Immunotherapeutic Effects of HCT

Graft-Versus-Leukemia (GVL) Effect
        Using donor lymphocyte infusions (DLI) or early withdrawal of immune suppression to enhance GVL
        Other approaches under evaluation

Early studies in hematopoietic cell transplantation (HCT) focused on delivery of intense myeloablative preparative regimens followed by “rescue” of the hematopoietic system with either an autologous or allogeneic bone marrow. Investigators quickly showed that allogeneic approaches led to a decreased risk of relapse caused by an immunotherapeutic reaction of the new bone marrow graft against tumor antigens. This phenomenon came to be termed the graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect, and has been shown to be associated with mismatches to both major and minor HLA antigens. The GVL effect is challenging to use therapeutically because of a strong association between GVL and clinical graft-versus-host disease (GVHD). For standard approaches to HCT, the highest survival rates have been associated with mild or moderate GVHD (overall grade I or II) compared with patients who have no GVHD and experience more relapse or patients with severe GVHD who experience more transplant-related mortality.

Understanding when GVL occurs and how to use GVL optimally is challenging. One method of study is comparing rates of relapse and survival between patients undergoing myeloablative HCT with autologous versus allogeneic donors for a given disease. In this setting, a clear advantage has been noted when allogeneic approaches are used for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). For ALL and AML specifically, autologous HCT approaches to most high-risk patient groups have shown results similar to chemotherapy, while allogeneic approaches have been superior.[1,2] Patients with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) generally fare better with autologous approaches, although there may be a role for allogeneic approaches in relapsed lymphoblastic lymphoma, lymphoma that is poorly responsive to chemotherapy, or lymphoma that has relapsed after autologous HCT.[3]

Further insights into the therapeutic benefit of GVL/GVT for given diseases have come from the use of reduced-intensity preparative regimens (refer to the Principles of HCT Preparative Regimens section of this summary for more information). This approach to transplantation relies on GVL, as the intensity of the preparative regimen is not sufficient for cure in most cases. Although studies have shown benefit for patients pursuing this approach if they are ineligible for standard transplantation,[4] because pediatric cancer patients can generally undergo myeloablative approaches safely, this approach has not been used for the majority of children with cancer who require HCT.

One can deliver GVL therapeutically through infusion of cells after transplant that either specifically or nonspecifically target tumor. The most common approach is the use of DLI. This approach relies on the persistence of donor T-cell engraftment after transplant to prevent rejection of donor lymphocytes infused to induce the GVL. Therapeutic DLI results in potent responses in patients with CML who relapse after transplant (60%–80% enter into long-term remission),[5] but responses in other diseases (AML and ALL) have been less potent, with only 20% to 30% long-term survival.[6] DLI works poorly in patients with acute leukemia who relapse early and who have high levels of active disease. Late relapse (>6 months after transplant) and treatment of patients into complete remission with chemotherapy prior to DLI have been associated with improved outcomes.[7] Infusions of DLI modified to enhance GVL or other donor cells (natural killer [NK] cells, etc.) have also been studied, but have yet to be generally adopted.

Another method of delivering GVL therapeutically is the rapid withdrawal of immune suppression after HCT. Some studies have scheduled more rapid immune suppression tapers based upon donor type (related donors more quickly than unrelated donors due to GVHD risk), and others have used sensitive measures of either low levels of persistent recipient cells (recipient “chimerism”) or minimal residual disease in order to assess risk of relapse and trigger rapid taper of immune suppression. A combination of early withdrawal of immune suppression after HCT with addition of DLI to prevent relapse in patients at high risk of relapse due to persistent/progressive recipient chimerism has been tested in patients transplanted for both ALL and AML. For patients with ALL, one study found increasing recipient chimerism in 46 of 101 patients. Thirty one of those patients had withdrawal of immune suppression and a portion went on to receive DLI if GVHD did not occur. This group had a 37% survival compared with 0% in the 15 patients who did not undergo this approach (P <.001).[8] For patients with AML after HCT, about 20% experienced mixed chimerism after HCT and were identified as high risk. Of these, 54% survived if they underwent withdrawal of immune suppression with or without DLI; there were no survivors among those who did not receive this therapy.[9]

Donor-derived NK cells in the post-HCT setting have been shown to promote engraftment, decrease GVHD, and lessen relapse of hematological malignancies.[10,11] NK cell function is modulated by interactions with a number of receptor families, including activating and inhibiting killer immunoglobulin-like receptors. The killer immunoglobulin-like receptor effect in the allogeneic HCT setting hinges upon expression of specific inhibitory killer immunoglobulin-like receptors on donor-derived NK cells and either the presence or absence of their matching HLA class I molecules (killer immunoglobulin-like receptor ligands) on recipient leukemic and normal cells. Normally the presence of specific killer immunoglobulin-like receptor ligands interacting with paired inhibitory killer immunoglobulin-like receptor molecules prevents NK cell attack of healthy cells. In the allogeneic transplant setting, recipient leukemia cells genetically differ from donor NK cells and they may not have the appropriate inhibitory killer immunoglobulin-like receptor ligand. This mismatch of ligand and receptor allows NK cell–based killing of recipient leukemia cells to proceed for certain donor-recipient genetic combinations.

The original observation of decreased relapse with certain killer immunoglobulin-like receptor-ligand combinations was made in the setting of T-cell depleted haploidentical transplantation and was strongest after HCT for AML.[11,12] Along with decreasing relapse, these studies have suggested a decrease in GVHD with appropriate killer immunoglobulin-like receptor-ligand combinations. Many subsequent studies did not detect survival effects for killer immunoglobulin-like receptor-incompatible HCT using standard transplantation methods,[13,14] which has led to the conclusion that T-cell depletion may be necessary to remove other forms of inhibitory cellular interactions. Decreased relapse and better survival has been noted with donor/recipient killer immunoglobulin-like receptor-ligand incompatibility after cord blood HCT, a relatively T-cell depleted procedure.[15,16] The role of killer immunoglobulin-like receptor incompatibility in sibling donor HCT and in diseases other than AML is controversial.[17,18]

A current challenge associated with the killer immunoglobulin-like receptor field is that several different approaches have been used to determine what is killer immunoglobulin-like receptor compatible and incompatible.[12,19] Standardization of classification and prospective studies should help clarify the utility and importance of this approach. Currently, because a limited number of centers perform haploidentical HCT and the data in cord blood HCT are early, most transplant programs do not use killer immunoglobulin-like receptor mismatching as part of their strategy for choosing a donor. Full HLA matching is considered most important for outcome, with considerations of killer immunoglobulin-like receptor incompatibility remaining secondary.

With low risk of GVHD and demonstrated efficacy in decreasing relapse in post-haploidentical HCT settings, NK cell infusions have been studied as a method of treating high-risk patients and consolidating patients in remission. The University of Minnesota group initially failed to demonstrate efficacy with autologous NK cells, but found that intense immunoablative therapy followed by purified haploidentical NK cells and IL-2 maintenance led to remission in 5 of 19 high-risk AML patients.[20] Researchers at St. Jude Children’s Research Hospital treated ten intermediate-risk AML patients who had completed chemotherapy and were in remission with lower-dose immunosuppression followed by haploidentical NK cell infusions and IL-2 for consolidation.[21] Expansion of NK cells was noted in all nine of the killer immunoglobulin-like receptor-incompatible donor/recipient pairs. All ten children remained in remission at 2 years. A follow-up phase II study is underway, as are many investigations into NK cell therapy for a number of cancer types.

References

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