The allogeneic effect in non-Hodgkin's lymphoma

Allogeneic hematopoietic stem cell transplantation (HSCT) has been restricted to medically fit patients under the age of 55 years due to adverse effects of the intensive conditioning regimens. Autologous HSCT has not proven to be a particularly effective treatment for patients with low-grade non-Hodgkin's lymphoma (NHL). Much of the benefit of allogeneic HSCT appears to be mediated by a graft-vs.-tumor (GVT) effect. Reduced-intensity regimens in allogeneic HSCT have been developed to minimize conditioning regimen-related toxicities and to control the malignancy until a GVT effect is established. A number of studies investigating reduced-intensity allogeneic HSCT are discussed. Results from these studies suggest that indications for allogeneic transplant include patients with low-grade NHL with a sibling or matched donor who are under 60 years of age; young patients with mantle cell lymphoma who are in first remission and have a sibling or matched donor; patients with high-grade NHL who have already failed an autograft but have chemosensitive disease, and those under 30 years of age who have poor-risk disease and are in first remission. It is concluded that reduction in treatment-related mortality with reduced-intensity HSCT and the presence of GVT effects increases the applicability of allogeneic transplantation for NHL. However, treatment will be improved by optimizating conditioning regimens and a better understanding of patient selection criteria and the immune processes involved in graft-vs.-host disease and GVT.     

Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer.

PURPOSE: Allogeneic T lymphocytes can induce regression of metastatic breast cancer through an immune-mediated graft-versus-tumor (GVT) effect in murine models. To determine if a clinical GVT effect exists against metastatic breast cancer, allogeneic lymphocytes were used as adoptive cellular therapy after a reduced-intensity chemotherapy conditioning regimen and allogeneic hematopoietic stem-cell transplantation (HSCT) from human leukocyte antigen-matched siblings. PATIENTS AND METHODS: Sixteen patients with metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes, hormonal agents, and trastuzumab, received allogeneic HSCT. The reduced-intensity transplant conditioning regimen consisted of cyclophosphamide and fludarabine. To distinguish an immunological GVT effect from any antitumor effect of cytotoxic chemotherapy in the transplant-conditioning regimen, allogeneic T lymphocytes were removed from the stem-cell graft and were subsequently administered late postallogeneic HSCT. Allogeneic lymphocytes containing 1 x 10(6), 5 x 10(6), and 10 x 10(6) CD3(+) cells/kg were infused on days +42, +70, and +98 post-allogeneic HSCT, respectively. RESULTS: Objective tumor regressions occurred after day +28 post-allogeneic HSCT in six patients and were attributed to allogeneic lymphocyte infusions. Two of these responding patients had disease progression post-allogeneic HSCT before subsequent tumor regression. Tumor regressions occurred concomitantly with the establishment of complete donor T-lymphoid engraftment, were associated with the development of graft-versus-host disease (GVHD), and were abrogated by subsequent systemic immunosuppression for GVHD. CONCLUSION: Allogeneic lymphocytes can induce regression of advanced metastatic breast cancer. These results indicate that an immunological GVT effect from allogeneic lymphocytes exists against metastatic breast cancer and provide rationale for further development of allogeneic cellular therapy for this largely incurable disease.     

Graft-vs.-lymphoma effect in various histologies of non-Hodgkin's lymphoma

Generally, there is a significantly lower risk of lymphoma relapse following allogeneic than after autologous stem cell transplant. Factors contributing to this lower risk of relapse include an absence of the use of ablative conditioning, with a tumor-free graft, and the generation of a graft-vs.-tumor (GVT) immune response. Allogeneic transplantation, however, has the possibility of graft-vs.-host disease (GVHD). The use of autologous and conventional allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma, diffuse large cell lymphoma, chronic lymphocytic leukemia and multiple myeloma is discussed. Due to a 1-year transplant-related mortality of 30-40% and complications caused by GVHD, conventional, myeloablative, allogeneic transplantation is a high-risk option for low-grade lymphoproliferative disorders. Novel applications of allogeneic HSCT are described that take advantage of a GVT effect while reducing the risk of GVHD. Minimally myelotoxic pretransplant conditioning regimens allow host antigen-presenting cells to persist, enabling presentation of host minor histocompatibility antigens to donor T cells, causing a GVT response. Although complications may arise due to GVHD, non-myeloablative HSCT can be offered to patients previously ineligible for conventional high-dose treatment. A protocol developed in Seattle using a low-dose total body irradiation (TBI)-based conditioning regimen with immunosuppression using mycophenolate mofetil in combination with cyclosporin has been used in a multicenter trial. To overcome the problem of graft rejection fludarabine was later added to the protocol. A second protocol from a smaller trial used a preparative, conventional-dose regimen of fludarabine, given with cyclophosphamide. Rituximab was also given to provide synergistic action with the chemotherapy to enhance tumor control in the early post-transplant period to allow time for the establishment of the GVT effect. Following transplantation, GVHD prophylaxis was given using tacrolimus with methotrexate. A trial of a further variation of allogeneic HSCT, tandem auto/allo transplants, is described. First, high-dose therapy with autologous PBSC rescue was used to cytoreduce the disease. This was followed by a reduced-intensity or non-myeloablative allogeneic graft. This procedure was devised to take advantage of high-dose therapy and allogeneic HSCT. Results for non-myeloablative allogeneic HSCT are particularly promising in low-grade NHL and the GVT effect may augment response and delay or prevent relapse. However, for aggressive disease, non-myeloablative regimens are only indicated for patients with minimal disease, as the non-myeloablative regimens are unable to control the tumor before the generation of a GVT effect, and/or lack the ability to control rapidly proliferating disease. Patients with relapsed disease may require a higher-dose regimen or tandem transplant approach.     

Posttransplant administration of cyclophosphamide and donor lymphocyte infusion induces potent antitumor immunity to solid tumor

PURPOSE: Nonmyeloablative allogeneic stem cell transplantation (SCT) has been increasingly used for the treatment of hematologic and solid malignancies, and mature donor T cells are considered to be the main effectors of the graft-versus-tumor (GVT) activity. However, the association between degree of donor chimerism and intensity of GVT effects has not been fully elucidated. We recently proposed a unique nonmyeloablative cell therapy using posttransplant cyclophosphamide and donor lymphocyte infusion, by which a significant antitumor effect against murine renal cell carcinoma, RENCA, was induced, although the level of mixed chimerism was relatively low. In this study, we attempted to clarify a role of chimerism for in vivo antitumor effects on GVT effects in radiation-associated nonmyeloablative SCT. EXPERIMENTAL DESIGN: We assessed antitumor effects on RENCA tumors and the degree of donor chimerism after several doses of irradiation followed by allogeneic SCT and compared the results with those of cyclophosphamide-based cell therapy. RESULTS: Allogeneic SCT following sublethal irradiation (6 Gy) induced almost complete donor chimerism, whereas cyclophosphamide-based cell therapy produced low levels of donor chimerism. Nonetheless, GVT activity was much more potent in cyclophosphamide-based cell therapy than irradiation-conditioned SCT. Furthermore, cyclophosphamide-conditioned SCT induced more potent immune reconstitution with less severe graft-versus-host disease than irradiation-conditioned SCT. CONCLUSIONS: Our results indicate that a high level of chimerism is not essential for the in vivo antitumor effect of nonmyeloablative allogeneic cell therapy against solid tumor and that the recovery of peripheral lymphocytes after the initial immunosuppression might be a critical event for the elicitation of in vivo antitumor effects of that treatment modality.     

Enhancement of graft-versus-tumor activity and graft-versus-host disease by pretransplant immunization of allogeneic bone marrow donors with a recipient-derived tumor cell vaccine

Allogeneic bone marrow transplantation (BMT) can be accompanied by a beneficial T cell-mediated antitumor immune response known as graft-versus-tumor (GVT) activity. However, BMT donor T cells are not exposed to target antigens of GVT activity until transfer to the host, where tumor antigen presentation may be suboptimal. This study tested in a murine model the hypothesis that immunization of MHC-matched allogeneic donors with a recipient-derived tumor cell vaccine would substantially increase GVT activity and extend survival of BMT recipients with preexisting micrometastatic tumor. C3H.SW and C57BL/10 mice were immunized against a C57BL/6-derived fibrosarcoma or leukemia, and they were used as BMT donors. Recipients were H-2-matched, minor histocompatibility antigen-mismatched C57BL/6 mice with previously established micrometastatic tumors. Donor immunization led to a significant increase in GVT activity that was T cell dependent and cell dose dependent. In some settings, donor immunization also prolonged survival of recipients with preexisting micrometastatic tumors. However, donor immunization significantly increased the incidence of fatal graft-versus-host disease such that long-term survival was uncommon. In vitro cytotoxicity assays indicated that donor immunization induced both tumor-selective and alloreactive cytolytic T-cell populations. In vivo cross-protection assays showed that a substantial portion of the GVT effect was mediated by alloreactive cells not specific for the immunizing tumor. In conclusion, immunization of allogeneic BMT donors with a recipient-derived whole tumor cell vaccine substantially increases GVT activity but also exacerbates graft-versus-host disease.     

Advances in allogeneic stem cell transplantation: directing graft-versus-leukemia at solid tumors

Allogeneic stem cell transplantation was originally developed as a method to rescue hematopoietic function following high dose "myeloablative" therapy in the treatment of hematological malignancies. In the first two decades of its use, dose-intensive chemotherapy alone was credited with curing those patients who achieved sustained remission following this procedure. However, more recently investigators have come to recognize that antineoplastic effects mediated by immunocompetent donor T-cells transplanted with the stem cell allograft can be induced against hematological malignancies. Indeed, this graft-vs-leukemia (GVL) or graft-vs-tumor (GVT) effect is now felt to represent the principal modality required to sustain durable remissions of hematological malignancies following this approach. The powerful and potentially curative nature of the GVT effect in hematological cancers has recently lured oncologists into exploring the therapeutic potential of allogeneic stem cell transplantation as an investigational approach for treatment-refractory solid tumors. We review here the development and early clinical results of allogeneic stem cell transplantation as potential immunotherapy for solid tumors.     

Pretransplant tumor antigen-specific immunization of allogeneic bone marrow transplant donors enhances graft-versus-tumor activity without exacerbation of graft-versus-host disease

Allogeneic bone marrow transplantation (BMT) causes a beneficial graft-versus-tumor (GVT) immune response that is often associated with graft-versus-host disease (GVHD). There is substantial interest in developing therapeutic strategies that augment GVT without GVHD. We have demonstrated recently that immunization of BMT donors with cellular tumor vaccines leads to curative GVT but induces unacceptable GVHD because of the presence of recipient minor histocompatibility antigens (mHAgs) in whole-cell tumor vaccines. This study tested the hypothesis that immunization of BMT donors against a defined tumor-specific antigen with a vaccine not containing recipient mHAgs would help to separate the two responses by enhancing GVT activity without exacerbating GVHD, even when cellular vaccines were used after BMT. Recipient strain C57BL/6 fibrosarcoma cells engineered to express the well-characterized model tumor antigen, influenza nucleoprotein (NP), were used in these studies. C3H.SW donors were immunized against NP prior to BMT, and cytolytic T cells were transferred along with bone marrow into irradiated H-2-matched, mHAg-mismatched C57BL/6 recipients with established micrometastatic 205-NP tumors. Donor immunization led to a significant increase in GVT activity, as measured by reduction in tumor growth and enhanced survival. However, deaths in recipients of tumor antigen-specific immune BMT ultimately occurred because of the growth of antigen-loss variants; such tumor growth did not occur in animals receiving BMT from donors treated with whole-cell vaccines. Donor immunization did not lead to an exacerbation of GVHD, even when BMT recipients received additional immunization after BMT with a 205-NP "whole" tumor cell vaccine (which was shown to induce fatal GVHD when used for donor immunization). In conclusion, immunization of allogeneic BMT donors against a tumor-specific antigen significantly enhances GVT activity without an associated exacerbation of GVHD.     

Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy

The failure of conventional chemotherapy to improve survival in a large percentage of patients with advanced solid tumors has prompted the development of alternative anticancer approaches. Conventional allogeneic hematopoietic stem cell transplantation (HSCT) relies on myeloablative conditioning to eradicate the underlying disease, as well as suppress the patient’s immune response, allowing engraftment of the donor’s lymphohematopoietic system. Such preparative regimens are frequently associated with serious hematologic and nonhematologic toxicities, resulting in substantial morbidity and mortality. A significant curative component of allogeneic HSCT is the immune-mediated graft-versus-tumor (GVT) effect. Nonmyeloablative preparative regimens were designed to suppress host immunity to allow for sufficient engraftment of the donor immune system for the subsequent generation of GVT effects. These relatively low-dose preparative regimens are generally well tolerated and are associated with a reduction in the risk of transplant-related mortality. Nonmyeloablative HSCT provides a safer platform to explore the efficacy of allogeneic HSCT in patients with solid tumors. Initial reports have demonstrated that GVT may occur against several different solid tumors, including renal cell carcinoma, ovarian cancer, breast cancer and others. Based on these preliminary encouraging results, further exploration of nonmyeloablative HSCT for solid tumors is clearly warranted. The development of strategies to decrease graft-versus-host disease while enhancing post-transplant antitumor immunity will hopefully be forthcoming in the near future.     

Immunoablative reduced-intensity stem cell transplantation: potential role of donor Th2 and Tc2 cells

Allogeneic reduced-intensity stem cell transplantation (RISCT) decreases regimen-associated morbidity and mortality, but it is unfortunately still constrained by the same immune T-cell reactions that limit myeloablative transplantation, including graft rejection, graft-versus-host disease (GVHD), and suboptimal graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effects. Graft rejection is mediated by host T cells, whereas GVHD and GVL/GVT effects are initiated by donor T cells, and to this extent, future advances in RISCT will likely benefit from an ability to modulate both donor and host T-cell immunity. As a step in this direction, we have developed a RISCT approach that first involves chemotherapy-induced host T-cell ablation, and second involves administration of allogeneic inocula enriched for donor CD4(+) Th2 and CD8(+) Tc2 T-cell subsets that in murine studies mediate reduced GVHD. In a pilot clinical trial, "immunoablative" RISCT with human leukocyte antigen (HLA)-matched related allografts resulted in rapid and complete donor chimerism and GVL effects early post-transplant, with GVHD being the primary toxicity. Using this immunoablative RISCT approach, we are now evaluating the feasibility and safety of augmenting allografts with additional donor CD4(+) Th2 cells that are generated in vitro via CD3/CD28 costimulation in the presence of interleukin (IL)-4. We review the biology of host and donor T-cell immunity during allogeneic RISCT and discuss the strategies of host immunoablation and donor Th2 and Tc2 cell therapy as potential means to improve the clinical results in RISCT.     

Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy

The failure of conventional chemotherapy to improve survival in a large percentage of patients with advanced solid tumors has prompted the development of alternative anticancer approaches. Conventional allogeneic hematopoietic stem cell transplantation (HSCT) relies on myeloablative conditioning to eradicate the underlying disease, as well as suppress the patient's immune response, allowing engraftment of the donor's lymphohematopoietic system. Such preparative regimens are frequently associated with serious hematologic and nonhematologic toxicities, resulting in substantial morbidity and mortality. A significant curative component of allogeneic HSCT is the immune-mediated graft-versus-tumor (GVT) effect. Nonmyeloablative preparative regimens were designed to suppress host immunity to allow for sufficient engraftment of the donor immune system for the subsequent generation of GVT effects. These relatively low-dose preparative regimens are generally well tolerated and are associated with a reduction in the risk of transplant-related mortality. Nonmyeloablative HSCT provides a safer platform to explore the efficacy of allogeneic HSCT in patients with solid tumors. Initial reports have demonstrated that GVT may occur against several different solid tumors, including renal cell carcinoma, ovarian cancer, breast cancer and others. Based on these preliminary encouraging results, further exploration of nonmyeloablative HSCT for solid tumors is clearly warranted. The development of strategies to decrease graft-versus-host disease while enhancing post-transplant antitumor immunity will hopefully be forthcoming in the near future.     

Cellular tumor vaccines administered after T cell-depleted allogeneic bone marrow transplantation induce effective anti-tumor immune responses

In allogeneic hematopoietic stem cell (HSC) transplantation, graft vs. tumor (GVT) activity contributes to the cancer cure. It is closely associated with graft vs. host disease (GVHD), an immune response initiated by transplanted donor T-cell responses against host minor histocompatibility antigens (mHAgs). GVHD is prevented by T-cell depletion of the donor graft, but T-cell depletion also abrogates curative GVT. We wished to test the hypothesis that cellular tumor vaccines administered after T cell-depleted HSC transplant can induce significant GVT effects, despite the absence of transplanted mature donor T cells. In this investigation, a murine model of major histocompatibility complex (MHC)-matched, mHAg-mismatched allogeneic HSC transplant was studied. T cell-depleted or normal T cell-containing grafts were given to myeloablated recipients. Following reconstitution the recipients were vaccinated with tumor vaccines. GVT responses were measured in vitro by T-cell function assays and flow cytometry, and in vivo by tumor burden or survival. Post-transplant tumor vaccines induced effective anti-tumor responses in recipients of T cell-depleted transplants, producing cytolytic and cytokine responses, reduced tumor burden and prolonged survival. Recipients of T cell-depleted transplants that still have significant thymic function may be suitable subjects for post-transplant vaccine therapy.     

Allogeneic hematopoietic stem-cell transplantation for hematological malignancies

Allogeneic transplantation of hematopoietic stem cells (HSC) is a curative treatment for hematological malignancies aiming to eradicate the malignant clone using the immunological conflict inherent to donor HSC installation in the recipient. The different possible sources of HSCs (bone marrow, blood, and cord blood) and better knowledge of HLA typing has led to the development of new transplantation techniques and modalities (transplantations after non-myeloablative conditioning, haploidentical transplantations, etc.), which should improve patient survival and extend allograft indications. HSC allografting is subject to immunological reactions stemming from the histocompatibility discrepancy between donor and recipient. For the most part, these are reactions of the graft against the host (graft-versus-host disease: GVHD) and graft rejection (host-versus-graft: HVG). This immunological conflict can also be responsible for recognizing and destroying the recipient's residual tumor cells, which carry specific tumor antigens and/or minor antigens of histocompatibility (graft-versus-leukemia effect, GVL or graft-versus-malignancy effect, GVM). The posttransplantation period can also be riddled with various complications such as veno-occlusive disease, endocrine complications, as well as complications arising from infections and secondary neoplasms because of a more or less substantial and durable immune deficiency. Acute and chronic leukemias are the major indications for HSC allogeneic transplantation, for which the results are variable and closely related to the patient status, the hematological disease, and the transplant procedure. Other hematological diseases are also indications for allogeneic transplantation but are rarer, for which allogeneic transplantation remains nevertheless the only curative treatment, despite an overly high level of toxicity. Improvement in the results of unrelated transplantations, use of peripheral HSC or cord blood cells, development of non-myeloablative conditioning regimens, and techniques of ex vivo manipulation of the graft have allowed HSC allogeneic transplantation indications to be extended. The antitumor efficacy of donor lymphocytes infusion for relapses after transplantation mirrors the GVL effect and is the first stage in a targeted cellular immunotherapy using sensitized lymphocytes or dendritic cells.     

Advances in pediatric hematopoietic stem cell transplantation

Allogeneic and autologous hematopoietic stem cell transplantation (HSCT) has become a therapeutic option for an increasing number of patients with otherwise incurable leukemias, solid tumors, immunodeficiencies, hemoglobinopathies and metabolic diseases. For patients requiring an allogeneic transplant, the addition of unrelated cord blood units and partially matched family member donors as alternate stem cell sources has increased the chances that an appropriate donor can be identified. In addition, new approaches to stem cell graft engineering are yielding insights into potential cellular immune therapies, which may decrease the adverse effects of HSCT such as graft-versus-host disease (GVHD) and harness the alloimmune graft-versus-leukemia effect. Novel conditioning regimens, primarily reduced intensity and non-myeloablative regimens, allow patients with significant co-morbidities to undergo transplantation with reduced morbidity and mortality. Combinations of immune-modulatory cytokines and monoclonal antibodies with autologous and allogeneic transplantation are among the advances being explored in contemporary HSCT.     

Nonmyeloablative allogeneic stem cell transplantation: early promise and limitations

Allogeneic stem cell transplantation is used to treat a variety of malignant and nonmalignant hematologic diseases. Conventionally, high-dose chemoradiotherapy-based preparative regimens were considered essential both for tumor eradication and facilitation of donor stem cell engraftment. It is now apparent that an immune-mediated graft-versus-tumor effect has a pivotal role in the curative potential of allogeneic stem cell transplantation. This has prompted the development of less toxic, nonmyeloablative but profoundly immunosuppressive preparative regimens, often fludarabine- or radiation-based. Full donor engraftment can be achieved; however, a significant number of patients achieve a mixed chimeric state. Mixed hematopoietic chimerism provides a platform for the use of adoptive immunotherapy using donor lymphocyte infusions to maximize the immune-mediated antitumor effect, but the optimal usage has yet to be determined. Immediate procedure-related mortality with nonmyeloablative regimens has been low, but graft-versus-host disease remains a major clinical concern and treatment challenge. Major tumor responses have been seen in many hematologic malignancies primarily including patients with highly chemorefractory disease. Follow-up data have been short and additional time is needed to determine the efficacy and toxicities of this immunotherapy. This approach has potential for widespread clinical application including HLA mismatched and matched unrelated donor transplantation, exploration of a graft-versus-solid tumor effect, and correction of phenotypic expression in nonmalignant disorders.     

非清髓性同种造血干细胞移植治疗恶性实体瘤13例

目的:探讨非清髓性同种外周血造血干细胞移植治疗复发及难治性实体瘤的疗效及安全性,并研究移植物抗肿瘤效应(GVT)产生的抗肿瘤免疫效果.方法:13例患者.其中原发不明癌5例,其他经手术,放、化疗治疗后复发及多部位转移,难治性实体瘤8例.年龄17～69岁,中位年龄45岁.ECOG分级:0级5例,1级6例,2、3级各1例.全部患者给予非清髓性预处理方案进行同种外周血造血干细胞移植.供者为HLA完全相合者10例,非血缘关系者3例.ABO血型相合9例,不相合者4例.采集CD34~+数为1.4～6.6×10~4/kg,平均为3.46×10~6/kg.预处理方案三种:供者为同胞的患者采用环磷酰胺+氟达拉宾方案;非血缘供者患者采用氟达拉宾+马法兰方案.移植物抗宿主病(GVHD)防治采用环孢素A或加用甲氨蝶呤.疗效判定以治疗前后肿瘤大小做为移植物抗肿瘤(GVT)效果判定.同时观察同种造血干细胞移植的副作用.结果:全部患者均获造血重建,移植后中性粒细胞>0.5×10~9/L平均时间11.9天,血小板>20×10~9/L平均时间14.9天,不良反应主要表现为胃肠道、皮肤黏膜及神经系统.急性GVHD9例,经治疗后好转.慢性GVHD8例,均为广泛型.GVT效应:1例GVT+++,肿瘤完全消失,无瘤生存887天.3例GVT++,无瘤生存334天.5例GVT+,无瘤生存117～203天.移植效果:以持续3个月以上统计,CRI例,PR2例,SD4例,PD5例,移植相关死亡1例.总有效率为53.8%.不良反应:主要为急性GVHD,表现为胃肠道反应如腹泻,感染等,肝静脉血栓及脑病少见,经对症治疗好转.结论:对复发及难治性实体瘤,特别是原发不明癌采用非清髓性同种外周血造血干细胞移植可提高疗效,并通过移植物抗肿瘤效应使瘤体减小,延长患者生存期.本疗法具有较好的安全性.     

Natural killer cell alloreactivity in allogeneic hematopoietic transplantation

PURPOSE OF REVIEW: This review will focus on the translation of natural killer cell recognition of missing self into the clinical practice of allogeneic hematopoietic transplantation and discuss how it has opened innovative perspectives in the cure of leukemia. Allogeneic hematopoietic stem cell transplantation from a human leukocyte antigen-matched sibling can cure leukemia but 75% of patients do not have a matched donor, one alternative source of stem cells includes full haplotype mismatched family members. As haploidentical transplantation must be extensively T cell depleted to prevent lethal graft-versus-host disease, it cannot rely on donor T cells for the graft-versus-leukemia effect. Mismatched transplantation, however, triggers alloreactivity mediated by natural killer cells which is based upon 'missing self recognition'. RECENT STUDIES: Recent studies using preclinical murine models of haploidentical transplantation demonstrated that conditioning with alloreactive natural killer cells ablates the recipient immune system and leukemia cells. In the clinical setting of mismatched hematopoietic stem cell transplantation, donor versus recipient natural killer cell alloreactivity has been associated with better outcome, particularly in patients with acute myeloid leukemia who are transplanted in remission. SUMMARY: Given the benefits of natural killer cell alloreactivity, it is expected that it will encourage greater use of haploidentical transplants for the large numbers of leukemia patients without matched donors.     

A pilot study of allogeneic cellular therapy for patients with advanced hematologic malignancies

Allogeneic hematopoietic stem cell transplantation provides curative therapy for some patients with advanced hematologic malignancies. Disease response after allogeneic transplant is, at least in part, mediated by donor immune cells. In this report we describe a cellular therapy using haploidentical peripheral blood stem cells administered after very low dose total body irradiation (TBI) (100 cGy). The donor cells were anticipated to be rejected, so no graft-versus-host (GVHD) prophylaxis was used. Patients with persistent disease beyond 8 weeks could be further treated with infusions of irradiated haploidentical donor cells. Of the 10 patients enrolled in the study, durable engraftment of allogeneic cells was seen in one patient. Two patients with resistant relapsed acute myelogenous leukemia (AML) had a disease response. Analysis of T cell reactivity from one patient who achieved a complete response but did not have durable engraftment of donor cells indicated that disease response was associated with the generation of host-derived anti-leukemic cytotoxic CD8+ T cells that reacted with an AML-associated proteinase 3 epitope. Results from this patient suggest that allogeneic therapy induced a host anti-tumor response associated with cytotoxic T cells reactive with a low affinity self-antigen.     

Clinical Studies in Hematologic Microtransplantation

The anti-tumor effects of allogeneic hematopoietic stem cell transplantation depend upon engraftment of donor cells followed by a graft-versus-tumor (GVT) effect. However, pre-clinical and clinical studies have established that under certain circumstances, anti-tumor responses can occur despite the absence of high levels of durable donor cell engraftment. Tumor response with little or no donor engraftment has been termed “microtransplantation.” It has been hard to define conditions leading to tumor responses without donor cell persistence in humans because the degree of engraftment depends very heavily upon many patient-specific factors, including immune status and degree of prior therapy. Likewise, it is unknown to what degree donor chimerism in the blood or tissue is required for an anti-tumor effect under conditions of microtransplantation. In this review, we summarize some key studies supporting the concept of microtransplantation and emphasize the importance of recent large studies of microtransplantation in patients with acute myelogenous leukemia (AML). These AML studies provide the first evidence of the efficacy of microtransplantation as a therapeutic strategy and lay the foundation for additional pre-clinical studies and clinical trials that will refine the understanding of the mechanisms involved and guide its further development as a treatment modality.     

异基因造血干细胞移植治疗首例自体移植复发霍奇金淋巴瘤的临床分析

目的探讨霍奇金淋巴瘤自体移植复发后行异基因造血干细胞2次移植的可能性和安全性。方法对1例10年前行自体造血干细胞移植复发的霍奇金淋巴瘤患者,行异基因造血干细胞移植,供者为患者母亲,采用外周血干细胞移植,预处理方案采用氟达拉滨+马法兰+兔抗人淋巴细胞免疫球蛋白,预防移植物抗宿主病采用环孢素A、霉酚酸酯、甲氨蝶呤,输注单个核细胞数14.03×108/kg,CD34+细胞6.57×106/kg。结果 2次移植后移植物成功植入,形成完全供者来源造血,移植后第20天骨髓初步植活,造血功能恢复后患者出现皮肤植物抗宿主病,FISH嵌合状态供者细胞植入率为100%,随访至今一直长期无病生存。结论异基因造血干细胞移植,可有效治疗自体移植复发的霍奇金淋巴瘤,是安全有效的挽救治疗措施。