Shimon Slavin

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Shimon Slavin, MD, Professor of Medicine, pioneered the use of personalized anti-cancer immunotherapy mediated by donor lymphocytes and innovative methods for stem cell transplantation for cure of malignant and life-threatening non-malignant disorders, including treatment of autoimmune diseases and induction of transplantation tolerance to bone marrow and organ allografts. More recently, Slavin pioneered the use of multi-potent mesenchymal stromal cells for multi-system regenerative medicine. Slavin authors 4 books, >660 scientific publications and serves on many editorial boards and many national and international advisory boards. Slavin received many international awards in recognition of his contributions for treatment of cancer and non-malignant disorders.

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Interleukin-7 induced facilitation of immunological reconstitution of sublethally irradiated mice following treatment with alloreactive spleen cells in a murine model of B-cell leukemia/lymphoma (BCL1)

Bone Marrow Transplantation, 2007

Interleukin-7 (IL-7) plays a key role in maturation and function of both T and B cells. We invest... more Interleukin-7 (IL-7) plays a key role in maturation and function of both T and B cells. We investigate the potential use of recombinant human IL-7 for facilitation of graft-versus-leukemia (GVL) effects mediated by T cells following transplantation in a murine model. Administration of IL-7 in vivo to allogeneic-transplanted mice improved disease-free survival: 67% of mice treated with IL-7 remained alive and disease free for more than 60 days, in comparison to 17% of the controls (Po0.05). Similar results were obtained when C57BL/6 spleen cells sensitized against irradiated B-cell leukemia (BCL 1 ) cells in the presence of IL-7 were transplanted to F 1 mice, followed by IL-7 treatment in vivo. Of the BALB/c mice that received spleen cells from F 1 mice treated with IL-7 following transplantation of C57BL/6 spleen cells sensitized with irradiated BCL 1 in the presence of IL-7, only 29% developed leukemia, as compared to 79% in the control group (Po0.05). Mice treated with IL-7 showed increased splenic and thymic cellularity and improved T cell-dependent proliferative responses compared to the controls (Po0.05). IL-7 may provide a novel tool to enhance immune reconstitution following transplantation of mismatched stem cells and for enhancement of GVL effects mediated by alloreactive lymphocytes.

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Adoptive immunotherapy with haploidentical allogeneic peripheral blood lymphocytes following autologous bone marrow transplantation

Experimental Hematology, 2000

Objective. Patients who undergo autologous bone marrow transplantation for acute leukemia are at ... more Objective. Patients who undergo autologous bone marrow transplantation for acute leukemia are at high risk for relapse. We have evaluated the feasibility of administering cell-mediated immunotherapy with family-related haploidentical lymphocytes following autologous bone marrow transplantation in order to evoke a graft-vs-leukemia effect in the autologous setting. Patients and Methods. Twenty-six patients aged 1.5-48 years were enrolled in this study. Eighteen suffered from acute myeloid leukemia, seven from acute lymphoblastic leukemia, and one from myelodysplastic syndrome. Eleven patients were transplanted in first remission, six in second remission, one in fourth remission, and eight in relapse. Conditioning consisted of Busulfan/Cyclophosphamide or Busulfan/Thiotepa/Cyclophosphamide. Nineteen patients (Group A) were treated with gradual increments of haploidentical donor T cells, starting on day ϩ 1, with an additional course of T cells plus intravenous recombinant human interleukin-2 one month later if no signs of graft-vs-host disease developed in the interim. Seven patients (Group B) were treated with high-dose haploidentical T cells on day ϩ 1 in conjunction with intravenous recombinant human interleukin-2. Results. Donor cells were detected in the peripheral blood of both groups 12-48 hours postcell-mediated immunotherapy, peaking at 48 hours. Three patients in Group A developed transient Grade I graft-vs-host disease. One patient in Group B developed Grade I, and three Grade IV, graft-vs-host disease. Group A patients engrafted normally, but the Group B patients with Grade IV graft-vs-host disease showed no signs of engraftment. Conclusion. Our results show that it is feasible to induce graft-vs-host disease in the autologous stem cell transplantation setting. However, the high-dose regimen of haploidentical T cells in conjunction with interleukin-2 results in severe toxicity and nonengraftment.

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Potential use of interleukin-6 in bone marrow transplantation: effects of recombinant human interleukin-6 after syngeneic and semiallogeneic bone marrow transplantation in mice

Blood, 1994

The potential of recombinant glycosylated human interleukin-6 (rhIL-6) for enhancing immunohemato... more The potential of recombinant glycosylated human interleukin-6 (rhIL-6) for enhancing immunohematopoietic reconstitution and survival after syngeneic and semiallogeneic bone marrow transplantation (BMT) in BALB/c mice subjected to total body irradiation (TBI) was investigated. rhIL-6 produced enhanced reconstitution of white blood cells as assessed on days 8 and 14 after syngeneic BMT and of platelets as assessed on day 10. Moreover, rhIL-6 treatment produced significant improvement of survival in lethally irradiated mice receiving either syngeneic or semiallogeneic BMT with limiting number of BM cells. This effect of IL-6 was not seen with large BM cell inocula producing high survival by themselves. rhIL-6 showed no toxic effects and did not affect the survival of mice that were lethally irradiated but not reconstituted by BM cells. However, the sensitivity of mice to sublethal irradiation was increased by rhIL-6 in the absence of BM cell transplantation. In experimental conditions ...

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Non myeloablative therapie für toleranzinduktion

Non-myeloablative tolerogenic treatment

Non-Myeloablative Tolerogenic Treatment

3-FMB stem-bone

Control of minimal residual cancer by low dose ipilimumab activating autologous anti-tumor immunity

Pharmacological research : the official journal of the Italian Pharmacological Society, 2014

In this perspective article, we address the controversy regarding the safety-efficacy issue in ip... more In this perspective article, we address the controversy regarding the safety-efficacy issue in ipilimumab trials. While the CTLA-4 blockade interrupted T-cell pathways responsible for immune down-regulation and mediated regression of established malignant tumors in a minority of patients, this has to be weighed against the immune related adverse events (irAEs) suffered by the majority. Based on two groundbreaking but neglected proof-of-principle papers that demonstrated augmented graft-vs.-malignancy (GVM) effect that reversed the relapse of malignancy without worsening the graft-vs.-host disease (GVHD) by a CTLA-4 blockade, here we suggest a therapeutic paradigm shift, which may help break the impasse and resolve this timely issue in oncology.

Salivary immunoglobulins in recipients of bone marrow grafts. I. A longitudinal follow-up

Bone marrow transplantation, 1994

Patients receiving bone marrow transplantation (BMT) are prone to a variety of bacterial, viral a... more Patients receiving bone marrow transplantation (BMT) are prone to a variety of bacterial, viral and fungal infections in their oral cavity. We have therefore followed alterations in salivary Ig levels associated with BMT. Most of the patients were transplanted with allogeneic, MHC-matched BM after T cells were depleted by ex vivo treatment with an anti-lymphocytic monoclonal antibody (Campath-1) and autologous complement. Parotid saliva was collected at various time intervals before and after BMT, and IgM, IgG and IgA concentrations were determined by an enzyme linked immunosorbent assay (ELISA). A gradual fall in Ig levels was detected following patient's conditioning with a combination of chemo- and radiation therapy beginning 10 days prior to BMT. A rise in the titer of salivary Ig could be detected as early as 4 days post-BMT, which increased continuously and reached plateau levels within 2-3 weeks. However, about 3 weeks later the Ig titers decreased again and persisted at ...

Heparanase Promotes Engraftment and Prevents Graft versus Host Disease in Stem Cell Transplantation

PLoS ONE, 2010

Background: Heparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfa... more Background: Heparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation. Design and Methods: Applying a mouse model of bone marrow transplantation and transgenic mice over-expressing heparanase, we evaluated the effect of heparanase on the engraftment process and the development of graft-versus-host disease. Results: Analysis of F1 mice undergoing allogeneic bone marrow transplantation from C57BL/6 mice demonstrated a better and faster engraftment in mice receiving cells from donors that were pretreated with heparanase. Moreover, heparanase treated recipient F1 mice showed only a mild appearance of graft-versus-host disease and died 27 days post transplantation while control mice rapidly developed signs of graft-versus-host disease (i.e., weight loss, hair loss, diarrhea) and died after 12 days, indicating a protective effect of heparanase against graft-versus-host disease. Similarly, we applied transgenic mice over-expressing heparanase in most tissues as the recipients of BMT from C57BL/6 mice. Monitoring clinical parameters of graft-versus-host disease, the transgenic mice showed 100% survival on day 40 post transplantation, compared to only 50% survival on day 14, in the control group. In vitro and in vivo studies revealed that heparanase inhibited T cell function and activation through modulation of their cytokine repertoire, indicated by a marked increase in the levels of Interleukin-4, Interleukin-6 and Interleukin-10, and a parallel decrease in Interleukin-12, tumor necrosis factor-alfa and interferon-gamma. Using point mutated inactive enzyme, we found that the shift in cytokine profile was independent of heparanase enzymatic activity. Conclusions: Our results indicate a significant role of heparanase in bone marrow transplantation biology, facilitating engraftment and suppressing graft-versus-host disease, apparently through an effect on T cell activation and cytokine production pattern.

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A longitudinal follow-up of salivary secretion in bone marrow transplant patients

Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 1995

Salivary gland dysfunction is a common sequela of the bone marrow transplantation procedure. We d... more Salivary gland dysfunction is a common sequela of the bone marrow transplantation procedure. We determined the effect of different bone marrow transplantation protocols on parotid salivary flow rate. Salivary secretion was substantially reduced during conditioning of all the recipients. A gradual flow rate reconstitution could be detected as soon as a few days after the bone marrow transplantation. Eight patients conditioned with total lymph node irradiation and chemotherapy or chemotherapy alone displayed earlier and complete recovery of saliva secretions 2 to 5 months after the grafting. Recovery was delayed and incomplete when total body irradiation was added to the conditioning regimen (seven patients). Six of these patients also developed graft-versus-host disease. The results suggest that total body irradiation induces irreversible damage to the parotid glands resulting in profound xerostomia followed by opportunistic infections. Chemotherapy with or without total lymph node irradiation does not induce such damage.

Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation

Experimental Hematology, 2008

Objective. The stem cell fraction of mesenchymal stromal cells (MSCs) is capable of selfrenewal a... more Objective. The stem cell fraction of mesenchymal stromal cells (MSCs) is capable of selfrenewal and under inductive conditions differentiates into bone, cartilage, hematopoietic stroma, and other mesenchymal tissues. Therefore, MSCs represent a promising source for hard tissue repair therapies. MSCs are also immunosuppressive and prevent activation of allogeneic lymphocytes in vitro. Thus it has been suggested that they might be able to engraft in allogeneic recipients and downregulate recipients' immunity. In this study we examined whether MSCs retain their immunomodulating properties in vivo after allotransplantation. Materials and Methods. MSCs were propagated from bone marrow (BM), placenta, or umbilical cord tissues. Using a murine parental-into-F 1 model of graft-vs-host disease (GVHD) we tried to control GVHD by intravenous transplanting parental or recipient MSCs together with parental lymphocytes (day 0) and on days +7 and +14. MSCs' immunosuppressive potential in vivo was also examined by comparing their ability to construct ectopic bone after local transplantation with osteogenic inductor (demineralized bone matrix) under the kidney capsule of syngeneic and allogeneic recipients. Results. Repeated IV MSC injections failed to reduce GVHD-related recipient mortality. Local implantation of MSCs propagated from BM, placenta or umbilical cord resulted in ectopic bone formation in syngeneic recipients and in transplant rejection by allogeneic mice. Conclusion. MSCs lose their immunosuppressive potential in mismatched setting. Ó 2008 ISEH-Society for Hematology and Stem Cells. Published by Elsevier Inc. Early mesenchymal stromal progenitors (MSPs) are constantly present in adult bone marrow (BM), and can be found in the skin, brain, muscle, embryonic placenta, umbilical cord (UC), and other tissues. These cells, described by Friedenstein et al. [1], have the capacity of prolonged self-renewal and, in an inductive microenvironment, differentiate into specialized mesenchymal tissues, such as hematopoietic stroma, bone, cartilage, adipose tissue, and others [2-6]. These features explain the growing interest in exploring MSP potential for hard tissue repair and treatment of myelodysplastic syndromes. Primary cultures of mesenchymal stromal cells (MSCs), isolated by their characteristic adherence to plastic, preserve MSPs capable of multipotential differentiation. However, no surface markers are currently available that distinguish early MSPs from more mature cultured fibroblasts [7]. Recently, fibroblasts in MSC cultures were shown to function as powerful suppressors of immune responses in vitro. They inhibit proliferation of T lymphocytes stimulated by alloantigens or mitogens [8-13], proliferation and maturation of dendritic cells [14], and proliferation of antigen-activated B cells [15]. The suppression is genetically unrestricted [10,11] and may be triggered by direct cell-to-cell contact [9] or by soluble factors that cause cell-division arrest [9,12,13]. Although mesenchymal fibroblasts express major histocompatibility complex (MHC) class I in culture, they lack MHC class II and several costimulatory molecules [10,11,16]. It was therefore suggested that MSCs expanded in vitro might be able to engraft in allogeneic recipients and downregulate immunity after implantation [10,11,17]. Several experimental and clinical results support this hypothesis: infusion of third-party MSCs has been shown to

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Non-myeloablative stem cell transplantation (Nst) For the treatment of malignant and non-malignant diseases

Experimental Hematology, 2000

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Low-dose gamma-irradiation promotes survival of injured neurons in the central nervous system via homeostasis-driven proliferation of T cells

European Journal of Neuroscience, 2004

Protective autoimmunity was only recently recognized as a mechanism for attenuating the progressi... more Protective autoimmunity was only recently recognized as a mechanism for attenuating the progression of neurodegeneration. Using a rat model of optic nerve crush or contusive spinal cord injury, and a mouse model of neurodegenerative conditions caused by injection of a toxic dose of intraocular glutamate, we show that a single low dose of whole-body or lymphoid-organ gamma-irradiation significantly improved the spontaneous recovery. Animals with severe immune deficiency or deprived of mature T cells were unable to benefit from this treatment, suggesting that the irradiation-induced neuroprotection is immune mediated. This suggestion received further support from the findings that irradiation was accompanied by an increased incidence of activated T cells in the lymphoid organs and peripheral blood and an increase in mRNA encoding for the pro-inflammatory cytokines interleukin-12 and interferon-gamma, and that after irradiation, passive transfer of a subpopulation of suppressive T cells (naturally occurring regulatory CD4(+)CD25(+) T cells) wiped out the irradiation-induced protection. These results suggest that homeostasis-driven proliferation of T cells, induced by a single low-dose irradiation, leads to boosting of T cell-mediated neuroprotection and can be utilized clinically to fight off neurodegeneration and the threat of other diseases in which defense against toxic self-compounds is needed.

Induction of Early Post-Transplant Graft-versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Elimination of Alloantigen-Primed Donor Lymphocytes for Prevention of Graft-versus-Host Disease

Cancer Research, 2005

Graft-versus-leukemia (GVL) effects can be induced in tolerant mixed chimeras prepared with nonmy... more Graft-versus-leukemia (GVL) effects can be induced in tolerant mixed chimeras prepared with nonmyeloablative conditioning. GVL effects can be amplified by post-grafting donor lymphocyte infusion (DLI). Unfortunately, DLI is frequently associated with graft-versus-host disease (GVHD). We investigated the feasibility of induction of potent GVL effects by DLI using intentionally mismatched lymphocytes followed by elimination of alloreactive donor T cells by cyclophosphamide for prevention of lethal GVHD following induction of very short yet most potent GVL effects. Mice inoculated with B-cell leukemia (BCL1) and mismatched donor lymphocytes were treated 2 weeks later with low-dose or high-dose cyclophosphamide. All mice receiving cyclophosphamide 2 weeks after DLI survived GVHD, and no residual disease was detected by PCR; all control mice receiving DLI alone died of GVHD. Analysis of host (female) and donor (male) DNA showed that cyclophosphamide treatment eradicated most alloreactive...

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Murine B-cell leukemia lymphoma (BCL1) cells as a target for NK cell-mediated immunotherapy

Bone Marrow Transplantation, 2004

Natural killer (NK) cells are important for their ability to recognize and lyse tumor cells and v... more Natural killer (NK) cells are important for their ability to recognize and lyse tumor cells and virus infected cells. NK cells express triggering receptors that are specific for non-MHC ligands. This article describes the 35 S release cytotoxic assay, which measures the ability of NK cells derived from spleen cells taken from polyIC-treated mice to lyse B-cell leukemia (BCL1) cells. BCL1 cells express ligands for NKp46 on the cell surface membrane and they are sensitive to allogeneic but not syngeneic IL-2 activated natural killer cells.

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Immunotherapy of hematologic malignancies and metastatic solid tumors in experimental animals and man

Bone Marrow Transplantation, 2000

Following engraftment of donor hematopoietic cells and induction of host-versus-graft tolerance, ... more Following engraftment of donor hematopoietic cells and induction of host-versus-graft tolerance, immunocompetent lymphocytes of donor origin can induce graftversus-leukemia (GVL) and graft-versus-tumor (GVT) effects. Engraftment of allogeneic bone marrow cells can be accomplished following non-myeloablative conditioning while possibly controlling graft-versus-host disease (GVHD). GVL and GVT effects may thus be successfully accomplished following non-myeloablative stem cell transplantation (NST) as shown by data derived from experimental animals and man.

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Post transplant persistence of host cells augments the intensity of acute graft-versus-host disease and level of donor chimerism, an explanation for graft-versus-host disease and rapid displacement of host cells seen following non-myeloablative stem cell transplantation?

Bone Marrow Transplantation, 2006

Although the use of non-myeloablative stem cell transplantation (NST) reduces the severity of gra... more Although the use of non-myeloablative stem cell transplantation (NST) reduces the severity of graft-versus-host disease (GVHD), GVHD remains a major complication following allogeneic transplantation. Since following NST in comparison with myeloablative conditioning, higher proportions of host immunohematopoietic cells may persist while donor-derived alloreactive lymphocytes are being infused, thus possibly serving as host antigen presentation for continuous stimulation of donor T cells, we speculated that GVHD may be similarly amplified by conditioning followed by intentional administration of host cells. This hypothesis was tested in a preclinical animal model. Increased incidence of GVHD, higher mortality and increased levels of chimerism were observed in recipients reconstituted with host cells, particularly with non-irradiated spleen cells. Graft-versus-leukemia effect was not impaired by post transplant cell administration. These results suggest that GVHD may be amplified by recipient cell infusion using either irradiated or viable stimulatory host cells, thus possibly explaining in part higher than anticipated incidence of GVHD and rapid displacement of host cells and conversion to 100% donor type cells following NST. Administration of irradiated host antigen-presenting cells post transplantation may thus represent a potential approach for amplification of the alloreactive capacity of donor lymphocytes following stem cell transplantation.

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Mini-allografts: ongoing trials in humans

Bone Marrow Transplantation, 2000

Conventional allogeneic stem cell transplantation is a valuable approach to therapy for many hema... more Conventional allogeneic stem cell transplantation is a valuable approach to therapy for many hematologic malignancies. However, high-dose conditioning regimens designed both to control the malignancy and to prevent graft rejection are associated with a high incidence of acute and long-term side-effects. This has largely precluded the use of allografting for patients older than 55 years or for younger patients with certain preexisting organ damage. In order to manage the sideeffects, transplants have traditionally been delivered in highly specialized hospital wards or intensive care settings. Thus, an important goal is to develop safer allografting procedures that can be extended to older patients or patients with pre-existing organ dysfunction who are currently excluded from consideration for transplant. Recent observations have shown that donor lymphocyte infusions (DLI) can eradicate some malignancies that relapse after conventional allografting. These observations confirmed earlier evidence in favor of a graft-versus-leukemia effect based on the association of graft-versus-host disease (GVHD) with a lower likelihood of relapse of malignancy after allografting. Given the potential efficacy of DLI as the sole modality for eradication of malignancy, new strategies for allografting can incorporate the concept of less intensive conditioning therapy which is given with the sole aim of facilitating allogeneic engraftment. Recent pre-clinical studies in a canine model have shown that conditioning regimens for allografting can be markedly reduced in intensity yet still achieve the goal of engraftment. This review briefly summarizes the initial translational clinical studies, using a minimally myelosuppressive-conditioning regimen based on low dose total body irradiation (TBI) or fludarabine alone or in combination with other drugs followed by a short course of immunosuppression with post-grafting cyclosporine and methotrexate or mycophenolate mofetil. Bone Marrow Transplantation (2000) 25, 345-350.

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Shimon Slavin

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