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Shimon Slavin

Publications and source records attributed to Shimon Slavin.

70 records · Page 4Linked to original sources
PubMed2002

Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?

Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.

Animals↗
PubMed2002

Maternal-fetal relationship, natural chimerism and bilateral transplantation tolerance as the basis for non-myeloablative stem cell transplantation.

Bone marrow transplantation (BMT) which represents an important clinical tool for treatment of patients with a wide variety of malignant and non-malignant diseases, however, the procedure is associated with procedure-related toxicity and mortality as well as unavoidable late complications. Many of the undesirable consequences of BMT are caused directly or indirectly by the intensive conditioning administered during the pre-transplant period. However, if the main goal of the BMT procedure is to enable immunotherapy by alloreactive donor lymphocytes, the conditioning prior to BMT needs to be reconsidered, because transplantation tolerance across major histocompatibility complex (MHC) occurs spontaneously in nature, as evidenced by the fact that pregnant females do not reject their conceptus. In fact, as shown by Owens in the 1940s, placental parabiosis in utero leads to permanent mixed chimerism and bilateral transplantation tolerance. These observations followed by experiments carried out in the 1950s by Billingham et al. suggested that infusion of parental stem cells into neonates with no exogenous immunosuppressive treatment resulted in mixed chimerism and permanent transplantation tolerance to donor alloantigens. Thus, a window of opportunity provided shortly after delivery, was sufficient for induction of tolerance without the need for heavy conditioning. Tolerant recipients were shown to be chimeras with only a small proportion of donor cells. However, without corroborating evidence that transplantation tolerance could be intentionally induced, the approach could not be applied in clinical practice for immunocompetent recipients. Starting in 70s, we documented the feasibility of establishing bilateral transplantation tolerance by mixed chimerism following non-myeloablative conditioning in immu. nologically mature recipients across MHC in mice, rats and dogs. Several studies have shown that reduced intensity conditioning can be very useful for immunoregulation whereas more intensive the pre-grafting immunosuppression resulted in more aggressive the GVHD. These and other findings suggested that lower intensity conditioning may be sufficient for engraftment of donor stem cells, thus suggesting that immunosuppression without myeloablation may be sufficient for prevention of allograft rejection. Following engraftment of donor stem cells, donor lymphocytes infused with bone marrow or mobilized blood stem cells can eradicate residual hematopoietic cells of host origin, occasionally non-hematopoietic tumor cells of host origin as well. Whenever indicated, donor lymphocytes infusion (DLI) can be used at a later stage post BMT to eradicate residual malignant cells of host origin or for the treatment of residual or recurrent disease. Taken together, ongoing clinical studies suggest that high-dose, myeloablative chemoradiotherapy, could be safely replaced with non-myeloablative conditioning (NST).

Animals↗
PubMed2002

Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?

Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.

Animals↗
PubMed2002

Nonmyeloablative allogeneic bone marrow transplantation as immunotherapy for hematologic malignancies and metastatic solid tumors in preclinical models.

OBJECTIVE: We previously demonstrated that a combination of mild total lymphoid irradiation (TLI) with selective depletion of the host's donor-reactive cells allows for stable and graft-vs-host disease (GVHD)-free engraftment of allogeneic bone marrow (BM). In this study, we investigated the efficacy of this nonmyeloablative strategy for BM transplantation (BMT) as immunotherapy for minimal residual disease. MATERIALS AND METHODS: BALB/c mice inoculated with leukemia (BCL1) or breast carcinoma (4T1) cells were conditioned for BMT with TLI (200 cGy) followed by priming with donor (C57BL/6) BM cells on day 1, and by injection with 200 mg/kg cyclophosphamide on day 2. After conditioning (day 3), recipients were transplanted with BM cells from the same donor. Treated animals were monitored for 230 days for survival, development of leukemia/solid tumor, and GVHD. RESULTS: BMT converted the mice to complete chimeras and prevented development of leukemia in 90% of recipients and locally growing breast carcinoma in 40% of the mice. Immunization of donors of the second BM with 4T1 cells prevented development of breast carcinoma in 80% of 4T1 inoculated mice. Fewer animals treated for malignancy by nonmyeloablative BMT died of GVHD than those treated by myeloablative BMT. However, late GVHD-related mortality in mice treated for leukemia was higher than after nonmyeloablative BMT to naive recipients (p < 0.00001). Infusion of host-type anti-donor immune lymphocytes 8 days after BMT improved the survival of recipients treated for leukemia without affecting engraftment and the graft-vs-leukemia potential of donor BM. CONCLUSIONS: Effective eradication of malignant cells can be achieved following allogeneic BMT after nonmyeloablative conditioning.

Animals↗
PubMed2002

Non-myeloablative stem cell transplantation for the treatment of cancer and life-threatening non-malignant disorders; past accomplishments and future goals.

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, autologous and allogeneic bone marrow or mobilized blood stem cells transplantation were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartment and therefore, highly toxic myeloablative regimen were considered mandatory for more effective eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT. Thus, eradication of blood cancer cells, especially in patients with CML and less frequently in patients with other hematologic malignancies, could be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft versus leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. Based on the cumulative clinical experience and experimental data in animal models of human diseases it appears that induction of host versus graft tolerance as step one, may allow durable engraftment of donor immunocompetent lymphocytes, which may be used for induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, malignant, genetically abnormal or self-reactive alike. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using a safer conditioning as part of the transplant procedure, with the goal in mind to induce host versus graft tolerance to enable subsequent induction of GVL, possibly graft versus tumor or even graft versus autoimmunity effects, rather than attempt to eliminate host cells with hazardous myeloablative chemoradiotherapy. The latter hypothesis suggested that effective BMT procedure may be accomplished without lethal conditioning of the host, using new well tolerated non-myeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical data that will be presented suggests that effective BMT procedures may be accomplished with well-tolerated non-myeloablative stem cell transplantation (NST) regimen, with no major toxicity. Thus, new NST approaches may offer the feasibility of safer BMT procedure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality. Taken together, our cumulative data suggest that high dose chemotherapy and radiation therapy may be successively replaced by a more effective biologic tool, alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures for safer and more effective treatment of patients in need of BMT.

Autoimmune Diseases↗
PubMed2002

Treatment of leukemia by alloreactive lymphocytes and nonmyeloablative stem cell transplantation.

Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and nonmalignant diseases, especially acute and chronic leukemias. Until recently, myeloablative regimens were considered mandatory for effective eradication of all malignant cells of host origin. Our preclinical and ongoing clinical studies indicated that eradication of host immunohematopoietic cells, including chemoradiotherapy-resistant leukemia, could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following induction of host-versus-graft transplantation tolerance mediated by engraftment of donor stem cells in the course of BMT. Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and less frequently in patients with other hematologic malignancies, could be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-leukemia (GVL) effects might be a useful tool for both treatment and prevention of relapse. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using a safer conditioning as part of the transplant procedure, with the goal in mind to induce host-versus-graft tolerance to enable subsequent induction of GVL effects rather than attempt to eliminate host cells with hazardous myeloablative chemoradiotherapy. The latter hypothesis suggested that effective BMT procedure may be accomplished without lethal conditioning of the host, using a new well-tolerated nonmyeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical observations suggest that effective treatment of leukemia may be accomplished with a well-tolerated nonmyeloablative stem cell transplantation (NST) regimen, while avoiding immediate and late toxicity and minimizing procedure-related mortality. Taken together, our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by a more effective biological tool-alloreactive donor lymphocytes-thus setting the stage for innovative immunotherapeutic procedures for more selective and effective treatment of patients in need of BMT, including those resistant to conventional chemoradiotherapy.

Hematopoietic Stem Cell Transplantation↗
PubMed2002

Intra-arterial catheter directed therapy for severe graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), resulting in death in the majority of steroid-resistant patients. We assessed the efficacy of regional intra-arterial treatment in patients with resistant hepatic and/or gastrointestinal (GI) GVHD. In total, 15 patients with steroid resistant grade 3-4 hepatic (n = 4), gastrointestinal (GI) (n = 8) GVHD or both (n = 3) were given intra-arterial treatment. Patients with hepatic GVHD received methotrexate and methylprednisolone into the hepatic artery. Patients with GI GVHD were treated with infusions of methylprednisolone into the superior and inferior mesenteric arteries. Two patients with pronounced upper GI symptoms also received upper GI treatment. In total, 25 procedures were carried out (range 1-3 per patient). Hepatic response was observed in four out of seven (57%) patients with hepatic GVHD, three (43%) featuring good response. Complete responses were observed in nine (82%) GI GVHD patients, with median time to initial and complete response of 3 d (range 1-7) and 15.8 d (range 4-33) respectively. Regional treatment of severe GVHD with intra-arterial treatment appears to be effective and safe. GI treatment maybe more effective than intrahepatic treatment. Early administration of isolated intra-arterial therapy in high-risk patients may further improve the outcome and reduce untoward effects of systemic immunosuppressive treatment.

Adolescent↗
PubMed2002

Intraportal and systemic allogeneic cell therapy in a murine model of hepatic metastatic breast cancer.

Allogeneic immunocompetent splenocytes were tested for their ability to exert a GVT effect in a murine model of liver metastasis. Mammary carcinoma cells originating from an H-2(d) mouse were inoculated through the PV of F(1) (H-2(d/b)) mice, to mimic clinical hepatic involvement in malignant disease. Cell therapy was given either locally (PV) or systemically by IV inoculation to test differential efficacy of the GVT effect, and the differential expression of GVHD symptoms induced by diverse routes of administration. Livers of mice treated with H-2(b) derived splenocytes given PV or IV remained tumor-free for at least 4 weeks following tumor inoculation. Furthermore, all secondary recipients of adoptively transferred (AT) liver cells were tumor-free for >300 days. In contrast, all livers of untreated control mice or mice treated with syngeneic splenocytes displayed tumor metastases as early as 2 weeks following tumor inoculation, and large local tumors developed in AT secondary recipients. Our data demonstrate the efficacy of allogeneic cell therapy, given either locally or systemically, in the eradication of liver metastases. However, diverse routes of cell therapy administration did not show any difference in the expression and outcome of GVHD.

Animals↗
PubMed2002

Fibrin microbeads for isolating and growing bone marrow-derived progenitor cells capable of forming bone tissue.

It has been demonstrated that bone marrow (BM)-derived pluripotent stem cells can be incorporated into muscle, bone, nerve, lung, stomach, intestine, and skin. Fibrin-based biodegradable microbeads (FMB) were developed for culturing, in suspension, a high density of cells, mostly of mesenchymal origin. In the current study, FMB were used to isolate and expand mesenchymal progenitor cells from BM of mice and rats. Cells from BM isolated on FMB (FMB-BM cells) were visualized by fluorescent confocal microscopy and quantified by a modified MTS colorimetric assay. Downloading the BM cells from FMB onto plastic induced their differentiation into islets of cells with osteogenic phenotype that secreted mineralized extracellular matrix. This was augmented by inducers of osteogenesis, such as ascorbic acid, beta-glycerophosphate, and dexamethasone, or osteoblast-growth peptides (OGP). Implanting FMB-BM cells under the kidney capsule in mouse tested the osteogenic potential of these cells in vivo. Thirty days after implantation, bone structures with typical BM elements were seen in 8/53 kidneys in 6-Gy-irradiated mice and in 1/10 kidneys in nonirradiated recipients; bone formation was verified by soft x-ray imaging and elemental analysis that showed elevated Ca and Fe in the implant region. FMB-BM cells - downloaded onto plastic flasks, cultured for 2 weeks, mechanically harvested and then implanted - induced 100% bone formation in both irradiated (6/6) and nonirradiated (3/3) mice. Histology revealed well-organized bone structures under the kidney capsule, including osteoblasts and typical elements of BM. Our findings demonstrate that FMB are capable of isolating and expanding progenitor cells from BM for osteogenesis and possibly for regenerating other mesenchymal tissues.

Animals↗
PubMed2002

Donor lymphocyte infusion: the use of alloreactive and tumor-reactive lymphocytes for immunotherapy of malignant and nonmalignant diseases in conjunction with allogeneic stem cell transplantation.

Donor lymphocyte infusion (DLI), pioneered in Jerusalem in January 1987, represents the first proof of principle of the absolute efficacy of immunotherapy as a means of curing cancer. Immunotherapy with alloreactive donor lymphocytes can eliminate "the last tumor cell" even in patients with hematological malignancies resistant to maximally tolerated doses of chemoradiotherapy. Alloreactive lymphocytes that can mediate anti-tumor effects following induction of host-versus-graft tolerance induced by transplantation of donor stem cells, can induce graft-versus-malignancy (GVM) effects which are usually accompanied by graft-versus-host disease (GVHD). However, occasionally GVM effects may also be accomplished independently of clinically overt GVHD. Interestingly, allogeneic donor lymphocytes may also eliminate undesirable host-derived hematopoietic cells in a large number of nonmalignant indications including genetic diseases, diseases caused by deficiency of stem cell products, and autoimmune disorders mediated by self-reactive lymphocytes. The cumulative clinical experience suggests feasibility of effective induction of graft-versus-leukemia (GVL); graft-versus-lymphoma (GVLy); graft-versus-multiple myeloma, as well as graft-versus-solid tumors (GVT), well-documented in patients with renal and breast cancer, even in patients with resistant disease that have failed myeloablative chemoradiotherapy. These observations that suggested that cell therapy by donor lymphocytes is the main therapeutic benefit of bone marrow transplantation (BMT) led to development of the nonmyeloablative approach for safer allogeneic stem cell transplantation. Nonmyeloablative stem cell transplantation (NST) makes it possible to offer an option for cure to elderly patients with no upper age limit, as well as to patients with poor performance status not considered eligible for conventional BMT. Using well-tolerated NST regimen, allogeneic stem cell transplantation can be accomplished with minimal procedure-related toxicity and mortality, possibly even on an outpatient basis. Immunotherapy mediated by adoptive allogeneic cell-mediated immunotherapy can be further improved by utilizing specifically immune donor lymphocytes, thus maximizing their efficacy against undesirable target cells of host origin on the one hand, while minimizing their ontoward efficacy against normal cells of host origin that could result in GVHD on the other. Taken together, DLI and subsequently NST, may have opened new horizons for treatment of life-threatening malignant and nonmalignant disorders correctable by allogeneic stem cell transplantation. It is anticipated that further improvement of reactivity and specificity of donor lymphocytes will lead to safer clinical application of cell therapy for a larger number of indications toward improving disease-free survival in a large number of indications while minimizing immediate and late procedure-related complications.

Animals↗
PubMed2001

Cell Therapy With Preimmunized Effector Cells Mismatched for Minor Histocompatible Antigens in the Treatment of a Murine Mammary Carcinoma.

SUMMARY: Cell therapy with allogeneic donor cells mismatched for minor histocompatible (MiHC) antigens was applied to a murine mammary carcinoma (4T1) model to test the feasibility of graft versus tumor (GVT) effect against metastatic epithelial tumor cells. BALB/c mice bearing a 4T1 tumor of BALB/c origin were given syngeneic or MiHC-mismatched splenocytes. GVT effects were determined in secondary recipients of adoptively transferred lung cells derived from primary hosts who had previously been inoculated intravenously with 4T1 cells, and injected with one of the following: 1) naive BALB/c splenocytes, 2) naive DBA/2 splenocytes, 3) 4T1-immune DBA/2 splenocytes, or 4) DBA/2 splenocytes immunized with host-derived BABL/c spleen cells. Naive DBA/2 splenocytes inhibited tumor growth only slightly and only slightly prolonged the survival of secondary recipients, in comparison with fully matched tumor/host BALB/c spleen cells. An efficient GVT reaction was demonstrated in vitro and in vivo with MiHC-mismatched DBA/2 splenocytes from mice presensitized by multiple injections of irradiated tumor or BALB/c-derived spleen cells. All 30 mice adoptively inoculated with lung cells from primary hosts that had previously been treated with these presensitized effector cells were tumor free for >250 days. Secondary recipients inoculated with lung cells from mice given naive BALB/c or DBA/2 spleen cells died of metastatic tumors within 33 to 46 days. These results suggest that preimmunized donor cells represent an effective tool against metastatic disease; hence, the next goal should be to control graft-versus-host disease while exploiting the GVT potential.

Journal Article↗
PubMed2000

New Developments in the Therapy of Acute Myelocytic Leukemia.

Current conventional treatment for patients with acute myelogenous leukemia results in a high percentage of clinical responses in most patients. However, a high percentage of patients still remain refractory to primary therapy or relapse later. This review examines the search for new agents and new modes of therapy. In Section I, Dr. Estey discusses new agents directed at various targets, such as CD33, angiogenesis, inappropriately methylated (suppressor) genes, cell cycle checkpoints, proteosomes, multidrug resistance (MDR) gene, mitochondrial apoptotic pathway. He also reviews preliminary results of phase I trials with the nucleoside analog troxacitabine and liposomal anthracyclin and suggests new strategies for trials of new agents. In Section II, Dr. Jones revisits differentiation therapy and presents results of preclinical and clinical studies that demonstrate that a variety of clinically applicable cell cycle inhibitors (interferon, phenylbutyrate, vitamin D, retinoids, bryostatin-1) preferentially augments growth factor-mediated induction of myeloid leukemia terminal differentiation, as well as blocks growth factors' effects on leukemia proliferation. The combination of cell cycle inhibition plus myeloid growth factors may offer a potential treatment for resistant myeloid leukemias. In Section III, Drs. Levitsky and Borrello address the question of tumor vaccination in AML and shows that, although tumor rejection antigens in AML have not been formally identified to date, a growing number of attractive candidates are ripe for testing with defined antigen-specific vaccine strategies. Interestingly, the ability to drive leukemic blasts to differentiate into competent antigen presenting cells such as dendritic cells may be exploited in the creation of cellular vaccines. Ultimately, the successful development of active immunotherapy for AML will require integration with dose-intensive chemotherapy, necessitating a more complete understanding of host immune reconstitution. In Section IV, Dr. Slavin reviews the concept of delivering non-myeloablative stem cell transplantation (NST) and delayed lymphocyte infusion (DLI) to increase tolerance in particular in high risk and older patients, and take advantage of the graft-versus-leukemia (GVL) effect. All these approaches hold promise in reducing morbidity and mortality and differ from the older concepts aiming at delivering the highest possible doses of chemotherapy and/or total body irradiation to reach maximum leukemia cell kill, whatever the toxicity to the patient.

Journal Article↗
PubMedDate not supplied

Depletion of alloantigen-primed lymphocytes overcomes resistance to allogeneic bone marrow in mildly conditioned recipients.

OBJECTIVE: Successful implantation of allogeneic bone marrow (BM) cells after nonmyeloablative conditioning would allow to compensate for the inadequate supply of compatible grafts and to reduce mortality of graft-vs.-host disease (GVHD). Recently, we proposed to facilitate engraftment of mismatched BM by conditioning for alloantigen-primed lymphocyte depletion (APLD) with cyclophosphamide (CY). Here we summarize the experimental results obtained by this approach. MATERIALS AND METHODS: Naive or mildly irradiated BALB/c mice were primed with C57BL/6 BM cells (day 0), treated with CY (day 1) to deplete alloantigen-primed lymphocytes, and given a second C57BL/6 BM transplant (day 2) for engraftment. Recipients were repeatedly tested for chimerism in the blood and followed for GVHD and survival. The protocol was also tested for inducing tolerance to donor tissue and organ allografts, and for treatment of leukemia, breast cancer, and autoimmune diabetes in NOD mice. RESULTS: APLD by 200 mg/kg CY provided engraftment of allogeneic BM from the same donor in 100% mildly irradiated recipients. Eighty percent chimeras remained GVHD-free more 200 days. All chimeras accepted permanently donor skin grafts and donor hematopoietic stromal progenitors. Allogeneic BM transplantation (BMT) after APLD had a strong therapeutic potential in BALB/c mice harboring malignant cells and in autoimmune NOD recipients. Tolerance-inducing CY dose could be reduced to 100 mg/kg. Conditioning for APLD resulted in engraftment of allogeneic BM after a significantly lower radiation dose than treatment with radiation and CY alone. CONCLUSION: Our results demonstrate that conditioning for APLD has a definite advantage over general immunosuppression with CY and radiation therapy.

Animals↗