Allogeneic blood or marrow transplantation is the most effective modality to date to eradicate hematologic malignancies in patients at high risk to relapse or resistant to conventional doses of chemoradiother-apy. A standard autoBMT as well as alloBMT appear most suitable in patients with hematologic malignancies and solid tumors sensitive to chemoradiotherapy, since the rescue procedure enables administration of higher than conventional doses of cytoreductive antitumor agents. Following myeloablative chemoradiotherapy supported by autoBMT, however, the rate of anticipated relapse is much higher due to the lack of graft versus leukemia (GVL) effects mediated by al-loreactive donor-derived T cells . A number of approaches are available to improve antitumor effects induced by donor T cells, including the use of no or low doses of post-transplant immunosuppressive agents which may help resident T cells to induce their antitumor effects [72-74], However, this approach has already been proven to be relatively hazardous since recipients of fully matched marrow allografts, let alone less than perfectly matched allografts or matched unrelated allografts, may develop GVHD which may be associated with immediate and late complications with the risk of lethal outcome. Since the GVL effects are mediated by donor alloreactive T cells, GVL effects can also be induced for prevention or treatment of established relapse by administration of DLI [75, 76], Allogeneic cell-mediated immunotherapy (alloCT) by DLI can be administered in graded increments of donor-derived peripheral blood lymphocytes in order to allow better control of GVHD , We [77, 78] and others  have previously documented that by increasing the time interval between alloBMT and DLI resistance to GVHD increases as well, therefore recipients may occasionally be able to safely receive large inocula of donor-derived PBL with a marked graft versus leukemia (GVL) capacity while completely avoiding severe GVHD. Furthermore, we have recently documented that host-type tumor cells resistant to DLI may still respond to unstimulated or in vitro activated lymphocytes supported in vivo by a short course of well tolerated doses of rIL-2 [76, 78]. The same rational was already successfully applied in clinical practice, as recently shown in a cohort of patients with a variety of hematologic malignancies relapsing following alloBMT . Taken together, our data suggest that alloCT, especially when antileukemia effector cells are activated by rIL-2, may develop into a very effective modality for both treatment and prevention of relapse in patients with resistant disease [75, 76] or at high risk to relapse ,
The marked therapeutic benefits of alloCT induced by DLI always carry the risk of GVHD, with an incidence and severity that are unpredictable. As such, GVHD is in fact an iatrogenic "autoimmune disease" which may attack in principle any organ or tissue. New approaches to limit the life span of donor-derived T cells in case of uncontrolled GVHD are currently under development. The most promising modality for controlling GVHD, and its incidence after discontinuation of anti-GVHD prophylaxis, is the use of donor T cells transduced with the herpes simplex virus thymidine kinase gene . Genetically modified T cells of donor origin still retain their GVL capacity. Hence, in the event of uncontrolled GVHD these antitumor effector cells can be successfully eliminated by administration of conventional doses of ganciclovir . The feasibility to eliminate safely and consistently GVHD induced intentionally by donor lymphocytes to enhance GVL effects may pave the way for using DLI to treat hematologic malignancies and maybe metastatic solid tumors not curable by any of the currently available modalities. GVL or possibly the graft versus tumor effect (GVT) of fully mismatched cells that could possess a more effective antitumor potential may be intensified. GVL as well as GVT effects initiated by DLI are most likely induced by the minor histocompatibility complex (MiHC) and major histocompatibility complex (MHC) incompatibility which may determine the cytotoxic T-lymphocyte precursor activity, as implied by recent investigations in experimental animals and man.
The first successful clinical trials introducing DLI for both the treatment or for prevention of relapse following alloBMT were carried out at Hadassah in Jerusalem, in early 1987 . Our data were subsequently confirmed in prospective studies in Europe  and the USA ,
Since GVL effects mediated by donor lymphocytes constitute the main therapeutic effect against malignant tumor cells of host origin, we asked whether or not equally potent GVL effects might be inducible following nonmyeloablative stem-cell transplantation, or in other words, can standard alloBMT be replaced by nonmyeloablative conditioning? Accordingly, we have recently developed a new approach to the therapy for diseases treatable by conventional alloBMT, focusing on the use of donor T cells to eradicate malignant and also nonmalignant cells of host origin, thus avoiding the need for myeloablative conditioning , Our protocol was based on minimizing the intensity of the conditioning regimen to the range of nonmyeloablative treatment, followed by infusion of G-CSF-mobilized donor stem cells enriched with circulating T lymphocytes collected by apheresis. The main focus is on intensive short-term immunosuppression with fludarabine and antithymocyte globulin (ATG) with low-dose oral busulfan (8 mg/kg) prior to infusion of blood stem cells. GVL effects were mediated initially by the large number of donor-derived immunocompetent T lymphocytes given together with donor stem cells. GVL effects could be subsequently increased with alloCT by DLI on an outpatient basis.
Our preliminary data in nearly 50 patients with standard indications for allogeneic BMT, namely, acute leukemia; chronic leukemia; non-Hodgkin's lymphoma; myelodysplastic syndrome and multiple myeloma indicate that the nonmyeloablative conditioning is extremely well tolerated, with no severe procedure-related toxicity. Transplantation of G-CSF mobilized blood stem cells, with a short course of low dose cyclosporin A as the sole anti-GVHD prophylaxis, resulted in stable partial or complete chimerism in all recipients. In some patients the absolute neutrophil count (ANC) did not decrease below 0.1 x 109/L whereas some patients never experienced ANC < 0.5 x 109/L. ANC > 0.5 > 109/L was reached within 10-32 (median 15) days. Platelet counts did not decrease below 20 x 109/L in 4 patients who required no platelet support at all; overall platelet counts >20 x 109/L were achieved within a median of 12
days. Severe GVHD (grade III & IV) was the single major complication and the cause of death, in most of the cases only after early discontinuation of CSA. Relapse could frequently be reversed by alloCT. Successful eradication of malignant (as well as genetically abnormal host hematopoietic cells) by allogeneic nonmyeloablative stem-cell transplantation could represent a new approach for safer treatment of a large variety of clinical syndromes whenever an indication for alloBMT exists. Transient mixed chimerism which may protect the host from severe acute GVHD may be successfully reversed post-alloBMT, first by earlier discontinuation of CSA or with graded increments of DLIs late post-alloBMT, thus resulting in eradication of malignant or genetically abnormal progenitor cells of host origin.
Our preliminary experience seems promising and suggests that allogeneic nonmyeloablative stem-cell transplantation may result in complete elimination of malignant or genetically abnormal host cells with no or minimal procedure-related toxicity and mortality . For young patients, in contrast to myeloab-lative allogeneic BMT, allogeneic nonmyeloablative stem-cell transplantation may reduce the incidence of growth retardation and infertility which stems from the unique sensitivity to chemoradiotherapy of the growth centers in the bones, the gonads and testicles. For elderly individuals with a matched donor available, who were denied alloBMT until recently, nonmyeloablative stem-cell transplantation may offer an option for cure with no upper age limit. It remains to be seen whether a similar therapeutic approach can be developed for patients with matched unrelated donors and for patients with no matched donors, as well as for malignancies other than those originating in hematopoietic stem cells.
The principle behind the new allogeneic nonmyeloablative stem-cell transplantation protocol, was to maximize transient immunosuppression with nonmyeloablative agents rather than attempt to eradicate all tumor cells or genetically abnormal stem cells which are expected to be eliminated over time by alloreac-tive T cells of donor origin. Based on our preliminary experience, that needs to be confirmed in a larger series of patients observed for a longer time period, major advantages are to be expected if it can be confirmed that allogeneic nonmyeloablative stem-cell transplantation can safely replace alloBMT. Perhaps even more important, the state of transient or stable mixed chimerism that results from allogeneic nonmyeloablative stem-cell transplantation may eventually help in designing strategies to better control GVHD.
One of the questions that needs to be answered is whether, or not, similar GVT effects can be induced against metastatic solid tumors. Several years ago, we used allogeneic BMT to prevent spontaneously occurring lymphosarcoma in (NZBxNZW)Fl mice , Interestingly, effective GVT effects, similar to GVL were documented despite the complete lack of host versus graft and graft versus host responsiveness. Subsequently, we induced GVT effects in a murine model of a transplantable metastasizing mammary solid tumor, resembling human disease (4T1) , The presence of GVT effects was investigated by inoculating 4T1 cells into chimeric mice reconstituted with MiHC or MHC incompatible marrow allografts . Intravenously inoculated pulmonary metastases that resulted in typical widespread lethal disease in all untreated BALB/c or F1 recipients, were completely eliminated following inoculation into DBA/2^ BALB/c or C57BL/6->F1 chimeras (Morecki and Slavin, submitted for publication). Elimination of all metastatic cells was confirmed by adoptive transfer of single-cell suspensions of lung cells obtained from inoculated controls and chimeras, the former, in contrast to the latter, resulting in death of 100% of the secondary recipients. Our data imply that in this animal model allogeneic cells in a stable chimera resisted breast cancer cell metastases. The existence of a GVT effect in a murine model of mammary carcinoma, suggests the possible use of allogeneic cell therapy for prevention and/or treatment of relapse in patients with metastatic breast cancer and possibly other solid tumors, similarly to the already proven GVL effects in hematologic malignancies.
We have recently documented possible antitumor responses in 6 patients with documented metastatic breast cancer relapsing following autologous blood stem-cell transplantation, treated with donor lymphocytes obtained from an HLA-matched sibling , Donor lymphocytes were activated with rIL-2 in vitro and in vivo. One of the patients treated with no evidence of disease at the time of alloCT is still event-and disease-free over 5 years past therapy. None of the data presented here shows conclusive evidence for GVT effects comparable to GVL effects in patients with hematologic malignancies, However, in addition to the cumulative experience with blood cancer and the murine data presented here, the possibility exists that GVT effects might be effective against metastatic solid tumors, especially against minimal residual disease.
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