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Stem Cells, Vol. 15, No. 4, 248-258, July 1997
© 1997 AlphaMed Press

Concise Reviews

Mechanisms of the Graft-versus-Leukemia Reaction

A.J. Barrett

Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

Key Words. Graft-versus-leukemia • Graft-versus-host disease • Bone marrow transplantation • Leukemia • Immunogenicity • T cells

Correspondence: Dr. A.J. Barrett, BMT Unit, Hematology Branch, NHLBI, Building 10, Room 7C 103, 9000 Rockville Pike, Bethesda, MD 20892, USA.


   Abstract
Top
 Abstract
General Considerations
 Immunobiology of GVL
 Immunogenicity of Leukemia
 Leukemia Antigens
 Clinical Considerations
 Conclusions
 References
 
It is now clear that the graft-versus-leukemia (GVL) effect which accompanies allogeneic bone marrow transplantation for hematological malignancies is a powerful therapeutic weapon which, if harnessed, could improve our ability to treat refractory malignant disorders. Advances in the understanding of the alloimmune response now provide a clearer picture of the mechanisms involved in the GVL reaction: the CD4+ T cell plays a central role in the orchestration of leukemia cell killing. The immunogenicity of the leukemia is also a major factor determining the effectiveness of the GVL response. The characterization of antigens restricted to leukemia and hematopoietic tissues should make it eventually possible to produce specific and powerful antileukemic alloresponses in donor lymphocytes by adoptive immunotherapy or by vaccines.


   General Considerations
Top
 Abstract
 General Considerations
Immunobiology of GVL
 Immunogenicity of Leukemia
 Leukemia Antigens
 Clinical Considerations
 Conclusions
 References
 
The term graft-versus-leukemia (GVL) is used here to describe the immune-mediated response which conserves a state of continued remission of a hematological malignancy following allogeneic marrow stem cell transplants. Although the evidence for a GVL effect after allogeneic bone marrow transplantation (BMT) is now well accepted, the mechanisms involved in the effect are not completely known [1]. However, because graft-versus-host disease (GVHD) is intimately associated with GVL, it can be assumed that similar mechanisms control GVHD and GVL. GVHD requires the recognition by donor T cells of antigens presented by major histocompatibility complex (MHC) molecules on the recipient cells initiating clonal expansion of responders and an effector response involving lymphocytes and cytokines [2]. In GVHD, this leads to the clinical features of acute and chronic GVHD. In GVL reactions, the alloresponse suppresses residual leukemia. GVHD reactions are directed against a broad spectrum of tissues, including the skin, mucosa, the biliary tree, exocrine glands, synovia, lungs and bone marrow. The dominant antigens on leukemia cells driving the GVL response are not known: major or minor histocompatibility antigens coexpressed on GVHD targets (such as normal skin and gut cells) and leukemic cells could induce a nonspecific GVH/GVL alloresponse [3]. The response against either normal or malignant bone marrow-derived cells may also overlap. Thus GVL may in part be a graft-versus-marrow effect involving lymphoid or myeloid lineages or both. Additionally, leukemia cells could induce a more specific alloresponse if they express antigens, either not present or underexpressed in cells of other tissues [1].

The mechanism whereby the GVL response confers a permanent state of remission (cure) following the transplant deserves some consideration as hematological malignancies become better understood and as their hierarchical structure becomes increasingly appreciated. Many leukemias are complex populations comprised of progenitor cells with infinite self-renewal capacity, intermediate cells (blasts) capable of limited self-renewal and end cells with no capacity for further division [4-7]. Clearly a GVL effect is more likely to result in leukemia eradication, if the immune attack is directed against the earlier cells in the hierarchy. However, a situation could be imagined where immune regulation does not damage dormant leukemic progenitors but prevents large-scale production of blast cells. In a steady-state, such a mechanism would be perceived as a clinical cure (with or without detectable residual disease, depending on the sensitivity of the assay). Such considerations govern whether to be curative the GVL response is required lifelong or only for a defined period. The need for a continuing GVL response has clinical implications: at any time, failure of immune surveillance could upset the balance between the GVL effectors and their targets, resulting in leukemic relapse. Furthermore, the prolonged persistence of subclinical disease could increase the chance of clonal progression and relapse due to leukemic escape from immune control [8]. In this regard, much has yet to be learned about the factors governing the susceptibility of specific leukemias to GVL: clinical evidence links the best GVL responses with chronic, slowly proliferating malignancies and with acute myeloid rather than acute lymphoid leukemia ( Table 1).


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  		Table 1. GVL effect in different hematological malignancies
 
Within a working framework of the alloresponse, we are beginning to piece together the characteristics of GVL reactions. Some progress has been made in identifying the induction and effector mechanisms of the antileukemic response, GVL responses distinct from GVHD reactions and the antigens that drive GVL reactions. With this new understanding, we are developing strategies to confer GVL after bone marrow stem cell transplants and donor lymphocyte transfusions (DLT). In this review, recent work in the field is presented and clinical implications discussed.


   Immunobiology of GVL
Top
 Abstract
 General Considerations
 Immunobiology of GVL
Immunogenicity of Leukemia
 Leukemia Antigens
 Clinical Considerations
 Conclusions
 References
 
Experimental Systems Used to Study GVL
The GVL effect was first suggested by Barnes and Loutit in 1956 from observations in a murine transplantation model [9]. Subsequently, adoptively transferred lymphocytes have been used to confer an antileukemic action in rodents inoculated pre- or post-transplant with defined doses of leukemia cell lines or radiation-induced leukemias [10]. More recently, human GVL responses have been studied in vivo by establishing human leukemias in severe combined immunodeficient mice and adoptively transferring T cells [11-14]. Insight into human GVL responses has also been gained through functional studies of T cells obtained after BMT or DLT [15]. Involvement of specific effector cells in GVL is summarized in Table 2 and discussed below.


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  		Table 2. Effector cells in GVL
 
T Cells and GVL
The relative contribution of the CD4+ and CD8+ T cell subsets to GVL reactivity has been investigated extensively both in animal models and in man. Mice receiving CD8– depleted marrow, or marrow with the addition of purified CD4+ T cells, had a low incidence of GVHD with high leukemia-free survival [16], supporting an important role of CD4+ cells in GVL. CD8+ T cells also mediate GVL reactivity: mice receiving CD8-depleted donor marrow had a higher leukemia relapse incidence than those receiving CD4-depleted marrow [17, 18]. In experimental mouse transplants the addition of purified CD8+ T cells to the graft had an antitumor effect and facilitated engraftment without inducing GVHD [19]. We can conclude that in general both CD4+ and CD8+ T cell subsets contribute to GVL reactions. However, the dominant mechanism is strain specific and varies with the degree of donor-recipient histocompatibility. In man, CD4+ and CD8+ alloreactive cells with antileukemic activity have been generated in vitro by several investigators [20-24]. After BMT there is an increase of CD4+ precursors recognizing leukemia demonstrated by helper T lymphocyte precursor frequency assays [25]. We demonstrated the presence of donor-derived cytotoxic T cells in the blood of chronic myelogenous leukemia (CML) patients after BMT, showing specific reactivity to the patient's leukemia cells. Depletion of CD4+ cells from the responding population significantly reduced the cytotoxic T lymphocyte precursor frequency against the recipient's leukemia cells whereas CD8+ depletion had only a modest effect [26]. These results suggest that CD4+ T cells play a prominent role in the GVL response after BMT in man. Clinical trials with CD8-depleted marrow transplants or CD8-depleted peripheral blood leukocytes to treat relapsed leukemia after BMT lend support to the possibility that the residual GVL effect is mediated by CD4+ cells. Nimer et al. [27] using CD8-depleted marrow transplants observed a significantly lower incidence of GVHD without an increase in the rate of leukemia relapse compared with T-replete transplants. Giralt et al. [28] used CD8-depleted DLT to treat leukemia relapsing after BMT and observed a 60% response with only a 20% incidence of GVHD. Contrasting with these data are other clinical studies showing that CD4-depleted marrow transplants with an adjusted CD8+ T cell content significantly reduce GVHD without affecting engraftment and immune reconstitution [29]. These clinical observations should be interpreted with caution. It is possible that the separation of GVL and GVHD observed may simply be the result of transplanting low but nevertheless sufficient residual doses of immunocompetent cells, since similar results have been obtained using unmanipulated T cells [30].

Natural Killer (NK) Cells and GVL
Autologous antileukemic effects of NK cells in animals and man have been recognized for at least a decade [31]. Alloresponding NK cells recognize differences in the target's MHC class I [32, 33] and class II [34] molecules. However, the alloresponses of NK cells to leukemia are still poorly characterized because the precise recognition targets on the leukemias are not known. In a murine model, the susceptibility of experimental leukemias to GVL was shown to be closely related to their susceptibility in vitro to NK-mediated cytotoxicity [35]. In man, low NK function and delayed recovery after BMT for myeloid leukemias correlated with subsequent relapse of leukemia suggesting that NK function played a part in the GVL effect [36]. Much remains to be understood about NK reactivity to different leukemias.

Lymphokine Activated Killer (LAK) Cells and GVL
NK cells and some T cells activated with interleukin 2 (IL-2) can show MHC-unrestricted cytotoxicity. The antileukemic effect of alloreacting LAK cells was first demonstrated in a study where LAK cells generated from donor lymphocytes circulating after BMT were shown to kill the recipient's CML target [37]. IL-2-induced LAK activity increases rapidly after BMT and after DLT, used to induce remission in patients relapsing after BMT for CML [38]. IL-2 production following BMT may therefore contribute to some MHC-unrestricted antileukemic effect. However, the importance of the contribution of LAK activity to the GVL process in clinical BMT is not known.

A Model of GVL In Vivo—Importance of CD4+ Cells
We can now construct a hypothetical model of the GVL response in human leukemia transplants. The process, traced from the initiation of the alloresponse through a stage of clonal expansion to the effector phase, involves interactions between multiple lymphocyte subsets and cytokines.

Stimulation of the Alloresponse   The allogeneic T cell response involves the recognition of disparities of major and minor MHC class I and II antigens by CD8+ and CD4+ cells, respectively. Antigens common to leukemia cells and other tissues may be presented to the donor T cells by a variety of nonleukemic recipient tissues. However, recognition by donor T cells of leukemia-restricted antigens would require either direct antigen processing and presentation by the leukemia, or presentation of leukemia antigens by host- or donor-derived professional antigen-presenting cells (APC) (e.g., dendritic cells, macrophages). While class II molecules are mainly involved in exogenous antigen presentation [39], they also present endogenous antigens [40]. Therefore, leukemia cells expressing MHC class II could themselves present endogenous antigen. Dendritic cells derived from Ph+ chromosome-positive CD34+ cells are competent APC, stimulating antileukemic T cell responses [41]. The ability of leukemia cells to stimulate alloresponses is closely related to their MHC class II expression [42]. Furthermore, leukemic monocytes in CML are competent APC: capturing, processing and presenting exogenous protein antigens [43]. Proteins derived from leukemia cell breakdown could thus provide exogenous antigen presentation by leukemic APC through MHC class II [44].

Clonal Expansion   Following antigen recognition, T cell activation is necessary for the immune response. The activation of CD28 on the T cell by B7.1 and B7.2 (CD80, CD86) costimulatory molecules governs whether the T cell undergoes clonal expansion or, in the absence of a signal, becomes anergic. The production by CD4+ T cells of IL-2 and IL-12 provides helper activity to CD8+ cells and NK cells, recruiting them into an integrated immune response [45]. The process can be very rapid, as GVHD can occur within 7-10 days of the transplant. The GVL process is often slower. After DLT it may take several months to establish remission [46]. This slow response may be due to the time taken for clonal expansion from a very low frequency of T cell precursors with antileukemic specificity [20].

Effector Mechanisms   It is thought that the GVL effect is mediated in three ways [47-52]: A) direct killing of leukemia cells by perforin and granzyme attack from cytotoxic lymphocytes (CD4+, CD8+ and NK cells); B) apoptotic death through the fas/fas ligand pathway (CD4+ and CD8+ T cells), and C) cytokine-mediated leukemia cell death or control of proliferation (mainly CD4+ cells). Leukemia-reactive T cell clones derived from responders to HLA identical, or closely identical, leukemia cells have been used to study GVL mechanisms [21-24]. An important observation is that cytotoxicity against the committed stem cell progenitors of CML, measured by a colony inhibition assay, is more readily demonstrable than chromium or dye-release cytotoxicity against unselected CML targets. This suggests that progenitor cells (and therefore relevant GVL targets) are very susceptible to alloimmune attack [53]. Chronic and some acute myeloid leukemias express fas antigen [54, 55]. Fas antigen-mediated apoptosis of the target appears to be an important mechanism by which T cells mediate the GVL effect at the cellular level. T cells also mediate a GVL effect by cytokine production. In addition to cytokines produced by T cells that act in an autocrine or paracrine manner to recruit effectors and enhance effector cell cytotoxicity, the Th1-type cytokines, interferon-gamma (IFN-{gamma}) and tumor necrosis factor-alpha (TNF-{alpha}), inhibit hematopoiesis, [56, 57] while the Th2-type cytokines, GM-CSF and IL-3, stimulate hematopoiesis. It appears that CML progenitors are more sensitive to the inhibitory cytokines than normal progenitor cells, whereas normal progenitor cells are more responsive to the stimulatory cytokines than leukemia cells [20]. This differential sensitivity (which may translate into a GVL effect in vivo) may be explained in the expression of fas antigen by leukemic but not by normal CD34+ cells [54]. TNF-{alpha} triggering apoptosis through fas could thus preferentially inhibit leukemia cell growth.

The Central Role of CD4+ Cells in the GVL Response   It now appears that as well as initiating the alloresponse, CD4+ T cells are also involved in the effector phase of GVL. CD4+ cells are cytotoxic to leukemia cells [20, 22-24] and they produce cytokines with a wide spectrum of biological activities: production of IL-2 and IL-12 recruits NK cells and CD8+ T cells into the immune responses and augments their antitumor cytotoxicity [58, 59]. IFN-{gamma} and TNF-{alpha} inhibit leukemia cells directly [60] and both cytokines upregulate MHC and fas antigen expression [61] rendering targets susceptible to cytotoxicity by T cells. CD4+ cells, therefore, have a role both as effectors and as orchestrators of the GVL response ( Fig. 1).



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  		Figure 1. A three-phase model of the GVL response.

 

   Immunogenicity of Leukemia
Top
 Abstract
 General Considerations
 Immunobiology of GVL
 Immunogenicity of Leukemia
Leukemia Antigens
 Clinical Considerations
 Conclusions
 References
 
The observation that there is a wide spectrum of responses of different leukemias to BMT and DLT suggests that the characteristics of the malignant cell determine its susceptibility to the GVL effect. To be susceptible to GVL, the leukemia should ideally function both as a stimulator and as a target for the donor immune system. Leukemic immunogenicity is governed by key cell surface molecules as well as a less well-characterized intrinsic malignant potential. To stimulate a specific antileukemic immune response, the leukemia cell must present leukemia-restricted antigens to T cells through either MHC class I or II. This requires an adequate density of MHC molecules on the cell surface, as well as sufficient representation of an immunodominant peptide antigen. Furthermore, the T cell must receive a costimulatory signal from the B7 molecules on the leukemia cell to initiate clonal expansion [62-64]. As targets for T cell attack, leukemia cells must again present their antigen through the appropriate MHC molecule. Their susceptibility to perforin and granzymes and expression of fas determine their susceptibility, respectively, to lysis and apoptosis. In addition, they may show different susceptibilities to regulatory effects of other cytokines such as tumor necrosis factor and interferon. Susceptibility to NK cell attack may be determined by the degree of expression of certain adhesion molecules [65]. At present we only know in general terms how these features correspond with a clinical GVL effect. Only CML has been studied in enough detail to relate its immunogenicity to its susceptibility to clinical GVL. Unlike acute leukemia cells, which are more resistant to GVL effects, CML cells in chronic phase appear to have the full complement of features necessary for immunogenicity: they have high expression of MHC class I and II [8], they process and present antigen through MHC class II [43], they express fas on CD34+ targets [55] and their progenitors are susceptible to cytotoxic T cells and cytokine inhibition [20].


   Leukemia Antigens
Top
 Abstract
 General Considerations
 Immunobiology of GVL
 Immunogenicity of Leukemia
 Leukemia Antigens
Clinical Considerations
 Conclusions
 References
 
Donor T cells can exert a GVL effect by recognizing minor histocompatibility antigens (mHA) presented by the leukemia cell through MHC class I and II molecules. The mechanism of self-peptide processing and presentation is summarized in Figure 2. Very little detail of the mHA system is yet known and the precise peptide sequences of the antigens that stimulate the GVL response are unknown [3, 66]. We can, however, define three functional categories of antigen: ubiquitous, tissue-specific and leukemia-specific ( Table 3). Ubiquitous antigens are widely distributed in recipient tissues. In HLA-matched transplants they represent mHA such as H-Y and HA-3, HA-4 and HA-6 [67-69]. Such antigens are predicted to induce nonspecific GVHD/GVL reactions. The identification of an mHA, HA-2, present only on cells of the lymphocytic and myeloid series, is of great significance since it is the first well-characterized tissue-restricted alloantigen [70]. The peptide sequence did not match perfectly with any known protein sequence but has some similarities to cytoskeletal proteins. The identification of other tissue-restricted proteins is a new area of research. From analysis of natural peptides present in MHC molecules it appears that self-peptides can be derived from all parts of the cell ( Fig. 3). Candidate proteins inducing strong GVL responses may well turn out to be normal differentiation proteins of myeloid or lymphoid cells, overexpressed in leukemic cells, and represented by several common alleles. A range of proteins, such as the lineage specific surface markers CD45 (pan-leucocyte) [71], CD19, (B cells) [72], CD33 and granule proteins (myeloid cells) [73] are therefore being studied for evidence of polymorphism and the ability of their peptides to stimulate T cell responses.



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  		Figure 2. Self-antigen processing through endogenous pathways. Self-proteins are broken down in the cytoplasm by proteasome enzyme complexes. Peptides enter the endoplasmic reticulum by an active process and combine with MHC class I molecules and ß-2 microglobulin. The trimolecular process is transported to the cell surface in class I vacuole to be presented to the CD8+ T cells. In the endoplasmic reticulum (ER), alpha and beta chains of MHC class II molecules form a stable trimeric complex with the invariant chain. Peptides combine with MHC class II molecules in post-ER vacuoles by displacing the invariant chain. MHC class II molecules present the peptide to CD4+ T cells. Accessory and costimulatory molecules were omitted for clarity.

 

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  		Table 3. Candidate leukemia antigens with potential GVL reactivity
 


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  		Figure 3. Cellular origin of candidate tissue-specific antigens.

 
The third potential source of leukemia antigens are the chromosomal translocations, point and frame-shift mutations and deletions, which characterize many leukemias. Peptide sequences derived from the area of mutation or fusion region of translocations, could function as neoantigens [8]. Initial hope that the BCR-ABL fusion gene product is a leukemia-specific antigen in CML for a long time has been unrealized. Although BCR-ABL-derived peptides bind to HLA class I and class II molecules and stimulate specific CD4+ and CD8+ T cells responses [8, 74-78], T cells generated in vitro have not shown any cytotoxicity to HLA-matched leukemia cells expressing the BCR-ABL protein. There is, however, a recent report of CML-specific proliferation of a CD4+ T cell clone generated against large BCR-ABL peptide sequences [79]. This is the first evidence that peptides from the BCR-ABL protein are naturally processed and presented by the leukemia cell. However, the observation falls short of proving that BCR-ABL protein is a dominant antigen in the GVL response.


   Clinical Considerations
Top
 Abstract
 General Considerations
 Immunobiology of GVL
 Immunogenicity of Leukemia
 Leukemia Antigens
 Clinical Considerations
Conclusions
 References
 
GVL Reactivity after BMT and DLT
The evidence for GVL after allogeneic BMT in man comes from analyses of relapse in large numbers of patients grafted with or without T cell depletion. Statistically, patients are at more risk of leukemic relapse if they do not develop acute or chronic GVHD, or have received a T cell depleted BMT. However, there is also evidence for a GVL effect of T-replete BMT without an accompanying GVHD reaction [80]. The most convincing data for a significant GVL effect in clinical practice come from the now well-substantiated antileukemic effect of DLT to induce remission and possibly cure leukemia relapsing after allogeneic BMT [15, 81]. Again, although GVHD increases the chance of a leukemic response, some patients achieve stable leukemia remissions without developing acute or chronic GVHD.

After allogeneic BMT and DLT there is an early rise in cells with LAK reactivity of T cell and NK phenotype [82]. The frequency of cytotoxic T lymphocyte precursors with antileukemic reactivity also increases. Split-well analysis shows that such precursors have leukemia specificity [25]. In one study CD4+ but not CD8+ T cell and NK cell numbers after BMT were higher in patients who did not relapse, and superior NK function was also associated with continued remission [30]. As previously mentioned, there is some evidence from CD8+ depletion of BMT and donor lymphocytes that CD4+ T cells are more important than CD8+ T cells in the GVL response to CML [27-29]. However, the conclusions that CD4+ cells are necessary and sufficient to confer GVL must be balanced against the possibility that the GVL effect is conferred by a small number of residual CD8+ T cells or accompanying NK cells in the transplant. Factors affecting immune responsiveness also affect relapse after BMT: immunosuppression with cyclosporine promotes leukemic relapse, and relapse can be reversed by stopping cyclosporine [83]. Conversely, data from lymphocyte add-back studies and DLT to treat relapsed leukemia indicate that IL-2 and IFN-{alpha}, which enhance GVHD and lymphocyte reactivity, also enhance GVL responses [8, 84].

Diversity of GVL Response in Different Leukemias
BMT statistics and more recent results of DLT to treat relapse post-transplant [80, 81] indicate that there are wide differences in the susceptibility of the leukemia to GVL effects. Myeloid leukemias appear to be more susceptible to GVL while acute lymphoblastic leukemia is the least susceptible. CML in early (molecular) relapse chronic phase is the most responsive to DLT; later relapse shows intermediate responsiveness and relapse in accelerated or blast phase demonstrates the least. These observations suggest that several factors govern leukemia susceptibility: A) degree of disease progression—early relapse being more favorable than either later relapses or relapse of more advanced leukemia; B) lineage of the leukemia—the more powerful GVL response of DLT in myeloid leukemias could be due to better immunogenicity, or the more frequent occurrence of lineage restricted minor antigens in myeloid cells, and C) pace of disease—recent reports of responses of relapsed myeloma [85-87] to DLT suggest that, together with CML, myeloma is susceptible to GVL effects because they have a slower pace of proliferation and progression than the acute leukemias. However, these possibilities remain unproven.

Mechanisms of Relapse
Relapse of leukemia following BMT could be due either to a failure of the antileukemic preparative regimen, or of the GVL response. Case reports, where relapse was reversed by stopping immunosuppression, support the idea that residual leukemia is controlled by a competent donor immune system [83]. In other instances, where relapse follows rapidly after transplant, it is more likely that leukemic cytoreduction from the preparative regimen was inadequate and that residual leukemia outstripped the developing GVL response. A third possibility is that leukemic relapse after BMT represents a form of immune escape ( Fig. 4). Data supporting this possibility come from a paired study of leukemia samples obtained before marrow transplant and at relapse post-transplant. Many of the relapsed leukemias showed alterations in surface phenotype, including downregulation of MHC class I and II antigens, associated with a decreased ability to stimulate allogeneic proliferative T cell responses, and decreased susceptibility to lysis by cytotoxic T lymphocytes or NK cells. These findings, coupled with other evidence of clonal progression in the relapsed leukemia, suggested that the allograft selected leukemia subclones resistant to the GVL effect [8].



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  		Figure 4. Leukemia escape by clonal selection.

 
Separating GVL and GVHD ( Table 4)
Immunosuppressives used to prevent GVHD in current use, such as cyclosporine and methotrexate also have a nonselective, negative effect on GVL. New approaches to prevent GVHD with anticytokine agents [88, 89], bias of T cells to the Th1 functional type [90, 91], and induction of anergy by blockade of the CD28/B7 costimulatory molecules [64, 92] all suffer, at least in theory, from a similar lack of selectivity such that the benefit from GVHD reduction is likely to be offset by an increase in leukemic relapse. Other strategies, however, may prove more flexible. For example, there is experimental evidence that T cell depletion followed by delayed add-back of immune competent donor cells confers a GVL with only a low risk of acute GVHD [93]. Clinical studies are beginning to confirm experimental predictions, although donor lymphocyte transfusions used to treat leukemia relapsing after BMT can cause GVHD, approximately 25% of patients with CML achieve a remission without clinical GVHD [46]. In HLA-matched sibling BMT for CML, T cell depletion followed by cyclosporine treatment and graded add-back of donor T cells from as early as day 30 confers protection from relapse, with a low incidence of severe acute GVHD. Without cyclosporine cover, smaller T cell doses given after 100 d from BMT also achieve a GVL effect with a low risk from GVHD [94]. Another way of conferring GVL, while preventing serious consequences from GVHD, is to transfer to the recipient T cells marked with a "suicide gene" (viral thymidine kinase) which renders the cells susceptible to elimination by ganciclovir [95, 96]. In this way, gene-marked T cells, given for their GVL effect, can be eliminated at the onset of a serious GVHD reaction. It remains to be seen whether GVL responses will be effective in the brief window in time between the infusion of gene-marked T cells and their removal at the onset of the GVHD reaction. Since CD4+ and CD8+ subsets are both involved in GVHD and GVL reactions, it does not appear possible to completely separate GVL from GVHD by transplanting marrow depleted of either one of the two major subsets. A more promising way of separating GVL from GVHD is based upon the possibility of selecting, for transfer to the recipient, T cell clones which preferentially recognize leukemia. Two approaches are being investigated: negative selection of GVHD-reacting T cells and positive selection of leukemia-reactive T cells. Negative selection involves the in vitro stimulation of donor T cells with nonleukemic cells from the recipient (usually lymphocytes). Responding donor cells are eliminated by addition of antibodies to CD25 activation markers, coupled to toxins or immunomagnetic beads [97-99]. Remaining cells conserve reactivity to recipient leukemia: Epstein-Barr virus transformed B cells and third party stimulators [100, 101]. Clinical trials with this selective immunodepletion are now underway. Alternatively, it may soon be possible to positively select T cells with a restricted, primarily antileukemic, repertoire by selecting the appropriate T cell receptor Vß subgroup by immunomagnetic bead technology [102]. The advantage of this form of selection would be the possibility of augmenting GVL reactions by transfusing large numbers of leukemia-reacting cells taken from repeated apheresis donations.


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  		Table 4. Improving the specificity and potency of the GVL response
 
Expanding Leukemia-Reactive T Cells
It appears that the precursor frequency of antileukemia reactive T cells is very low, typically in the order of 1/1,000,000 in the unprimed donor [26]. Attempts to expand T cell clones with leukemia specificity therefore require highly efficient in vitro T cell selection and expansion techniques, or a vaccine approach. Current techniques to raise donor-specific antileukemia cell T cell lines for clinical use are imperfect—not all donor-recipient pairs generate specific cytotoxic antileukemia clones, and T cell expansion in vitro is unreliable [103]. This may be due in part to the failure of the leukemia cell stimulators to present an immunodominant antigen to the responder. Our current inability to define tissue-restricted antigens on leukemia is a major limitation to generating antileukemic T cell clones. In this regard the generation of antileukemic cytotoxic T cells responding to peptides derived from the myeloid-restricted granule protein proteinase-3 may serve as a model for generating strong T cell responses to identified antigens [73]. The difficulties of generating T cells in vitro for adoptive immunotherapy encourage continued attempts to design leukemia vaccines which could be administered to the donor, or the recipient, after transplantation to boost specific immunity. Some progress has been made in the immunotherapy of multiple myeloma by vaccinating the donor with myeloma protein to generate idiotype-specific alloreacting T cells [104]. However, it has yet to be demonstrated that donor vaccination improves the already demonstrable graft-versus-myeloma effect after allogeneic BMT [85-87]. The possibility of using as vaccines peptides derived from a leukemia-specific fusion protein such as p210, p190 in Ph+ leukemias, t15;17 fusion protein in acute myeloid leukemia (AML M3) [105] or leukemia cells transfected with costimulatory molecules is also under investigation (see below).

Improving the Immunogenicity of the Leukemia
As more is learned about the defects in surface expression of critical molecules on malignant cells, it becomes more feasible to design ways to correct the defects and render the leukemia susceptible to immune attack. The cytokines IFN-{gamma} and GM-CSF upregulate MHC molecule expression and render defective leukemia cells susceptible to cytolysis by alloreacting CTL [8]. IL-2 and IFN-{alpha} used in conjunction with DLT improve the clinical response but, to improve their effectiveness, more has to be learned about their mode of action [84]. The importance of costimulation by the leukemia cell in generating a strong immune response has opened up the possibility of using leukemia cell vaccines transfected with the B7 costimulatory molecules [63]. In animal models this can render nonimmunogenic tumors strongly immunogenic not only to the transfected cell but to the native tumor. Other promising transfection strategies include the use of the IL-12 gene to upregulate T cell responses to the malignancy [106].


   Conclusions
Top
 Abstract
 General Considerations
 Immunobiology of GVL
 Immunogenicity of Leukemia
 Leukemia Antigens
 Clinical Considerations
 Conclusions
References
 
Since it first became accepted in the 1980s that GVL was a clinical as well as an experimental reality, much progress has been made in understanding and characterizing the GVL reaction. While the separation of GVL from GVHD is theoretically predicted and has, in limited circumstances, been achieved clinically, our inability to identify antigens driving leukemia-specific alloresponses remains the biggest single obstacle to improving the strength and specificity of GVL in clinical practice. However, progress in this field is gaining momentum and we can expect that the next century will see major advances in manipulation of the alloimmune response to the benefit of patients with a variety of malignant disorders.


   References
Top
 Abstract
 General Considerations
 Immunobiology of GVL
 Immunogenicity of Leukemia
 Leukemia Antigens
 Clinical Considerations
 Conclusions
 References
 

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accepted for publication on February 14, 1997.




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