Since the 1950s there has been experimental and subsequently clinical evidence for an effect of allogeneic hematopoetic cells against leukemias (graft versus leukemia, GvL) and, more recently, solid tumors (graft versus tumor, GvT). The success of donor leukocyte infusions (DLI) as a therapy for relapsed chronic myelogenous leukemia (CML) after bone marrow transplant (BMT) is the ultimate proof of the antitumor activity of allogeneic cells. The mechanisms responsible for this effect, in particular the specific effector cell(s), the target antigens, and the cytotolytic pathways, remain under investigation. These mechanisms and other strategies (timing of lymphocyte infusion, suicide vectors, cytokines) are being studied by many investigators in an effort to separate GvL/GvT from its main side effect, graft-versus-host disease (GvHD). Evidence that GvL/GvT activity is an essential component of conventional hematopoetic cell transplants (HCT) and the success of DLI have resulted in the development of nonmyeloablative stem cell transplantation (NST), which depends largely on the induction of GvL/GvT to mediate antitumor activity. Future developments are likely to include a broadening of clinical indications, mainly in the field of solid tumors, as well as more refined ex vivo manipulation of graft and vaccinations strategies. In summary, GvL/GvT has evolved from a useful side effect of allogeneic stem cell transplantation into the primary focus of novel approaches in stem cell and adoptive therapies.
The terms graft versus leukemia and graft versus tumor describe the therapeutic effects of allogeneic cells against malignancies after hematopoetic cell transplantation or donor leukocyte infusion. In its simplest form, this effect is observed with the transplantation of unmanipulated grafts, but manipulation of these cells ex vivo before reinfusion is an increasingly important therapeutical modality and links this effect to strategies described elsewhere in this encyclopedia. The earliest description of a GvL effect dates back to murine BMT experiments in the 1950s, when it was found that mice reconstituted with "homologous" (allogeneic) bone marrow after leukemia inoculation and irradiation had prolonged survival when compared to mice reconstituted with "isologous" (syngeneic) marrow. With the introduction of allogeneic HCT as a treatment option for human hematologic malignancies starting in the 1970s, GvL entered the realm of clinical medicine. It has since been increasingly recognized as an important mechanism by which HCT eliminates leukemia cells in addition to the effects of the high-dose chemotherapy or radiation therapy used in the conditioning regimen. Two important developments of the 1990s have focused even more attention on GvL: The discovery that DLI can induce remissions in patients with relapsed leukemias after HCT and the development of stem cell transplantation with nonmyeloablative conditioning regimens. Today, GvL/GvT has moved to the forefront of clinical strategies as well as immunological and oncological research: DLI has come into routine clinical practice and is currently the standard of care for relapsed CML post-HCT. The most firm and compelling evidence to date of a clinically relevant graft-versussolid tumor effect has been established in patients with metastatic renal cell carcinoma who were treated with nonmyeloablative HCT. Multiple strategies to characterize target antigens of GvL/GvT, to enhance GvL/GvT, and to separate it from harmful GvHD are being pursued.
II. EXPERIMENTAL AND CLINICAL EVIDENCE
Since the original mouse experiments by Barnes and Loutit, it has been firmly established in many murine models that donor T cells [and natural killer (NK) cells] prolong survival or contribute to the eradication of hematopoetic malignancies. A smaller number of animal studies has addressed the effect of grafts against solid tumors, but several published studies demonstrate this effect.
A. Graft versus Leukemia
In the clinical setting, evidence for graft versus leukemia was initally difficult to separate from the effect of high-dose chemotherapy or radiation in the conditioning regimen and was derived from indirect observations.
1. A number of case reports indicate a temporal association between withdrawal of immunosuppression and/or a flare of graft-versus-host disease and the induction of complete remission in relapsed patients after HCT.
2. The incidence of leukemic relapse is lower after matched sibling BMT than after grafts from identical twins. Similarly, several studies have shown increased relapse rates after autologous compared to allogeneic transplant, but these data may be compromised by the possibility of tumor cell contamination in the autograft.
3. Large retrospective studies confirm that both acute and chronic GvHD are protective against relapse after GvHD.
4. The incidence of leukemic relapse is higher in recipients of T-cell-depleted (TCD) allogeneic marrow than in recipients of unmodified allogeneic marrow. This difference holds up even if adjusted for the presence or absence of GvHD. In fact, one large retrospective study by the International Bone Marrow Transplant Registry (IBMTR) found that the risk of relapse was still higher for recipients of TCD marrow with GvHD than for recipients of non-TCD marrow without GvHD. In addition to providing evidence for the existence of a GvL effect, these observations also underline the pivotal role of T cells as mediators of this effect. However, widely varying methods for Tcell depletion and more recent developments in this field necessitate a more specific analysis of different methods of T cell depletion (see Section IV).
5. The most direct and relatively recently discovered evidence for GvL in the clinical setting is the effectiveness of donor leukocyte infusion. In 1990, Kolb and co-workers reported complete remissions in three patients who received a transfusion of donor lymphocytes ("buffy coat") for hematological relapse of CML after BMT. Interferon-α had failed in these patients and they did not receive any further chemotherapy. The effect of DLI was durable and was associated with only mild and treatment responsive GvHD in two of the three patients. DLI has since become standard therapy for CML and induces complete (molecular) remissions in the majority of patients with cytogenetic (88%) or hematological (72%) relapse and in 22% of patients with relapse in accelerated or blast phase. Although the numbers are smaller, DLI seems to be considerably less effective for other hematological malignancies in the order of CML>acute myeloid leukemia (AML)>acute lymphoid leukemia (ALL). The relative ineffectiveness of DLI in ALL is in contrast to the close correlation between GvHD and protection from relapse, as well as the superiority of allogeneic over syngeneic HCT in this disease. Small series and anecdotal reports of responses in juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM), polycythemia vera, and myelodysplastic syndrome (MDS) exist.
B. Graft versus Solid Tumor
Until very recently, clinical evidence for a graft-versus-solid tumor effect was anecdotal at best. A limited number of case reports describe remissions after allogeneic bone marrow transplantation for adult nephroblastoma, metastatic ovarian cancer, metastatic renal cell cancer, and metastatic and locally recurrent breast cancer. One study of allogeneic HCT in 10 patients with metastatic breast cancer showed a modest benefit with one patient in complete remission, four in partial remission, and four with stable disease. Because all these transplants were performed with high-dose chemotherapy and/or radiation as myeloablative regimen, it is impossible to separately evaluate the efficacy of a potential graft-versus-tumor effect. Such a comparison is feasible, however, in pediatric high-risk neuroblastoma, for which a large number of autotransplants and a smaller number of allograft procedure have been performed. Several matched pair analyses and case control studies have demonstrated no benefit or even a worse outcome for allogeneic compared to autologous transplantation, thereby negating a GvT effect for this malignancy.
Nonmyeloablative stem cell transplant is a recently developed strategy that relies to a larger extent than conventional HCT on a GvL effect. It attempts to achieve complete chimerism with a less intensive, mostly immunosuppressive, fludarabine-based conditioning regimen. This regimen is designed not to eradicate the malignancy, but to provide sufficient immunosuppression to achieve engraftment of an allogeneic graft, which in turn attacks the disease via GvL. Posttransplant DLI can augment this effect if needed. The most experience with this approach has so far been generated in low-grade lymphomas, for which the GvL benefit of an allogeneic transplant had previously been offset (particularly in the elderly patient population) by a high transplant-related mortality. This relatively new strategy is currently being tested at many centers and it remains to be seen if the promise of less side effects (especially GvHD) with this concept holds true.
The most convincing evidence to date for a clinically relevant GvT effect has been published by Childs and co-workers in patients with metastatic renal cell carcinoma. Metastatic renal cell tumor has an extremely poor prognosis and is usually resistant to systemic chemotherapy. In their study, Childs and colleagues treated 19 consecutive patients with a nonmyeloablative regimen of cyclophosphamide and fludarabine, followed by a matched (or one antigen mismatched) sibling peripheral blood stem cell allograft. Cyclosporine was used as GvHD prophylaxis. Patients were eligible to receive additional DLI depending on their degree of chimerism, the absence of GvHD, and their disease status. They found that 3 of 19 patients remained in full remission and 9 additional patients with partial response were alive 3-18 months posttransplant. A response was significantly associated with the development of GvHD and/or the withdrawal of immunosuppression. GvHD was the major side effect (2 patients with grade IV, 1 with grade III, and 7 with grade II) and there were two transplant-related deaths (1 from steroid-resistant GvHD, 1 from bacterial sepsis).
III. MECHANISMS OF THE GRAFT VERSUS LEUKEMIA/GRAFT VERSUS TUMOR (GvL/GvT) EFFECT
The mechanisms that underlie the GvL/GvT effect are of great interest not only with regard to their basic immunological mechanisms, but also with regard to the clinical goal of enhancing GvL/GvT, while at the same time trying to prevent GvHD. This section concentrates on three central questions in the study of the mechanisms of the GvL/GvT effect that are relevant in different attempts to separate GvL/GvT from GvHD.
1. Which subset of cells exerts the GvL/GvT effect?
2. How do these cells make the distinction between malignant cells and normal host tissue?
3. How do these cells kill or inhibit or inactivate the malignant cells?
Unfortunately, several decades of extensive investigations have not yielded a simple answer to any of these questions. There is, however, growing evidence for a multifactorial network of several effector populations, host targets, and effector mechanisms whose importance might vary significantly in different species, strains, tumor models, and MHC or minor histocompatibility antigen (miHA) mismatches.
A. The Effector Cell
T cells are critical in the GvL/GvT response. This is true in virtually all animal models tested as well as in humans and evidence for this is very convincing. The depletion of T cells from the graft in animal models or in human HCT increases the risk of relapse or (depending on the stringency of T-cell depletion) in fact abrogates any GvL/GvT effect. In mouse models, a dose-response curve according to the number of transplanted T cells can be established.
Significant controversy exists regarding the relative role of different T-cell subsets. CD8+ as well as CD4+ cells have been shown to contribute to GvL in mouse models. The effect seems to be very model dependent. O'Kunewick and colleagues, for example, reported that CD8 depletion lowered GvL in an MHCmatched model, whereas in a MHC-mismatched model, only CD4 but not CD8 depletion had an effect on GvL. Human in vitro studies have demonstrated an increased frequency of leukemia-specific CTL predominantly of the CD4+ subtype. While a majority of clinical trials using selective T-cell depletion of the graft (in HCT or posttransplant DLI) focus on CD8 depletion, at least one study reports good results with CD4+ depletion and a fixed number of marrow CD8+ cells in the graft.
NK cells are another lymphocyte population that has been shown to have a potent antitumor effect and play a role in post-HCT GvL in murine studies. In humans, an early rise in lymphokine-activated killer cells of NK and of T-cell phenotype has been observed after allogeneic BMT and DLI.
Several murine studies are beginning to address the role of NKT cells, a recently described lymphocyte subset that expresses the αβ T-cell receptor as well as the murine NK marker NK1.1 and is characterized by heavily biased TCR gene usage and high levels of cytokine production. Interestingly, they occur at a much higher frequency in the marrow than in the peripheral blood and play a role in downregulating GvHD. NKT cells in vivo reject chemically induced tumors in mice; however, their importance in the role of post- HCT GvL/GvT has not been studied.
B. Target Antigens
Target antigens for a GvL/GvT effect can be divided into ubiquitous, tissue-restricted, and leukemia or tumor-specific antigens (Table I).
TABLE I Candidate Leukemia/Tumor Antigens with Potential GvL/GvT ReactivityUbiquitous Major histocompatibility antigens (irrelevant in "matched" transplants) Minor histocompatibility antigens: HA-3, H-Y Tissue restricted Minor histocompatibility antigens HA-1 (lymphohematopoetic system) HA-2 (lymphohematopoetic system) Overexpressed on leukemia/tumor cells Proteinase-3 Myeloperoxidase WT-1 Leukemia/tumor specific Bcr-abl fusion proteins p210 (CML) p190 (ALL) Other translocations PML-RAR α (APML) ETV6-AML1 (AML) MLL-AF4 (infant ALL, secondary AML) G250 (renal cell carcinoma) RAGE-1 (renal cell carcinoma)
1. Ubiquitous antigens include the major histocompatibility antigens (MHC), which are irrelevant in so-called "matched" sibling or matched unrelated donor transplants. In partially mismatched transplants they contribute to GvL/GvT in experimental models as well as in human clinical studies, but have the major disadvantage of also being targets for GvHD activity. Ubiquitously expressed minor histocompatibility antigens (miHA) have been identified and can be recognized by cytotoxic T cells. These T-cell clones are also capable of antigen-specific in vitro growth inhibition of leukemic precursors. While these antigens are potentially relevant in matched transplants, their use in exploiting a GvL effect is limited again by the fact that they are also target antigens for GvHD.
2. Of greater therapeutic interest are tissuerestricted miHA, which are only expressed on hematopoetic cells. This group includes HA-1 and HA-2, and these antigens are of considerable interest as a target for GvL. A protocol using in vitrogenerated donor CTL specific for host HA-1 or HA-2 is currently being developed by Goulmy and coworkers. The limitation of this protocol is that it is restricted to donor/recipient pairs that (a) are both HLA-A2 positive and (b) are discordant for HA-1 or HA-2, both of which are not highly polymorphic (HA-1 is present in 69% of HLA-A2-positive individuals, HA-2 in 95%). Another note of caution in this attempt is the somewhat surprising finding that despite its restriction to hematopoetic tissue, HA1 mismatches have been correlated with higher frequencies of GvHD.
3. A third group of GvL target antigens consists of leukemia- or tumor-specific antigens. These are attractive therapeutic targets because of their absence on normal tissues and therefore the selective toxicity of a potential GvL effect. While their importance as targets for allogeneic cells in an unmodified BMT is unclear, several groups have tried to engineer an immune response to peptides derived from leukemia-specific fusion proteins, the most prominent arguably being the different versions of BCR/ABL, which define CML and certain high-risk ALL. There is some limited evidence of success with vaccination strategies derived from these proteins, and further clinical studies are being carried out. In renal cell carcinoma, studies have defined several apparently tumor-specific antigens, with potential relevance for T-cell-based therapy, among them RAGE-1 and G250. Other examples from this class of GvL/GvT target antigens are tissue-restricted proteins that are strongly overexpressed on tumor cells and therefore become tumor specific for practical purposes. These include tyrosinase in melanoma, Her2/neu in breast cancer, and wt1 in acute leukemias. Proteinase 3, a myeloid tissue-restricted protein overexpressed on CML cells, has been demonstrated to play an important role in the in vivo immune response of patients with CML post-BMT. All of these antigens are actively being investigated in preclinical or clinical studies as targets for an allo- or autoimmune response, enhanced through different vaccination strategies. While many of these engineered immune responses surpass the definition of a GvL/GvT effect per se and are described in more detail elsewhere, attempts to enhance GvL by immunizing the donor are bringing these two approaches together.
The difficulties encountered in targeting leukemiaor tumor-specific antigens are closely related to known immune evasion mechanisms of the leukemias/ tumors. These include problems with (a) the processing of the antigen and the presentation on a professional antigen-presenting cell (APC) needed to elicit a primary T-cell response, (b) the continued expression of sufficient amounts of antigen on the leukemia/tumor cell in the context of MHC molecules, and (c) induction of anergy. While there is some evidence that leukemic cells might be able to act as (though not very efficient) antigen-presenting cells (with costimulatory molecules and adhesion molecules), they might also induce anergy if they express the antigen in the absence of costimulatory molecules. The uptake of apoptotic tumor cells by professional APCs is probably required in most cases in order to elicit a primary T-cell response. Finally, in the course of malignant progression, tumor cells frequently downregulate the surface expression of the antigen and/or the expression of MHC class I, thereby evading the recognition of potential tumor-specific T cells.
C. Cytotoxic Pathways
More recent studies have focused on the cytolytic pathways used by T cells (and other effector cells) to kill tumor cells. FasL- and perforin-deficient donor T cells have been compared with wild-type T cells in their ability to induce GvHD and GvL responses in several murine models. While the FasL-Fas pathway does not seem to contribute significantly to a GvL response, perforin-deficient donor T cells are not able to induce a GvL effect, pointing to a crucial importance of this pathway in the GvL activity. Similar studies with blocking antibodies against tumor necrosis factor (TNF)- deficient T cells demonstrated a role for TNF as a killing mechanism for GvL. A number of recently described additional members of the TNF receptor superfamily, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), tumor necrosis factor-related activation- induced cytokine (TRANCE), and tumor necrosis factor-like weak inducer of apoptosis (TWEAK), have not been studied with regards to their relevance in GvL. Especially TRAIL deserves further examination in this regard because it possesses very impressive selective antitumor activity in its soluble form. These data suggest that GvL/GvT activity could potentially be differentiated from GvHD activity through the differential use of cytolytic pathways by donor effector cells.
IV. ATTEMPTS TO SEPARATE GRAFT-VERSUS-HOST DISEASE AND GvL/GvT
Although GvHD and GvL/GvT are clearly linked, as discussed in Section II.A.3, large clinical studies also provide evidence that it is possible to achieve a GvL/GvT effect without overt GvHD. The incidence of relapse is higher in recipients of a syngeneic transplant than in recipients of an allogeneic transplant without GvHD. Similarly, the study by Horowitz and co-workers found a higher relapse rate for recipients of TCD grafts with GvHD than for recipients of unmodified allogeneic grafts without GvHD. A number of strategies to achieve a GvL/GvT effect in the absence of GvHD have been employed and are under investigation.
1. Delayed T-cell add-back. Murine studies have clearly shown that separating the timing of T-cell infusion from the "cytokine storm" caused by the conditioning regimen significantly reduces the incidence of GvHD while conserving the GvL effect. Clinical studies with delayed prophylactic T-cell infusion after a T-cell-depleted graft have yielded encouraging results. In CML a TCD BMT can be followed by titrated T-cell infusion only in the case of relapse and still efficiently induce remission.
2. T-cell suicide vectors. An inducible suicide vector, transfected into T cells, gives the option of deleting T cells in vivo in the case of significant GvHD. This strategy would leave recipients who do not develop GvHD with the full T-cell-mediated GvL effect, while recipients who do develop GvHD have at least had an initial GvL effect and can be rescued from their GvHD.
3. T-cell (subset) depletion. The plethora of strategies employed for T-cell depletion necessitates a detailed investigation of the effects of different techniques. Earlier observations that T-cell depletion does not alter overall survival because the decrease in GvHD mortality is accompanied by an increase in relapse and graft failure (see Section II.A.3) need to be reevaluated. Our institution and others have reported single institution studies with excellent results for T-cell-depleted grafts. A recent comparison of different techniques of T-cell depletion showed an advantage in overall survival for recipients of marrows depleted with T-cell antibodies with narrow specificity. Even more specific methods of negatively selecting alloreactive T cells or positively selecting leukemiareactive lymphocytes are under development.
4. Identification of specific tumor or GvHD antigens. As outlined in Section III.B, vaccination or in vitro activation and amplification of donor lymphocytes against tumor antigens could lead to enhanced GvL effect, whereas matching patients for miHC antigens could potentially further reduce GvHD.
5. Cytokine administration. Cytokines that can selectively upregulate GvL or downregulate GvHD activity of donor lymphocytes (sometimes by polarizing them to a Th-2 phenotype, which is presumed to dampen the development of GvHD) have been tested and are continously being sought. A number of agents have been used in animal models (including interleukin (IL)-11, IL-10, IL-12, interferon- ) or patients (including IL-2, anti-TNF antibodies, G-CSF), none with overwhelming success or only at the price of significant side effects. Two of the most recent cytokines under investigation that have shown promise in murine studies are keratinocyte growth factor and IL-7.
V. CLINICAL APPLICATION AND FUTURE DIRECTIONS
The GvL effect has been used clinically since the 1970s when the allogeneic bone marrow transplant was introduced as a therapy for hematological malignancies. Initially it was difficult to differentiate its antitumor effect from that of the myeloablative conditioning regimen. With the introduction of DLI in the early 1990s and the introduction of nonmyeloablative stem cell transplants in the late 1990s, the GvL/GvT effect has moved to the center of HCT approaches. An increasing number of malignancies has been recognized as susceptible to GvL/GvT effects (Table II).
TABLE II Susceptibility of Different Malignancies to GvL/GvT Effect(Post-HCT) DLI alone effective Other clinical evidencea References
Chronic myeloid leukemia++ Standard therapy for relapse post-BMT, effective in 70% ++ GvHD TCD Horowitz et al. (1990); Kolb et al. (1990, 1995) Acute myeloid leukemia + Remission induction in 15-30% of patients ++ GvHD Collins et al. (1997); Horowitz et al. (1990); Kolb et al. (1995) Acute lymphoid leukemia (+) Remission induction in 0-18% of patients
++GvHD Collins et al. (1997); Horowitz et al. (1990); Passweg et al. (1998) Chronic lymphoid leukemia + NST deMagalhaes-Silverman et al. (1997); Khouri et al. (1998) Juvenile mylelomonocytic leukemia (+) Case report of remission induction with discontinuation of immunosuppression and flare-up of GvHD, one report of NST Orchard et al. (1998); Slavin et al. (1998) Multiple myeloma + Effective in small series (+) Case reports of NST Collins et al. (1997); Porter et al. (1999); Slavin et al. (1998)
Myelodysplastic syndrome+ Effective in small series Collins et al. (1997); Kolb et al. (1995); Porter et al. (1996) Polycythemia vera (+) Effective in single case Kolb et al. (1995)
Non-Hodgkin's lymphoma? No remission in seven reported cases (+) NST? Carella et al. (2000); Collins et al. (1997); Slavin et al. (1998)
Hodgkin's disease(+) Only one remission in five reported cases (+) NST? Carella et al. (2000); Porter et al. (1999) Renal cell carcinoma + NST Childs et al. (2000)
Breast cancer(+) Case report of regression of liver metastases in association with GvHD Ben-Yosef et al. (1996); Ueno et al. (1998)
Ovarian center(+) Case report of remission induction with flare-up of GvHD Bay et al. (2000) Melanoma ? No remission in three reported cases, but model system for other T-cell-mediated therapies Porter et al. (1999)
Neuroblastoma - Allo-BMT inferior to auto-BMT in multiple studies Ladenstein et al. (1994); Matthay et al. (1995); Matthay et al. (1994); Philip et al. (1997)
aGvHD, increased relative risk of relapse for patients without GvHD; TCD, increased relative risk of relapse for recipients of T-cell-depleted grafts; NST, nonmyeloablative stem cell transplants effective.
However, susceptibility to GvL does not automatically translate into effective and proven therapy of these diseases with one of the three treatment categories that make use of the GvL/GvT effect clinically: conventional HCT, DLI, and NST.
Allogeneic myeloablative HCT continues to be standard therapy (in the presence of a suitable donor) for certain high-risk ALL in first complete reunion (CR1), for almost all ALL in CR2, for AML in CR1, for CML, for JMML, for MDS, and for a subset of patients with MM. It is being evaluated for a number of other diseases. DLI is an established therapy for relapsed CML post-HCT. Its efficacy in other relapsed hematologic malignancies (AML, ALL, MDS) is small or minimal. A recent phase I protocol studied its feasibility as a primary therapy for patients with different malignancies and reported some evidence of a GvT effect in this setting.
NSTs are still a new concept with limited followup, and some controversy still exists as to the morbidity of this approach. It remains to be seen if terms like "minitransplants" or "transplant lite" hold true to their promise. It is not yet state-of-the art therapy for any particular disease, although considerable experience exists in the field of low-grade lymphoma and it is proposed as a valid treatment option for this indication. Other hematologic malignancies and renal cell carcinoma are being evaluated as targets for this promising application of the GvL effect.
Future developments are certain to happen at a fast pace in the field of GvL/GvT. It is already arguably the only form of cancer immunotherapy that has made a significant clinical impact and has earned itself a place in the therapeutic repertoire for a number of malignancies. Recent progress in the field (especially the development of nonmyeloablative HCT) suggests that its scope is still expanding. Basic research and animal studies are going to further dissect the mechanisms of GvL/GvT, focusing on, but not limited to, the issues that were highlighted in Section III. The potential separation of GvL/GvT from GvHD will continue to be a major area of concern for researchers and clinicans alike; despite a vast array of studies, progress on this front has been slow over the last decades. Clinically, major areas of development are likely to be the optimization and more detailed indications for NST in hematological malignancies and solid tumors, as well as vaccination and adoptive immunotherapy strategies in the context of HCT that go beyond the scope of the GvL/GvT effect as discussed in this article.
Marcel R. M. van den Brink
Memorial Sloan-Kettering Cancer Center
ACUTE LYMPHOBLASTIC LEUKEMIA ; ACUTE MYELOCYTIC LEUKEMIA ; CANCER VACCINES: GENE THERAPY AND DENDRITIC CELL-BASED VACCINES ; CELL-MEDIATED IMMUNITY TO CANCER ; CHRONIC MYELOGENOUS LEUKEMIA ; MONOCLONAL ANTIBODIES: LEUKEMIA AND LYMPHOMA ; STEM CELL TRANSPLANTATION ; TUMOR ANTIGENS
donor leukocyte infusion Infusion of donor leukocytes (or mononuclear cells) into patients with malignancies, usually after HCT. The intent is to induce a (→) graft-versusleukemia or (→) graft-versus-tumor effect in order to treat or prevent relapse of the malignant disease.
graft-versus-host disease (GvHD) Condition that is caused by the attack of alloreactive donor cells against host tissues. Bowel, liver, and skin are classic target organs, but other tissues (lungs, thymus) might also be affected. GvHD is a major complication of (→) hematopoetic cell tranplantation or (→) donor leukocyte infusion and contributes significantly to transplant-related mortality.
graft-versus-leukemia and graft-versus-tumor effect Killing (or growth inhibition) of leukemia/tumor cells by allogeneic donor cells after (→) hematopoetic cell transplantation or (→) donor leukocyte infusion. Therapeutic use of this effect for the treatment of leukemia/solid tumors contributes to leukemic/tumor control and eventually to a decrease in death from leukemia/tumor and/or prolonged survival.
hematopoetic cell transplantation (HCT) Transfer of autologous or allogeneic lymphohematopoetic cells. Originally conceived as bone marrow transplantation, alternative sources of stem cells, such as umbilical cord blood cells or peripheral blood stem cells, are increasingly being used. While autologous HCT is used as a rescue after myeloablative chemo- or radiation therapy, allogeneic HCT provides the additional therapeutic advantage of a (→) graft-versusleukemia or (→) graft-versus-tumor effect when used in patients with malignancies. Preparative regimens prior to HCT have traditionally consisted of myeloablative radio- and/or chemotherapy, but (→) nonmyeloablative regimens for use with allogeneic HCT have been developed.
nonmyeloablative stem cell tranplantation (NST) Also called "minitransplants," NST is a term used for recently developed less intensive preparative regimens prior to (→) hematopoetic cell transplantation. NST uses the (→) graftversus- leukemia or (→) graft-versus-tumor effect as its primary therapeutic modality. While NST has the advantage of decreased toxicity from the preparative regimen, it still carries the risks of (→) graft-versus-host disease and prolonged immunosuppression.
Alyea, E. P., Soiffer, R. J., Canning, C., Neuberg, D., Schlossman, R., Pickett, C., Collins, H., Wang, Y., Anderson, K. C., and Ritz, J. (1998). Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant, Blood 91, 3671-3680.
Apperley, J. F., Mauro, F. R., Goldman, J. M., Gregory, W., Arthur, C. K., Hows, J., Arcese, W., Papa, G., Mandelli, F., Wardle, D., et al. (1988). Bone marrow transplantation for chronic myeloid leukaemia in first chronic phase: Importance of a graft-versus-leukaemia effect [published erratum appears in Br. J. Haematol. 70(2), 261 (1988)]. Br. J. Haematol. 69, 239-245.
Ashkenazi, A., Pai, R. C., Fong, S., Leung, S., Lawrence, D. A., Marsters, S. A., Blackie, C., Chang, L., McMurtrey, A. E., Hebert, A., et al. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155-162.
Attal, M., Socie, G., Molina, L., Jouet, J. P., Pico, J., Kuentz, M., Blaise, D., Milpied, N., Ifrah, N., Payen, C., and Tanguy, M. L. (1997). Allogeneic bone marrow transplantation for refractory and recurrent follicular lymphoma: A casematched analysis with autologous and recurrent follicular lymphoma: A case-matched analysis with autologous transplantation from the French bone marrow transplant group registry data. Blood 90(Suppl.1), 255a.
Barnes, D. W. H., and Loutit, J. F. (1956). Treatment of murine leukemia with x-rays and homologous bone marrow. Br. Med. J. 2, 626-627.
Barnes, D. W. H., and Loutit, J. F. (1957). Treatment of murine leukaemia with X-rays and homologous bone marrow. Br. J. Haematol. 3, 241-252.
Barrett, A. J., Mavroudis, D., Tisdale, J., Molldrem, J., Clave, E., Dunbar, C., Cottler-Fox, M., Phang, S., Carter, C., Okunnieff, P., et al. (1998). T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect. Bone Marrow Transplant. 21, 543-551.
Bartels, C. J., Rosenberg, S. A., and Yang, J. C. (1996). Adoptive cellular immunotherapy of cancer in mice using allogeneic T cells. Ann. Surg. Oncol. 3, 67-73.
Bay, J. O., Choufi, B., Pomel, C., Dauplat, J., Durando, X., Tournilhac, O., Travade, P., Plagne, R., and Blaise, D. (2000). Potential allogeneic graft-versus-tumor effect in a patient with ovarian cancer. Bone Marrow Transplant. 25, 681-682.
Ben-Yosef, R., Or, R., Nagler, A., and Slavin, S. (1996). Graftversus- tumour and graft-versus-leukaemia effect in patient with concurrent breast cancer and acute myelocytic leukaemia. Lancet 348, 1242-1243.
Carella, A. M., Cavaliere, M., Lerma, E., Ferrara, R., Tedeschi, L., Romanelli, A., Vinci, M., Pinotti, G., Lambelet, P., Loni, C., et al. (2000). Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J. Clin. Oncol. 18, 3918-3924.
Champlin, R. E., Passweg, J. R., Zhang, M. J., Rowlings, P. A., Pelz, C. J., Atkinson, K. A., Barrett, A. J., Cahn, J. Y., Drobyski, W. R., Gale, R. P., et al. (2000). T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: Advantage of T-cell antibodies with narrow specificities. Blood 95, 3996-4003.
Childs, R., Chernoff, A., Contentin, N., Bahceci, E., Schrump, D., Leitman, S., Read, E. J., Tisdale, J., Dunbar, C., Linehan, W. M., et al. (2000). Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N. Engl. J. Med. 343, 750-758.
Childs, R. W., Clave, E., Tisdale, J., Plante, M., Hensel, N., and Barrett, J. (1999). Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: Evidence for a graft-versus-tumor effect. J. Clin. Oncol. 17, 2044-2049.
Collins, R. H., Jr., Rogers, Z. R., Bennett, M., Kumar, V., Nikein, A., and Fay, J. W. (1992). Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: Apparent graft-versus-leukemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant. 10, 391-395.
Collins, R. H., Jr., Shpilberg, O., Drobyski, W. R., Porter, D. L., Giralt, S., Champlin, R., Goodman, S. A., Wolff, S. N., Hu, W., Verfaillie, C., et al. (1997). Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J. Clin. Oncol. 15, 433-444.
de Bueger, M., Bakker, A., Van Rood, J. J., Van der Woude, F., and Goulmy, E. (1992). Tissue distribution of human minor histocompatibility antigens: Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. J. Immunol. 149, 1788-1794.
Deichman, G. I., Kashkina, L. M., Kluchareva, T. E., Vendrov, E. L., and Matveeva, V. A. (1983). Inhibition of experimental and spontaneous lung metastases of highly metastatic Syrian hamster sarcoma cells by non-activated bone marrow and peritoneal exudate cells. Int. J. Cancer 31, 609-615.
deMagalhaes-Silverman, M., Donnenberg, A., Hammert, L., Lister, J., Myers, D., Simpson, J., and Ball, E. (1997). Induction of graft-versus-leukemia effect in a patient with chronic lymphocytic leukemia. Bone Marrow Transplant. 20, 175-177.
den Haan, J. M., Sherman, N. E., Blokland, E., Huczko, E., Koning, F., Drijfhout, J. W., Skipper, J., Shabanowitz, J., Hunt, D. F., Engelhard, V. H., et al. (1995). Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 268, 1476-1480.
Doney, K., Fisher, L. D., Appelbaum, F. R., Buckner, C. D., Storb, R., Singer, J., Fefer, A., Anasetti, C., Beatty, P., Bensinger, W., et al. (1991). Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation: Multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival. Bone Marrow Transplant. 7, 453-459.
Eibl, B., Schwaighofer, H., Nachbaur, D., Marth, C., Gachter, A., Knapp, R., Bock, G., Gassner, C., Schiller, L., Petersen, F., and Niederwieser, D. (1996). Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. Blood 88, 1501-1508.
Falkenburg, J. H., Goselink, H. M., van der Harst, D., van Luxemburg-Heijs, S. A., Kooy-Winkelaar, Y. M., Faber, L. M., de Kroon, J., Brand, A., Fibbe, W. E., Willemze, R., et al. (1991). Growth inhibition of clonogenic leukemic precursor cells by minor histocompatibility antigen-specific cytotoxic T lymphocytes. J. Exp. Med. 174, 27-33.
Fefer, A., Sullivan, K., Weiden, P., et al. (1987). Graft versus leukemia effect in man: The relapse rate of acute leukemia is lower after allogeneic than after syngeneic marrow transplantation. In "Cellular Immunotherapy of Cancer" (R. Truitt, R. P. Gale, and M. M. Bortin, eds.), pp. 401-408. A. R. Liss, New York.
Gale, R. P., and Champlin, R. E. (1984). How does bonemarrow transplantation cure leukaemia? Lancet 2, 28-30.
Gale, R. P., Horowitz, M. M., Ash, R. C., Champlin, R. E., Goldman, J. M., Rimm, A. A., Ringden, O., Stone, J. A., and Bortin, M. M. (1994). Identical-twin bone marrow transplants for leukemia. Ann. Intern. Med. 120, 646-652.
Giralt, S., Hester, J., Huh, Y., Hirsch-Ginsberg, C., Rondon, G., Seong, D., Lee, M., Gajewski, J., Van Besien, K., Khouri, I., et al. (1995). CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 86, 4337-4343.
Glass, B., Uharek, L., Zeis, M., Loeffler, H., Mueller-Ruchholtz, W., and Gassmann, W. (1996). Graft-versusleukaemia activity can be predicted by natural cytotoxicity against leukaemia cells. Br. J. Haematol. 93, 412-420.
Goldman, J. M., Gale, R. P., Horowitz, M. M., Biggs, J. C., Champlin, R. E., Gluckman, E., Hoffmann, R. G., Jacobsen, S. J., Marmont, A. M., McGlave, P. B., et al. (1988). Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk for relapse associated with T-cell depletion. Ann. Intern. Med. 108, 806-814.
Goulmy, E. (2000). Alloimmune T cells for adoptive therapy of hematological malignancies. In "Hematology 2000" (G. P. Schechter, N. Berliner, and M. J. Telen, eds.), pp. 366-370.
The American Society of Hematology, Washington, DC. Goulmy, E., Schipper, R., Pool, J., Blokland, E., Falkenburg, J. H., Vossen, J., Grathwohl, A., Vogelsang, G. B., van Houwelingen, H. C., and van Rood, J. J. (1996). Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graftversus- host disease after bone marrow transplantation. N. Engl. J. Med. 334, 281-285.
Herrera, C., Martin, C., Garcia-Castellano, J. M., et al. (1995). Prevention of GvHD by selective CD4 + T cell depletion plus adjustment of the CD8 cell content in donor bone marrow. Blood 86(Suppl. 1), 571a.
Higano, C. S., Brixey, M., Bryant, E. M., Durnam, D. M., Doney, K., Sullivan, K. M., and Singer, J. W. (1990). Durable complete remission of acute nonlymphocytic leukemia associated with discontinuation of immunosuppression following relapse after allogeneic bone marrow transplantation: A case report of a probable graft-versus-leukemia effect, Transplantation 50, 175-177.
Hoffmann, T., Theobald, M., Bunjes, D., Weiss, M., Heimpel, H., and Heit, W. (1993). Frequency of bone marrow T cells responding to HLA-identical non- leukemic and leukemic stimulator cells. Bone Marrow Transplant. 12, 1-8.
Horowitz, M. M., Gale, R. P., Sondel, P. M., Goldman, J. M., Kersey, J., Kolb, H. J., Rimm, A. A., Ringden, O., Rozman, C., Speck, B., et al. (1990). Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75, 555.
Hupperets, P. S., Havenith, M. G., and Blijham, G. H. (1992). Recurrent adult nephroblastoma: Long-term remission after surgery plus adjuvant high-dose chemotherapy, radiation therapy, and allogeneic bone marrow transplantation. Cancer 69, 2990-2992.
Jiang, Y. Z., Kanfer, E. J., Macdonald, D., Cullis, J. O., Goldman, J. M., and Barrett, A. J. (1991). Graft-versus-leukaemia following allogeneic bone marrow transplantation: Emergence of cytotoxic T lymphocytes reacting to host leukaemia cells. Bone Marrow Transplant. 8, 253-258.
Jiang, Y. Z., Mavroudis, D. A., Dermime, S., Molldrem, J., Hensel, N. F., and Barrett, A. J. (1997). Preferential usage of T cell receptor (TCR) V beta by allogeneic T cells recognizing myeloid leukemia cells: Implications for separating graft-versus-leukemia effect from graft-versus-host disease. Bone Marrow Transplant. 19, 899-903.
Kersey, J. H., Weisdorf, D., Nesbit, M. E., LeBien, T. W., Woods, W. G., McGlave, P. B., Kim, T., Vallera, D. A., Goldman, A. I., Bostrom, B., et al. (1987). Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N. Engl. J. Med. 317, 461-467.
Khouri, I. F., Keating, M., Korbling, M., Przepiorka, D., Anderlini, P., O'Brien, S., Giralt, S., Ippoliti, C., von Wolff, B., Gajewski, J., et al. (1998). Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J. Clin. Oncol. 16, 2817-2824.
Kolb, H. J., Mittermuller, J., Clemm, C., Holler, E., Ledderose, G., Brehm, G., Heim, M., and Wilmanns, W. (1990). Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76, 2462-2465.
Kolb, H. J., Schattenberg, A., Goldman, J. M., Hertenstein, B., Jacobsen, N., Arcese, W., Ljungman, P., Ferrant, A., Verdonck, L., Niederwieser, D., et al. (1995). Graft-versusleukemia effect of donor lymphocyte transfusions in marrow grafted patients: European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86, 2041-2050.
Krijanovski, O. I., Hill, G. R., Cooke, K. R., Teshima, T., Crawford, J. M., Brinson, Y. S., and Ferrara, J. L. (1999). Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 94, 825-831.
Kwak, L. W., Taub, D. D., Duffey, P. L., Bensinger, W. I., Bryant, E. M., Reynolds, C. W., and Longo, D. L. (1995). Transfer of myeloma idiotype-specific immunity from an actively immunised marrow donor. Lancet 345, 1016-1020.
Ladenstein, R., Lasset, C., Hartmann, O., Klingebiel, T., Bouffet, E., Gadner, H., Paolucci, P., Burdach, S., Chauvin, F., Pinkerton, R., et al. (1994). Comparison of auto versus allografting as consolidation of primary treatments in advanced neuroblastoma over one year of age at diagnosis: Report from the European Group for Bone Marrow Transplantation. Bone Marrow Transplant. 14, 37-46.
Lee, C. K., Gingrich, R. D., deMagalhaes-Silverman, M., Hohl, R. J., Joyce, J. K., Scott, S. D., Wen, B. C., and Schlueter, A. (1999). Prophylactic reinfusion of T cells for T celldepleted allogeneic bone marrow transplantation. Biol. Blood Marrow Transplant. 5, 15-27.
Mackinnon, S., Papadopoulos, E. B., Carabasi, M. H., Reich, L., Collins, N. H., Boulad, F., Castro-Malaspina, H., Childs, B. H., Gillio, A. P., Kernan, N. A., et al. (1995). Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: Separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 86, 1261-1268.
Martin, P. J., Clift, R. A., Fisher, L. D., Buckner, C. D., Hansen, J. A., Appelbaum, F. R., Doney, K. C., Sullivan, K. M., Witherspoon, R. P., Storb, R., et al. (1988). HLA-identical marrow transplantation during accelerated-phase chronic myelogenous leukemia: Analysis of survival and remission duration. Blood 72, 1978-1984.
Matthay, K. K., O'Leary, M. C., Ramsay, N. K., Villablanca, J., Reynolds, C. P., Atkinson, J. B., Haase, G. M., Stram, D. O., and Seeger, R. C. (1995). Role of myeloablative therapy in improved outcome for high risk neuroblastoma: Review of recent Children's Cancer Group results. Eur. J. Cancer 4, 572-575.
Matthay, K. K., Seeger, R. C., Reynolds, C. P., Stram, D. O., O'Leary, M., Harris, R. E., Selch, M., Atkinson, J. B., Haase, G., Hammond, G. D., et al. (1994). Comparison of autologous and allogeneic bone marrow transplantation for neuroblastoma. Prog. Clin. Biol. Res. 385, 301-307.
Mavroudis, D. A., Dermime, S., Molldrem, J., Jiang, Y. Z., Raptis, A., van Rhee, F., Hensel, N., Fellowes, V., Eliopoulos, G., and Barrett, A. J. (1998). Specific depletion of alloreactive T cells in HLA-identical siblings: A method for separating graft-versus-host and graft-versus-leukaemia reactions. Br. J. Haematol. 101, 565-570.
Molldrem, J. J., Lee, P. P., Wang, C., Felio, K., Kantarjian, H. M., Champlin, R. E., and Davis, M. M. (2000). Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nature Med. 6, 1018-1023.
Morecki, S., Moshel, Y., Gelfend, Y., Pugatsch, T., and Slavin, S. (1997). Induction of graft vs. tumor effect in a murine model of mammary adenocarcinoma. Int. J. Cancer 71, 59-63.
Morecki, S., Yacovlev, E., Diab, A., and Slavin, S. (1998). Allogeneic cell therapy for a murine mammary carcinoma. Cancer Res. 58, 3891-3895.
Moscovitch, M., and Slavin, S. (1984). Anti-tumor effects of allogeneic bone marrow transplantation in (NZB X NZW)F1 hybrids with spontaneous lymphosarcoma. J. Immunol. 132, 997-1000.
Naparstek, E., Or, R., Nagler, A., Cividalli, G., Engelhard, D., Aker, M., Gimon, Z., Manny, N., Sacks, T., Tochner, Z., et al. (1995). T-cell-depleted allogeneic bone marrow transplantation for acute leukaemia using Campath-1 antibodies and posttransplant administration of donor's peripheral blood lymphocytes for prevention of relapse. Br. J. Haematol. 89, 506-515.
Neumann, E., Engelsberg, A., Decker, J., Storkel, S., Jaeger, E., Huber, C., and Seliger, B. (1998). Heterogeneous expression of the tumor-associated antigens RAGE-1, PRAME, and glycoprotein 75 in human renal cell carcinoma: Candidates for T-cell-based immunotherapies? Cancer Res. 58, 4090-4095.
Nimer, S. D., Giorgi, J., Gajewski, J. L., Ku, N., Schiller, G. J., Lee, K., Territo, M., Ho, W., Feig, S., Selch, M., et al. (1994). Selective depletion of CD8+ cells for prevention of graft-versus-host disease after bone marrow transplantation: A randomized controlled trial. Transplantation 57, 82-87.
O'Kunewick, J. P., Kociban, D., Machen, L., and Buffo, M. (1992). Effect of selective donor T-cell depletion on the graft-versus-leukemia reaction in allogeneic marrow transplantation. Transplant. Proc. 24, 2998-2999.
O'Kunewick, J. P., Kociban, D. L., Machen, L. L., and Buffo, M. J. (1995). Evidence for a possible role of Asialo-GM1- positive cells in the graft- versus-leukemia repression of a murine type-C retroviral leukemia. Bone Marrow Transplant. 16, 451-456.
Odom, L. F., August, C. S., Githens, J. H., et al. (1981). "Graft-versus-leukemia" reaction following bone marrow transplantation for acute lymphoblastic leukemia. In "Graft-versus-Leukemia in Man and Animal Models" (J. P. O'Kunewick and R. F. Meredith, eds.), pp. 25-43.
CRC Press, Boca Raton, FL. Odom, L. F., August, C. S., Githens, J. H., Humbert, J. R., Morse, H., Peakman, D., Sharma, B., Rusnak, S. L., and Johnson, F. B. (1978). Remission of relapsed leukaemia during a graft-versus-host reaction: A "graft-versus-leukaemia reaction" in man? Lancet 2, 537-540.
Orchard, P. J., Miller, J. S., McGlennen, R., Davies, S. M., and Ramsay, N. K. (1998). Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia. Bone Marrow Transplant. 22, 201-203.
Papadopoulos, E. B., Carabasi, M. H., Castro-Malaspina, H., Childs, B. H., Mackinnon, S., Boulad, F., Gillio, A. P., Kernan, N. A., Small, T. N., Szabolcs, P., et al. (1998). T-celldepleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: Freedom from relapse in the absence of graft-versus-host disease. Blood 91, 1083-1090.
Passweg, J. R., Tiberghien, P., Cahn, J. Y., Vowels, M. R., Camitta, B. M., Gale, R. P., Herzig, R. H., Hoelzer, D., Horowitz, M. M., Ifrah, N., et al. (1998). Graft-versusleukemia effects in T lineage and B lineage acute lymphoblastic leukemia. Bone Marrow Transplant. 21, 153-158.
Peniket, A. J., Ruiz de Elvira, M. C., Taghipour, G., de Witte, T., Tazelaar, P. J., Carella, A., Vernant, J. P., Schaefer, U. W., Cleeven, M., Boogaerts, M. A., et al. (1990). Allogeneic transplantation for lymphoma produces a lower relapse rate than autologous transplantation but survival is worse because of higher treatment related mortality: A report of 764 cases from the EBMT lymphoma registry. Blood 90(Suppl.1), 255a.
Philip, T., Ladenstein, R., Lasset, C., Hartmann, O., Zucker, J. M., Pinkerton, R., Pearson, A. D., Klingebiel, T., Garaventa, A., Kremens, B., et al. (1997). 1070 myeloablative megatherapy procedures followed by stem cell rescue for neuroblastoma: 17 years of European experience and conclusions: European Group for Blood and Marrow Transplant Registry Solid Tumour Working Party. Eur. J. Cancer 33, 2130-2135.
Pinilla-Ibarz, J., Cathcart, K., and Scheinberg, D. A. (2000). CML vaccines as a paradigm of the specific immunotherapy of cancer. Blood Rev. 14, 111-120.
Porter, D. L., Connors, J. M., Van Deerlin, V. M., Duffy, K. M., McGarigle, C., Saidman, S. L., Leonard, D. G., and Antin, J. H. (1999). Graft-versus-tumor induction with donor leukocyte infusions as primary therapy for patients with malignancies. J. Clin. Oncol. 17, 1234.
Porter, D. L., Roth, M. S., Lee, S. J., McGarigle, C., Ferrara, J. L., and Antin, J. H. (1996). Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation. Bone Marrow Transplant. 18, 975-980.
Reittie, J. E., Gottlieb, D., Heslop, H. E., Leger, O., Drexler, H. G., Hazlehurst, G., Hoffbrand, A. V., Prentice, H. G., and Brenner, M. K. (1989). Endogenously generated activated killer cells circulate after autologous and allogeneic marrow transplantation but not after chemotherapy. Blood 73, 1351-1358.
Ringden, O., and Horowitz, M. M. (1989). Graft-versusleukemia reactions in humans: The Advisory Committee of the International Bone Marrow Transplant Registry. Transplant. Proc. 21, 2989-2992.
Rondon, G., Giralt, S., Huh, Y., Khouri, I., Andersson, B., Andreeff, M., and Champlin, R. (1996). Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia. Bone Marrow Transplant. 18, 669-672.
Sanders, J. E., Flournoy, N., Thomas, E. D., Buckner, C. D., Lum, L. G., Clift, R. A., Appelbaum, F. R., Sullivan, K. M., Stewart, P., Deeg, H. J., et al. (1985). Marrow transplant experience in children with acute lymphoblastic leukemia: An analysis of factors associated with survival, relapse, and graft-versus-host disease. Med. Pediatr. Oncol. 13, 165-172.
Sehn, L. H., Alyea, E. P., Weller, E., Canning, C., Lee, S., Ritz, J., Antin, J. H., and Soiffer, R. J. (1999). Comparative outcomes of T-cell-depleted and non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: Impact of donor lymphocyte infusion. J. Clin. Oncol. 17, 561-568.
Slavin, S., Nagler, A., Naparstek, E., Kapelushnik, Y., Aker, M., Cividalli, G., Varadi, G., Kirschbaum, M., Ackerstein, A., Samuel, S., et al. (1998). Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91, 756-763.
Smyth, M. J., Thia, K. Y., Street, S. E., Cretney, E., Trapani, J. A., Taniguchi, M., Kawano, T., Pelikan, S. B., Crowe, N. Y., and Godfrey, D. I. (2000). Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661-668.
Sullivan, K. M., and Shulman, H. M. (1989). Chronic graftversus- host disease, obliterative bronchiolitis, and graftversus- leukemia effect: Case histories. Transplant. Proc. 21, 51-62.
Sullivan, K. M., Weiden, P. L., Storb, R., Witherspoon, R. P., Fefer, A., Fisher, L., Buckner, C. D., Anasetti, C., Appelbaum, F. R., Badger, C., et al. (1989). Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia [published erratum appears in Blood 74(3), 1180 (1989)]. Blood 73, 1720-1728.
Sykes, M., Abraham, V. S., Harty, M. W., and Pearson, D. A. (1993). IL-2 reduces graft-versus-host disease and preserves a graft-versus- leukemia effect by selectively inhibiting CD4+ T cell activity. J. Immunol. 150, 197-205.
Townsend, R. M., Paterson, A., Hsieh, M. H., and Korngold, R. (1996). Studies of the graft-versus-myeloid leukemia responses following murine bone marrow transplantation. Blood 88(Suppl. 1), 244a.
Tricot, G., Vesole, D. H., Jagannath, S., Hilton, J., Munshi, N., and Barlogie, B. (1996). Graft-versus-myeloma effect: Proof of principle. Blood 87, 1196-1198.
Truitt, R. L., and Atasoylu, A. A. (1991). Contribution of CD4+ and CD8+ T cells to graft-versus-host disease and graft-versus-leukemia reactivity after transplantation of MHC- compatible bone marrow. Bone Marrow Transplant. 8, 51-58.
Tsukada, N., Kobata, T., Aizawa, Y., Yagita, H., and Okumura, K. (1999). Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood 93, 2738-2747.
Ueno, N. T., Rondon, G., Mirza, N. Q., Geisler, D. K., Anderlini, P., Giralt, S. A., Andersson, B. S., Claxton, D. F., Gajewski, J. L., Khouri, I. F., et al. (1998). Allogeneic peripheral-blood progenitor-cell transplantation for poorrisk patients with metastatic breast cancer. J. Clin. Oncol. 16, 986-993.
van Besien, K., Sobocinski, K. A., Rowlings, P. A., Murphy, S. C., Armitage, J. O., Bishop, M. R., Chaekal, O. K., Gale, R. P., Klein, J. P., Lazarus, H. M., et al. (1998). Allogeneic bone marrow transplantation for low-grade lymphoma. Blood 92, 1832-1836.
van der Harst, D., Goulmy, E., Falkenburg, J. H., Kooij-Winkelaar, Y. M., van Luxemburg-Heijs, S. A., Goselink, H. M., and Brand, A. (1994). Recognition of minor histocompatibility antigens on lymphocytic and myeloid leukemic cells by cytotoxic T-cell clones. Blood 83, 1060-1066.
Verdonck, L. F., Lokhorst, H. M., Dekker, A. W., Nieuwenhuis, H. K., and Petersen, E. J. (1996). Graft-versus-myeloma effect in two cases. Lancet 347, 800-801.
Vissers, J. L., De Vries, I. J., Schreurs, M. W., Engelen, L. P., Oosterwijk, E., Figdor, C. G., and Adema, G. J. (1999). The renal cell carcinoma-associated antigen G250 encodes a human leukocyte antigen (HLA)-A2.1-restricted epitope recognized by cytotoxic T lymphocytes. Cancer Res. 59, 5554-5559.
Walczak, H., Miller, R. E., Ariail, K., Gliniak, B., Griffith, T. S., Kubin, M., Chin, W., Jones, J., Woodward, A., Le, T., et al. (1999). Tumoricidal activity of tumor necrosis factorrelated apoptosis- inducing ligand in vivo. Nature Med. 5, 157-163.
Weiden, P. L., Flournoy, N., Thomas, E. D., Prentice, R., Fefer, A., Buckner, C. D., and Storb, R. (1979). Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N. Engl. J. Med. 300, 1068-1073.
Weiden, P. L., Sullivan, K. M., Flournoy, N., Storb, R., and Thomas, E. D. (1981). Antileukemic effect of chronic graft-versus-host disease: Contribution to improved survival after allogeneic marrow transplantation. N. Engl. J. Med. 304, 1529-1533.
Weisdorf, D. J., Nesbit, M. E., Ramsay, N. K., Woods, W. G., Goldman, A. I., Kim, T. H., Hurd, D. D., McGlave, P. B., and Kersey, J. H. (1987). Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: Prolonged survival associated with acute graft-versus- host disease. J. Clin. Oncol. 5, 1348-1355.
Weiss, L., Reich, S., and Slavin, S. (1995). The role of antibodies to IL-2 receptor and Asialo GM1 on graft-versusleukemia effects induced by bone marrow allografts in murine B cell leukemia. Bone Marrow Transplant. 16, 457-461.
Zeis, M., Uharek, L., Glass, B., Gaska, T., Steinmann, J., Gassmann, W., Loffler, H., and Muller-Ruchholtz, W. (1995). Allogeneic NK cells as potent antileukemic effector cells after allogeneic bone marrow transplantation in mice. Transplantation 59, 1734-1736.
Zeng, D., Lewis, D., Dejbakhsh-Jones, S., Lan, F., Garcia- Ojeda, M., Sibley, R., and Strober, S. (1999). Bone marrow NK1.1(-) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease. J. Exp. Med. 189, 1073-1081.