Biological purging of breast cancer cells using an attenuated replication-competent herpes simplex virus in human hematopoietic stem cell transplantation

Autologous hematopoietic stem cell transplantation after myelosuppressive chemotherapy is used for the treatment of high-risk breast cancer and other solid tumors. However, contamination of the autologous graft with tumor cells may adversely affect outcomes. Human hematopoietic bone marrow cells are resistant to herpes simplex virus type 1 (HSV-1) replication, whereas human breast cancer cells are sensitive to HSV-1 cytotoxicity. Therefore, we examined the utility of G207, a safe replication-competent multimutated HSV-1 vector, as a biological purging agent for breast cancer in the setting of stem cell transplantation. G207 infection of human bone marrow cells had no effect on the proportion or clonogenic capacity of CD34+ cells but did enhance the proliferation of bone marrow cells in culture and the proportion of CD14+ and CD38+ cells. On the other hand, G207 at a multiplicity of infection of 0.1 was able to purge bone marrow of contaminating human breast cancer cells. Because G207 also stimulates the proliferation of human hematopoietic cells, it overcomes a limitation of other purging methods that result in delayed reconstitution of hematopoiesis. The efficient infection of human bone marrow cells in the absence of detected toxicity suggests that HSV vectors may also prove useful for gene therapy to hematopoietic progenitor cells.     

异基因造血干细胞移植治疗白血病的临床研究

目的探讨异基因造血干细胞移植治疗白血病。方法脐血移植治疗儿童白血病3例,异基因外周血造血干细胞移植治疗白血病3例。结果6例患者完全植入,+15～+25天白细胞(WBC)>1.0×109/L,+35天～+51天血小板(Plt)>20×109/L。例1出现急性GVHDⅠ度,例5出现急性GVHDⅣ度,例6出现肝静脉闭塞综合征(VOD)、急性GVHDⅠ度、出血性膀胱炎(HC),例2移植后6个月复发,放弃治疗死亡。余5例正常生活或工作。结论异基因造血干细胞移植治疗白血病是安全有效的方法。     

异基因造血干细胞移植治疗白血病

目的探讨异基因造血干细胞移植(Allo-HSCT)治疗白血病的疗效、造血重建及生存情况.方法白血病患者10例,其中同胞间HLA相合的异基因外周血干细胞移植(Allo-PBSCT)7例,无亲缘关系HLA不全相合脐血移植(UCBT)3例.结果9/10例受者获造血重建,UCBT患者造血重建速度较HLA相合的同胞PBSCT慢,1例UCBT移植后35天造血未重建,回输自体外周血干细胞后,仍未能重建造血,于72天死亡.其余至今均无病生存.结论Allo-HSCT是目前治愈白血病的有效方法,对于无同胞HLA相合的供者,选择细胞数量较高、HLA 1～2个位点不合的UCBT仍然有效可行.     

间充质干细胞在造血干细胞移植中的应用

 间充质干细胞是一种能够从各种人成体组织分离出来的非造血多能干细胞,近年来,许多研究表明间充质干细胞具有免疫调节能力及促进组织重建等功能。就其在造血干细胞移植中的应用,如急慢性移植物抗宿主病（GVHD）、GVHD造成的移植失败、纯红细胞再生障碍性贫血及免疫性血小板减少性紫癜、出血性膀胱炎作以综述。     

Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia

There never has been a more difficult time to advise patients newly diagnosed with chronic myeloid leukemia (CML). Until recently,the options comprised noncurative but relatively nontoxic chemotherapy or potentially curative allogeneic stem cell transplantation,with its attendant morbidity and mortality. There now is the additional option of the tyrosine kinase inhibitor imatinib mesylate that has been in clinical practice for almost 5 years. Although data are emerging regarding the efficacy of imatinib, solid evidence of any prolongation in survival will be delayed for several years. Future management of CML will continue to depend on a combination of approaches that use allografting and targeted drug therapy. The next decade undoubtedly will witness the introduction of a number of agents capable of inhibiting signal transduction pathways,perhaps controlling CML in cases of primary or acquired imatinib resistance. In the absence of long-term outcome data for imatinib,it remains reasonable to propose that young patients with newly diagnosed CML who have HLA-identical or well-matched unrelated donors should undergo allogeneic transplantation using a standard or nonmyeloablative conditioning regimen. Similarly,patients who fail to respond to imatinib should be rescued with a transplant strategy. The role of molecular monitoring in these two strategies cannot be underestimated.     

Dendritic cells in allogeneic hematopoietic stem cell transplantation

In allogeneic hematopoietic stem cell transplantation (SCT), dendritic cells (DCs) as the most potent antigen-presenting cells play a central role in the development of acute and chronic graft-vs-host disease (GVHD), in graft-vs-leukemia or -malignancy reactions and in fighting infectious complications. Functional maturity and distribution of DC sub-types (DC1 and DC2) differ between the different stem cell sources used (bone marrow, granulocyte colony-stimulating factor-mobilised peripheral blood and cord blood) resulting in various rates of graft-vs-host disease and graft-vs-leukemia activity. Although DC recovery following stem cell transplantation is prompt, graft-vs-host disease and the use of immunosuppressive drugs result in qualitative and quantitative disturbances in DC  homeostasis and have been observed for up to 1 year after transplantation. Complete donor DC chimerism seems to be a pre-requisite for the development of chronic GVHD and for graft-vs-leukemia activity, at least following reduced-intensity transplants, although in the early phase of acute graft-vs-host disease the presence of host antigen-presenting cells is essential. Preliminary data show promising results with DC-based immunotherapy for treatment of viral and fungal infections and of leukemic relapse following allogeneic stem cell transplantation. More information on the mechanisms and interactions between dendritic cells and regulatory T cells is needed for DC vaccination concepts for modulation of graft-vs-host disease.     

Pediatric hematopoietic stem cell transplantation.

The successful use of allogeneic HSCT for children with malignant and nonmalignant diseases continues to be limited by the development of acute and chronic GVHD, infectious complications, delayed recovery of the immune system, acute and long-term toxicity, and relapse of disease. Significant advances have been made, particularly in the ability to identify suitable sources of HSC. Future advances will depend on a better understanding of the biology of HSC sources, GVHD, immune reconstitution, and common complications. Improved therapies are dependent on participation of children in well-designed, translational and clinical transplant studies.     

异基因造血干细胞移植治疗急性髓系白血病的现状

 异基因造血干细胞移植（allo-HSCT）是治疗急性髓系白血病（AML）的有效方法之一。allo-HSCT的治疗作用来自于预处理中的放疗和（或）化疗,以及供者免疫系统的移植物抗白血病（GVL）效应。近十年来,随着对白血病细胞生物学特性研究的不断深入,根据细胞遗传学和分子标志对AML进行危险程度分级,使我们能够挑选出哪些AML患者可以从allo-HSCT中获益。allo-HSCT治疗AML的临床疗效已有明显提高,并且适用范围也较前扩大,但在AML中的应用还存在一定差异。现对allo-HSCT治疗AML的机制、时机、疗效、供者选择及预处理方案进行讨论。     

Allogeneic hematopoietic stem cell transplantation for adult acute lymphocytic leukemia

Allogeneic hematopoietic stem cell transplantation (alloHCT) is the single most potent treatment modality to prevent relapse in adults with acute lymphocytic leukemia, but its optimal use and timing remains a matter of intense debate and research. There is general agreement that patients with clinical features of high risk for relapse should undergo alloHCT in first complete remission. However, newer studies suggest that even patients without these risk factors may benefit. Monitoring of minimal residual disease may improve risk stratification and may complement or replace conventional risk features. Prognosis in relapsed and refractory patients is dismal, and alloHCT should be performed as soon as possible. AlloHCT also offers the only reasonable chance for cure in Philadelphia chromosome-positive acute lymphocytic leukemia; the role of imatinib is not yet clearly defined. Recent developments in unrelated-donor transplantation and reduced-intensity conditioning allow the beneficial effects of alloHCT to reach a considerably wider patient population.     

Alloreactive natural killer cells in hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia can play a major role in reducing the risk of relapse by inducing a graft versus leukemia (GVL) effect. Here, we review the effectiveness of mismatching inhibitory killer-cell-immunoglobulin-like receptors (KIR) on donor natural killer (NK) cells as a mechanism for GVL. We review the range of KIR and the importance of T cell and NK cell content of the graft, together with considerations of the graft source. Further understanding of conditioning and mechanisms to reduce graft versus host disease (GVHD) will improve our ability to manipulate NK cells in HSCT.     

Allogeneic hematopoietic stem cell transplantation for patients with acute leukemia

Objective

The purposes of this study were to assess the efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia (AL) and analyze the factors affecting the prognosis of these patients.

Methods

The clinical and follow-up data of 93 AL patients (median age, 30 years) undergoing allogeneic HSCT in Xiangya Hospital over the past 12 years were collected, and the potential factors affecting the efficacy and prognosis of allogeneic HSCT patients were determined.

Results

Hematopoietic reconstitution was achieved in 90 patients. At the last follow-up, the incidences of severe acute graft versus host disease (aGvHD) and extensive chronic GvHD (cGvHD) were 14.0% and 20.0%, the 3-year cumulative incidence of transplantation related mortality (TRM) and relapse rate were 16.8%±6.1% and 21.3%±6.7%, and the estimated 3-year overall survival (OS) and disease-free survival (DFS) of the patients were 64.6%±5.4% and 56.5%±5.5%, respectively. Univariate analysis indicated that age older than 40 years, HLA mismatch, and severe lung infection within the first 100 days after transplantation were risk factors for severe aGvHD, age older than 40 years, HLA mismatch, severe lung infection within the first 100 days after transplantation, and severe aGvHD were risk factors for TRM, high-risk AL and lack of cGvHD were risk factors for relapse (all P<0.05). Survival estimation showed that HLA mismatch, severe lung infection occurring within the first 100 days post-transplantation, high-risk AL severe aGvHD and lack of cGvHD were risk factors associated with poor prognosis (all P<0.05). Further multivariate analyses revealed that severe lung infection within the first 100 days post-transplantation, severe aGvHD and lack of cGvHD were independent risk factors for unfavorable outcomes (all P<0.05).

Conclusions

Allogeneic HSCT can improve the DFS of AL patients, and severe lung infection within the first 100 days post-transplantation, severe aGvHD and lack of cGvHD are independent risk factors affecting the prognosis.Key Words: Leukemia, hematopoietic stem cell transplantation (HSCT), graft-versus-leukemia effect     

治疗相关性白血病异基因造血干细胞移植疗效分析

目的:探讨异基因造血干细胞移植（allo-HSCT）对治疗相关性白血病（TRL）的临床效果。方法:回顾性分析2012年4月至2020年2月于航天中心医院接受allo-HSCT的14例TRL患者的临床资料,分析其疗效及生存情况。结果:14例患者中,男性5例,女性9例;中位年龄35岁（12~59岁）;急性髓系白血病12例,慢性淋巴细胞白血病/小细胞淋巴瘤1例,急性淋巴细胞白血病1例。移植时4例骨髓完全缓解,3例骨髓部分缓解,其余7例均未缓解。亲缘全相合移植5例,单倍型移植9例,均采用清髓性预处理方案。14例患者均顺利植活,中位粒细胞植活时间为16 d（10~24 d）,中位血小板植活时间为13 d（10~34 d）。7例发生Ⅰ~Ⅱ级急性移植物抗宿主病（GVHD）,6例发生慢性GVHD,2例发生Ⅲ级肠道GVHD。中位随访时间32个月（4~97个月）,14例患者中5例死亡。结论:allo-HSCT可以改善TRL患者的预后,提高长期生存率。     

Revisiting the role of hematopoietic stem cell transplantation in chronic lymphocytic leukemia

Since the advent of hematopoietic stem cell transplantation more than 40 years ago, numerous methods of transplantation have been developed, modified and improved upon. Although hematopoietic stem cell transplantation has been used in a variety of malignant diseases since then, its use in the treatment of chronic lymphocytic leukemia has recently started to gain interest. Patients with chronic lymphocytic leukemia are generally elderly, and because of its relatively benign course, they were not considered suitable candidates for hematopoietic stem cell transplantation. Nonetheless, there have been marked improvements in transplantation techniques, including better conditioning regimens that have decreased treatment-related morbidity and mortality. In this article, the authors review the most recent data on hematopoietic stem cell transplantation in chronic lymphocytic leukemia as well as the change in risk stratification based on newer prognostic factors and its impact on treatment decisions in chronic lymphocytic leukemia.     

Revisiting the role of hematopoietic stem cell transplantation in chronic lymphocytic leukemia

Since the advent of hematopoietic stem cell transplantation more than 40 years ago, numerous methods of transplantation have been developed, modified and improved upon. Although hematopoietic stem cell transplantation has been used in a variety of malignant diseases since then, its use in the treatment of chronic lymphocytic leukemia has recently started to gain interest. Patients with chronic lymphocytic leukemia are generally elderly, and because of its relatively benign course, they were not considered suitable candidates for hematopoietic stem cell transplantation. Nonetheless, there have been marked improvements in transplantation techniques, including better conditioning regimens that have decreased treatment-related morbidity and mortality. In this article, the authors review the most recent data on hematopoietic stem cell transplantation in chronic lymphocytic leukemia as well as the change in risk stratification based on newer prognostic factors and its impact on treatment decisions in chronic lymphocytic leukemia.     

自体造血干细胞体外净化研究的新进展

高剂量化、放疗联合自体造血干细胞移植已广泛用于恶性肿瘤的治疗研究。综合资料显示,其对多发性骨髓瘤患者,可提高18％的5年无病生存率和40％的5年总生存率;对化疗敏感的复发性中高度恶性非霍奇金淋巴瘤患者,可提高10％左右的长期生存率。近10多年来,该项技术被试用于难治性乳腺癌、睾丸癌、卵巢癌、小细胞肺癌、鼻咽癌、儿童纤维母细胞瘤、软组织肉瘤等实体瘤的治疗研究,并已初步显示出较好的疗效。     

Graft-versus-Tax response in adult T-cell leukemia patients after hematopoietic stem cell transplantation

Adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) is characterized by poor prognosis after chemotherapy. Recent clinical trials have indicated, however, that allogeneic but not autologous hematopoietic stem cell transplantation (HSCT) for ATL can yield better clinical outcomes. In the present study, we investigated cellular immune responses of ATL patients who obtained complete remission after nonmyeloablative allogeneic peripheral blood HSCT from HLA-identical sibling donors. In the culture of peripheral blood mononuclear cells (PBMCs) from a post-HSCT but not pre-HSCT ATL patient, CD8(+) CTLs proliferated vigorously in response to stimulation with autologous HTLV-I-infected T cells that had been established before HSCT in vitro. These CTLs contained a large number of monospecific CTL population directed to a HLA-A2-restricted HTLV-I Tax 11-19 epitope. The frequency of Tax 11-19-specific CD8+ CTLs in this patient markedly increased also in vivo after HSCT, as determined by staining with HLA-A2/Tax 11-19 tetramers. Similar clonal expansion of HTLV-I Tax-specific CTLs exclusively directed to a HLA-A24-restricted Tax 301-309 epitope was observed in the PBMCs from another ATL patient after HSCT from a HTLV-I-negative donor. Among four post-HSCT ATL patients tested, HTLV-I-specific CTLs were induced in the PBMC culture from three patients but not from the remaining one who had later recurrence of ATL. These observations suggested that reconstituted immunity against antigen presentation in ATL patients after HSCT resulted in strong and selective graft-versus-HTLV-I response, which might contribute to graft-versus-leukemia effects.     

Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder of early childhood. In all, 21 patients with JMML who received donor leukocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT) for either mixed chimerism (MC, n=7) or relapse (n=14) were studied. Six patients had been transplanted from an HLA-matched sibling and 15 from other donors. Six of the 21 patients (MC: 3/7 patients; relapse: 3/14 patients) responded to DLI. Response rate was significantly higher in patients receiving a higher total T-cell dose (> or =1 x 10(7)/kg) and in patients with an abnormal karyotype. None of the six patients receiving DLI from a matched sibling responded. Response was observed in five of six patients who did and in one of 15 children who did not develop acute graft-versus-host disease following DLI (P=0.01). The overall outcome was poor even for the responders. Only one of the responders is alive in remission, two relapsed, and three died of complications. In conclusion, this study shows that some cases of JMML may be sensitive to DLI, this providing evidence for a graft-versus-leukemia effect in JMML. Infusion of a high number of T cells, strategies to reduce toxicity, and cytoreduction prior to DLI may improve the results.     

Nutritional assessment with different tools in leukemia patients after hematopoietic stem cell transplantation

Objective： Correct nutritional assessment is essential for leukemia patients after hematopoietic stem cell transplantation （HSCT）. This study aimed to investigate the best nutritional assessment method for leukemia patients after HSCT, and find the possible nutritional risk of the patients during the transplantation process in order to intervene in the patients with nutritional risks and undernourished patients timely, so that the entire transplantation process could be successfully completed. Methods： A prospective study was performed in 108 leukemia patients after HSCT, and different nutritional assessment methods, including nutritional risk screening 2002 （NRS2002）, mini nutritional assessment （MNA）, subjective globe assessment （SGA） and malnutritional universal screening tools （MUST）, were used. The associations between nutritional status of these patients and nutritional assessment methods were analyzed. Results： A total of 108 patients completed SGA, and 99 patients completed NRS2002, MNA and MUST. During the treatment process, 85.2% of the patients lost weight, wherein, 50% lost weight greater than 5%, and 42.6% had significantly reduced food intake. For nutritional risk assessment, the positive rates of NRS2002, MNA and MUST were 100%, 74.7% and 63.6%, respectively. There was a significant difference （P〈0.05） among the positive rates of NRS2002, MNA and MUST. In undernutrition assessment, the positive rate of SGA （83.3%） was significantly higher than that of MNA （17.2%） （P〈0.05）, and the incidence rate of nutritional risk among leukemia patients _〈30 years old was greater than that of patients 〉30 years old （P〈0.05）. Conclusions： Patients with leukemia were in poor nutritional status during and after HSCT. The leukemia patients 〈30 years old had a greater incidence rate of nutritional risk. As nutritional risk screening tool, the specificity of NRS2002 is not high, but it can be used for evaluating nutritional deficiencies. MNA is a good nutritional risk screening tool, but not an adequate tool for nutritional assessment. If assessment of undernutrition is necessary, the combination of all these screening tools and clinical laboratory indicators should he applied to improve accuracy.     

Reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematologic malignancy with a peak incidence over the age of 55 years. AML of older patients is less curable with conventional chemotherapy, and, when it relapses, is almost uniformly fatal. Novel treatments hold the promise of improving the results of therapy, but have failed so far to show dramatic change in the prognosis. Allogeneic stem cell transplantation using traditional myeloablative preparative regimens is not easily tolerated by the elderly and/or frailer patient, and may lead to prohibitive treatment-related mortality rates. Most patients treated in the past were younger and devoid of comorbid clinical conditions. Novel reduced-intensity regimens made allogeneic transplants applicable to the elderly, providing the benefit of the graft-versus-leukemia effect to a larger number of patients in need. Here we review the indications for allogeneic transplants in AML and discuss reduced-intensity conditioning regimens.