank in the US in 1991. The results of the first 25 unrelated donor cord blood transplants (UCBT), performed between 1993‐1996, were reported by my group in 1996.5 This was followed by additional reports of UCBT outcomes, all demonstrating that CB could be cryopreserved and banked, that CB conferred durable myeloid and lymphoid engraftment (albeit at a slower rate, increasing treatment‐related mortality than other sources of HSCs), and that CB was transplantable without full HLA matching without increasing the incidence of GvHD, thereby providing donors for patients unable to identify donors in their families or the adult unrelated registries.6-8 Over the subsequent decade, hundreds of cord blood banks, both public and private, were established worldwide. Internationally, an inventory approaching 800 000 units has been accrued to public cord blood banks. In the US, federally sponsored legislation, the C.W. Bill Young Cell Transplantation Program's National Cord Blood Inventory, which subsidizes banking of high quality cord blood units, was established in 2006. Of note, CB is the only HSC source that is licensed by the US Food and Drug Administration (FDA). Guidance for FDA licensure of public CB banks was issued in 2011 and finalized in 2014 and, to date, there have been 8 public CB banks licensed in the US.

The cell dose of the CB unit used in a transplant was established as a critical attribute for a successful transplant, and the minimum cell dose was set at 25 million cells/kg based on the pre‐cryopreservation count. This led to the successful use of CB as a donor for children in need of HSCT for malignant or non‐malignant conditions. In the early days of UCBT, it was assumed that a CB unit would not have enough cells to transplant most adults. Also, the size of the baby was determined to predict the size of a CB unit and since babies can only be so big, increasing the volume of collected CB was not going to solve this problem.9 In 2005, Juliet Barker and John Wagner showed that the dose of cells could be increased by utilizing 2 CB units for a single patient's transplant.10 Interestingly, only one CB donor would ultimately engraft, but the other unit appeared to serve a helper function that improved outcomes; yet, a landmark pediatric study conducted by the BMT‐CTN failed to demonstrate an advantage of double cord blood transplantation over single cord blood transplantation in pediatric patients with leukemia.11 Alternative approaches to expand CB cells prior to transplantation have been under investigation for more than a decade, and in the past few months, Nicord (Omidubicel), expansion of CD133 cells in nicotinamide, manufactured by Gamida Cell Ltd in Jerusalem, achieved the primary endpoint of accelerating neutrophil engraftment in a phase III registration trial and is under consideration for licensure from the US FDA. This is an exciting advance for the CB field, because it provides the opportunity to utilize the current public inventory of banked units for patients of all sizes and to shorten times to engraftment and length of hospitalization and to improve overall outcomes.

Despite the slower engraftment and increased transplant‐related mortality (TRM) associated with UCBT, overall outcomes focused on relapse‐free, GvHD‐free survival are equivalent or superior to those seen with other HSC sources. This is because the increased TRM is out competed by the decreased acute and chronic GvHD and improved protection against relapse in patients with hematological malignancies. Recent studies have shown a benefit for UCBT in adult patients with high‐risk hematological malignancies, where it is clear that graft vs leukemia (GVL) effects are preserved without increased GvHD.12 CB is also an ideal graft source for newborns and infants where cell dose is relatively higher and engraftment is rapid. In addition, because CB is essentially an “off‐the‐shelf” product, it is readily available as a donor source for infants diagnosed with congenital leukodystrophies or immune deficiency syndromes requiring transplantation in the first 1‐2 months of life. With more and more of these diseases being diagnosed through newborn screening, the need for CB as the donor source for transplantation will increase. Furthermore, for some genetic diseases, collection of autologous cord blood to be used as the source of HSCs for transfection provides an ideal, non‐invasive source of cells for this technology. In sickle cell disease, where maintenance of expression of the gamma gene is a novel approach to gene therapy, cord blood, where the gamma gene is biologically still “on” is the ideal source of HSCs for this approach.

The ability to identify a fully matched donor for a patient in need of an unrelated donor for transplant is decreasing and over the next 1‐2 generations, with additional mixing of races and ethnicities, expected to be even more difficult. Despite 22 million volunteer donors registered with the National Marrow Donor Program's Be the Match Registry and despite more than 32 million volunteer donors worldwide, full matching is becoming more and more challenging; therefore, a readily available source of donor cells that can be used without full matching but still capable of engrafting, causing minimal GvHD, and controlling leukemic relapse is highly desirable. Over the past 3‐5 years, the use of haplo‐identical related donors has emerged as a potential solution to this problem, but haplo transplants have increased relapse rates in some patients with blood cancers and increased rejection rates in some patients with genetic diseases, so haplo is not the perfect solution either.

Finally, CB banks have developed unique expertise in GMP manufacturing of cellular products. They have created infrastructure to recruit donors, procure CB and birthing tissues, determine donor eligibility, test, process, cryopreserve, ship and thaw qualified CB units for transplantation. In addition, they have the expertise and regulatory bandwidth to procure, harvest and store birthing tissues which can be utilized to manufacture cell therapies for use in regenerative medicine. Highly effective immunotherapies including allogeneic CAR‐NK and cytotoxic T‐cells (CTLs) have been manufactured from cord blood and are in development for commercialization.13, 14 Derivatives of cord blood CD14 monocytes are in clinical trials for treatment of hypoxic and demyelinating diseases15-18 and cord blood is being investigated as a therapy for children with autism spectrum disorder, a severely disabling disease with increasing prevalence in our society.19, 20 Finally cord and placental tissues are robust sources of mesenchymal stromal cells which are undergoing testing in many diseases as immune modulators and suppressors of pro‐inflammatory states,21 including as a treatment for complications of COVID‐19.22

So I'm not giving up on cord blood and products from related birthing tissues. The CB industry was the first to enter the regulated cell therapy environment, but its experience and progress to date can be leveraged for the development of many promising and exciting therapies to come.

在本期杂志中，Kindwall-Keller和Ballen简要介绍了过去30年间脐带血移植的优缺点和里程碑。1个首先，他们强调了脐带血作为造血移植供体细胞来源的优势，包括现成的可用性，对HLA错配的耐受性提高，急性和慢性GvHD的发生率降低，传染病传播的风险降低以及对白血病的防护提高高危患者人群中复发。他们还对脐带血在移植中的局限性提出了几个重要观点，强调移植速度慢，免疫重建延迟以及成本高昂。总体而言，该报告对这种新型移植物来源的总体前景有些悲观。

超过四十年前，Hal Broxmeyer表明脐带血（CB）是婴儿出生后残留在胎盘中的血液，通常作为医疗废物丢弃，富含造血干细胞和祖细胞（HSC）。2他进一步证明，与成人骨髓（BM）相比，CB细胞具有更高的增殖能力和干细胞与祖细胞的比率，这证实了古老的说法：“年轻人越好”。Broxmeyer带领纽约市的一组研究人员开发了收集和冷冻保存CB的技术，目的是进行以CB代替BM作为HSC来源的移植。1988年，由Eliane Gluckman在法国巴黎进行的第一例移植手术成功地使用了HLA同胞CB治疗5岁的范科尼贫血男孩。3多么令人惊奇的自然现象，允许回收本来可以丢弃的材料以挽救生命！

随后在兄弟姐妹之间进行的CB移植证明急性Gravs-vs-Host病（GvHD）的发病率降低了10倍，[ 4]这导致了这样的假设，即CB可以替代BM来完成HSC移植（HSCT）的供体HLA匹配。Pablo Rubinstein及其同事于1991年在美国建立了第一家无关的捐助者CB库。我的小组在1996年报告了1993年至1996年之间进行的前25次无关的捐助者脐带血移植（UCBT）的结果。5接下来是关于UCBT结局的其他报道，所有这些都表明CB可以被冷冻保存和保存，CB赋予了持久的髓样和淋巴样植入（尽管其速度较慢，与其他HSC来源相比，与治疗相关的死亡率增加），以及CB无需完全HLA匹配就可以移植，而不会增加GvHD的发生率，从而为无法确定其家庭或成人无关登记人的患者提供了捐助者。6-8在随后的十年中，全球建立了数百家公共和私人脐带血库。在国际上，公共脐带血库的库存已接近80万个单位。在美国，由联邦政府赞助的立法于2006年建立了CW Bill Young细胞移植计划的国家脐带血清单，该清单对高质量脐带血单位的储备进行了补贴。值得注意的是，CB是唯一获得美国许可的HSC来源食品和药物管理局（FDA）。FDA于2011年发布并于2014年最终确定了FDA对公共CB银行的许可的指南，迄今为止，在美国已有8家公共CB银行获得许可。

移植中使用的CB单元的细胞剂量被确定为成功移植的关键属性，根据冷冻保存前的计数，最小细胞剂量设定为2500万个细胞/ kg。这导致成功将CB用作需要HSCT的恶性或非恶性疾病儿童的捐助者。在UCBT的早期，人们认为CB单元没有足够的细胞来移植大多数成年人。同样，确定婴儿的大小可以预测CB单元的大小，并且由于婴儿只能这么大，因此增加收集的CB的体积并不能解决这个问题。9 2005年，朱丽叶·巴克（Juliet Barker）和约翰·瓦格纳（John Wagner）表明，通过为单个患者的移植使用2个CB单元，可以增加细胞剂量。10有趣的是，只有一个CB捐助者最终会植入，但是另一个单位似乎起到了辅助功能的作用，从而改善了结果。然而，BMT-CTN进行的一项里程碑式的儿科研究未能证明在患白血病的小儿患者中，双脐带血移植优于单脐带血移植。11在移植前扩增CB细胞的替代方法已经进行了十多年的研究，在过去的几个月中，由耶路撒冷Gamida Cell Ltd制造的Nicord（Omidubicel）在烟酰胺中扩增CD133细胞达到了主要终点。 III期注册试验中加速中性粒细胞植入的研究，正在考虑获得美国FDA的许可。对于CB领域而言，这是令人振奋的进步，因为它提供了一个机会，可以利用当前针对各种规模患者的库存病房公共库存，并缩短移植时间和住院时间，并改善总体疗效。

尽管与UCBT相关的植入速度较慢，且与移植相关的死亡率（TRM）增加，但以无复发，无GvHD生存为重点的总体结果与其他HSC来源的结果相同或更好。这是因为TRM的增加无法与急性和慢性GvHD的降低以及血液恶性肿瘤患者复发的保护措施相抗衡。最近的研究表明，在高危血液恶性肿瘤成年患者中，UCBT有益，很明显，在不增加GvHD的情况下，移植物抗白血病（GVL）作用得以保留。12CB还是细胞剂量相对较高且植入迅速的新生儿和婴儿的理想移植物来源。此外，由于CB本质上是一种“现货”产品，因此可以很容易地作为诊断为先天性白细胞营养不良或免疫缺陷综合征的婴儿的供体来源，需要在出生后的1-2个月内进行移植。随着越来越多的新生儿筛查诊断出这些疾病，对CB作为移植供体来源的需求将会增加。此外，对于某些遗传性疾病，自体脐带血的收集可用作HSC转染的来源，为该技术提供了理想的非侵入性细胞来源。在镰状细胞病中，维持伽马基因的表达是一种基因治疗的新方法，脐带血，

为需要无关的供体移植的患者确定完全匹配的供体的能力正在下降，并且在接下来的1-2代中，种族和种族的进一步混合预计将更加困难。尽管有2200万志愿者捐赠者在国家骨髓捐赠者计划的Be Match注册表中注册，尽管全球有3200万志愿者捐赠者，但完全匹配正变得越来越困难。因此，非常希望有一种供体细胞容易获得的，无需完全匹配就可以使用但仍能够移植，引起最小的GvHD并控制白血病复发的来源。在过去的3-5年中，使用与单倍身份相关的捐赠者已成为解决该问题的一种潜在方法，

最后，CB银行在蜂窝产品的GMP制造方面已发展出独特的专业知识。他们建立了基础设施，以招募捐献者，购买CB和分娩组织，确定捐献者的资格，测试，加工，冷冻保存，运送和融化合格的CB单位进行移植。此外，他们具有采购，收获和储存分娩组织的专业知识和监管带宽，可用于制造用于再生医学的细胞疗法。高度有效的免疫疗法包括同种异体CAR-NK和细胞毒性T细胞（CTL），已从脐带血中制备出来，并且正在商业化开发中。13，14脐带血CD14单核细胞衍生物正在临床试验中治疗缺氧和脱髓鞘疾病15-18目前正在研究脐带血作为自闭症谱系障碍儿童的一种疗法，这是一种严重的致残性疾病，在我们的社会中越来越流行。19，20最后，脐带和胎盘组织是间充质基质细胞的强大来源，正在接受许多疾病的检测，作为促炎状态的免疫调节剂和抑制剂，21包括作为治疗COVID-19并发症的方法。22

因此，我不会放弃脐带血和相关分娩组织的产物。CB行业是第一个进入受控细胞疗法环境的行业，但是其经验和迄今的进展可用于开发许多有前途和令人兴奋的疗法。