DOCSLIB.ORG

Special Report Second EBMT Workshop on Reduced Intensity Allogeneic Hemopoietic Stem Cell Transplants (RI-HSCT)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Bone Marrow Transplantation (2002) 29, 191–195

 2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00

www.nature.com/bmt

Special report Second EBMT Workshop on reduced intensity allogeneic hemopoietic stem cell transplants (RI-HSCT)

A Bacigalupo

Divisione Ematologia II Ospedale San Martino, Genova, Italy

Summary:

from AMGEN Europe, held a Workshop in Zurich on allogeneic transplantation following non-myeloablative conditioning. Tentative conclusions drawn from the 1999 EBMT/AMGEN Workshop were published (1) and were as follows:

A second meeting on reduced intensity allogeneic stem cell transplants (RI-HSCT) was convened in Zurich in February 2001 and focused on transplant-related mor- tality (TRM) and graft-versus-host disease (GVHD). Retrospective and prospective studies from the EBMT, national groups and single institutions included over 900 patients: the incidence of acute GVHD grade III– IV was 12% (1–17%), extensive chronic GVHD 42% (25–51%) and TRM 20% (14–38%). Conditioning regi- mens could be classified into four major groups based on (1) total body irradiation (TBI) 200 cGy, (2) busulfan 8 mg/kg, (3) thiotepa 10 mg/kg, and (4) melphalan 140 mg/m2: most of these regimens are given in association with fludarabine in different doses and use mobilized peripheral blood as a source of stem cells. The incidence of TRM is similar if not identical for all four regimens, whereas the risk of acute GVHD and chronic GVHD may vary with different protocols. Reduced intensity transplant programs are being explored in patients above the age of 60 and in patients with solid tumors: encouraging results are being recorded in individual patients. Overall these data confirm that allogeneic HSCT can be performed in elderly patients, although a TRM of approximately 15% must be expected and is age dependent. A high rate of extensive chronic GVHD is seen and should be followed carefully. The term mini- or micro-transplant is probably misleading and one should refer to this procedure as an allogeneic HSCT and further classify the intensity of the conditioning regimen.

• The term ‘minitransplant’ is probably misleading and reduced intensity allogeneic hematopoietic stem cell transplantation (RI-HSCT) is preferred.
• RI-HSCT is an experimental procedure. • RI-HSCT involves the use of normal donors and ethical issues apply as with any allogeneic transplant.
• Donors should be carefully evaluated because their
(probable) older age exposes them to an increased risk of complications.
• At present, RI-HSCT should be offered to patients who are otherwise not eligible for conventional allogeneic HSCT.
• Acute leukemia and myelodysplastic patients are probably not good candidates for RI-HSCT.
• RI-HSCT may be appropriate in chronic disorders such as chronic lymphoproliferative diseases. Chronic myeloid leukemia (CML) should be studied.
• Multiple myeloma (MM) patients may pose particular problems.
• It remains to be determined whether RI-HSCT is beneficial in patients with solid tumors.
• Immune reconstitution should be investigated further.

With these conclusions in mind a second Workshop was organized 2 years later by EBMT together with AMGEN. We now report the outcome of the second Workshop.

Bone Marrow Transplantation (2002) 29, 191–195 DOI:

10.1038/sj/bmt/1703355 Keywords: reduced intensity conditioning regimen; hemopoietic stem cell transplants; graft-versus-host disease

Retrospective studies

The Acute and Chronic Leukemia Working Party of the EBMT analyzed 154 acute leukemia and 270 chronic leukemia patients receiving reduced intensity transplants. Francesco Frassoni and Jane Apperley presented the data. Median age was 50 years: TRM was 20% for the acute leukemias and 22% for the chronic leukemias, the incidence of severe grade III–IV acute GVHD was 10% and 14%, respectively, and extensive chronic GVHD was 40% in both groups. The outcome of 58 chronic myeloid leukemia (CML) patients
In February 1999, the European Group for Blood and Marrow Transplantation (EBMT), with an educational grant

Correspondence: Dr A Bacigalupo, Divisione Ematologia 2 (PAD 5/II), Ospedale San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy Received 18 June 2001; accepted 23 August 2001

Second EBMT Workshop on RI-HSCT

A Bacigalupo

192

was comparable. The French and Italian Groups for Marrow Transplantation (SFGM and GITMO) presented 92 and 44 patients, respectively, with a median age of 50 and 52 years, and a TRM of 38% and 14%. Overall, these presentations comprised 969 patients with an average age of 47.7, an average follow-up of 300 days, with medians ranging from 244 to 814 days: the majority of them achieved full donor chimerism (79%). Severe acute GVHD developed in 12% and extensive chronic GVHD in 42% of patients. The average transplant-related mortality was 20%, which may be considered low for a cohort of patients with advanced age and advanced disease. cyclophosphamide (CY) 60 mg/kg as proposed by the French SFGM group, TBI 400 cGy + FLU 90 mg/m2 + CY 60 mg as proposed by the Munchen group, TBI 100 cGy + thiotepa (THIO) 10 mg/kg + CY 100 mg/kg as proposed by the Genoa group, and finally melphalan (MEL) 200 mg/m2 for a first autograft followed by TBI 200 cGy + FLU 90 mg/m2 proposed for myeloma patients as will be discussed later.

Busulfan 8 mg/kg + FLU 125 mg/m2 + antithymocyte globulin (ATG)

This was first described by Slavin and coworkers in 1998.4 The original publication included 26 patients receiving HLA-identical sibling peripheral blood cells following the BU + FLU + ATG regimen. With a median follow-up of 240 days and a median age of 33 the TRM was 15%, and severe acute and chronic GVHD was 15% and 34%. Variations on this protocol presented in Zurich included BU 4 mg/kg + FLU 150 mg/m2 + ATG proposed by the French SFGM and BU 8 mg/kg + FLU 150 mg/m2 + CY 120 mg/kg. Shimon Slavin reported on the Workshop held earlier this year and suggested that the original BU 8 + FLU 125 + ATG protocol will be compared with BU 8 + FLU 125 + CAMPATH 1H, to test whether a reduction in acute and chronic GVHD could be obtained.

Immunosuppressive conditioning regimens

Immunosuppressive regimens involve the use of agents with no significant long-term toxic effect on stem cells, such as cyclophosphamide, fludarabine and antibodies against T cells. CY alone has been used in over 5000 patients with non-malignant disorders, who were not discussed at the Workshop. The combination FLU-CY first described by Khouri and coworkers,2 was discussed for Hodgkin’s disease and for solid tumors, without specific update. Because this regimen relies entirely on the immunologic effect of the graft, most programs in Europe at present include one or more agents with some depleting effect on stem cells and therefore also on the tumor.

Thiotepa 10 mg/kg + cyclophosphamide 100 mg/kg

Thiotepa has been extensively used by M Martelli and coworkers in Perugia for mismatched grafts in conjunction with TBI and cyclophosphamide.5 More recently this group was the first to introduce fludarabine in the conditioning regimen.6 The program without TBI (THIO-CY) was described in 1996 with THIO 15 mg/kg + CY 150 mg/kg7 followed by HLA-identical PB grafts. The reduced intensity version THIO10 + CY100 was recently published in extenso.8 Forty-four patients were grafted in Genova, Firenze, Torino, Milano and presented at EBMT 2001.9 The median age was 52 years and median follow-up 814 days. Acute GVHD was low (2%), possibly because post-graft CsA + methotrexate (MTX) was not discontinued early, as reported in other studies. The rate of extensive chronic GVHD was also low (25%) possibly for the same reason. The overall TRM was 14%: it was 9% in patients receiving bone marrow grafts (BM) and 18% in patients receiving PB grafts. A variation of this regimen included THIO 10 mg/kg + CY 60 mg/kg + FLU 60 mg/m2 developed by Paolo Corradini in Milano10 and used for lymphoma patients, with very low TRM (6%). The latter protocol is now being used in Italy (GITMO) for low-grade lymphomas. Another variation is THIO 10 mg/kg + FLU 120 mg/m2 used in patients with myelodysplasia.

Reduced intensity conditioning regimens

Reduced intensity regimens involve the use of agents toxic for stem cells and tumor cells, such as busulfan or total body radiation, but in reduced doses as compared to a conventional transplant. The regimens presented at the Workshop could be divided into four major groups, most of them combined with fludarabine.

Total body irradiation (TBI) 200 cGy

This program was originally described by Storb and coworkers,3 and is also being explored in Leipzig, Germany as well as other transplant centers in the USA and in Europe. A summary was given by Dietger Niederwieser on 109 patients receiving TBI 200 cGy and fludarabine followed by unmanipulated peripheral blood (PB) cell transplants from HLA-identical siblings, and GVHD prophylaxis with cyclosporin (CsA) and mycofenolate mofetyl (MMF). The median age was 50 (18–71), the median follow-up 241 (100–934) days. There was no need for hospitalization in many patients, although some patients required admission to hospital for prolonged periods of time. Consistent with this is the fact that cGVHD developed in the extensive form in 50% of the patients. This may be due to several causes, among which are the use of unmanipulated PB transplants in all patients, old age, and early reduction or discontinuation of CsA. Overall TRM was low (15%) and progression-free survival at 2 years 43%. Variations of the original TBI 200 cGy regimen include the addition of fludarabine (FLU) 90 mg/m2 as described, TBI 500 cGy +

Melphalan (MEL) 140 mg/m2, fludarabine 150 mg/m2 and CAMPATH 1H

This was originally described11 by S McKinnon: 44 patients with lymphoma were grafted with this regimen in the UK, their median age was 41 (18–56) and median follow-up 365 days (60–870). In this regimen grade III–IV acute GVHD

Bone Marrow Transplantation

Second EBMT Workshop on RI-HSCT

A Bacigalupo

193

and extensive chronic GVHD were virtually absent, possibly as a consequence of using CAMPATH 1H in the conditioning regimen. TRM was 16% and progression-free survival at 2 years 66%. An update on 74 patients was discussed with similar results. The study is being extended to other UK centers. cGy, is unknown at present. However, we do have consistent data on conventional transplant in myeloma, and very little data on reduced intensity transplants, which should still be considered investigational in young patients.

Lymphoma

If we now compare results obtained with these four regimens in over 200 patients, one can appreciate some similarities and some diversities. The latter were median patient age (older in the TBI2 and THIO-CY programs) and median follow-up (longer in the THIO-CY). Also different was the incidence of acute GVHD grade III–IV and extensive chronic GVHD, lower in programs using either conventional 6–12 months in vivo immunosuppression or CAMPATH 1H. However, transplant-related mortality was comparable if not identical, ranging between 14% and 15%. This suggests that we can allograft older patients with advanced disease, with a 15% mortality. Although some data on other outcome measures such as survival and relapse were presented, it is probably better to restrict the present discussion mainly to GVHD and TRM, also because of the patient heterogeneity.
Norbert Schmitz reported 147 patients allo-grafted in 34 transplant centers, 80 of whom had received a prior autograft. A high relapse rate (60% at 2 years) suggested that reduced intensity conditioning in advanced and/or high grade lymphomas is unlikely to be successful. Progressionfree survival (PFS) at 2 years was superior in patients with chemosensitive disease, as compared to patients with chemoresistant disease (30% vs 10%; P Ͻ 0.0001). A state of remission or minimal residual disease prior to RI-HSCT might be desirable in patients with lymphoma. Some centers in Europe will be using a melphalan + FLU or FLU + CY regimen for poor risk Hodgkin’s disease (patients with early relapse or patients not entering complete remission). In Italy a GITMO trial in patients with low grade nonHodgkin’s lymphomas is being coordinated by Paolo Corradini: the primary end point is molecular remission. Centers in the UK are going to explore the association of MEL + FLU + CAMPATH under the coordination of University College London. Finally, the French group is exploring a regimen based either on BU 8 or TBI 500 in patients with lymphoma.

Specific disease-related programs

Solid tumors (ST)

The solid tumor experience was summarized by Giovanni Rosti and showed an increased interest in allogeneic HSCT for this indication: 20 patients grafted in 1998, 47 in 1999 and 97 in 2000. Within the ST Working Party, Dieter Niederwieser is responsible for the allogeneic program and Olle Ringden, in particular, for renal cell carcinoma. Nine renal cell carcinoma patients were grafted using the TBI 200 cGy regimen and two are alive and well. Felipe Prosper presented protocols for breast cancer, colon cancer, melanoma, ovarian cancer, and biliary tree neoplasms. It is probably too early to give a clear message on the role of allogeneic RI-HSCT in patients with solid tumors. Some responses are being recorded in breast cancer and renal cell carcinoma. Results in melanoma seem to be less encouraging. It would seem wise to assess the role of allograft from HLA-identical sibling transplantation before expanding the program to unrelated donors.

Chronic lymphocytic leukemia (CLL)

Mauricette Michallet presented data on 14 CLL patients prepared for an allograft with fludarabine and an alkylating agent (either BU or MEL): at a median follow-up of 7 months TRM was 7% and GVHD was seen in 47% of patients. CLL patients are being entered in programs designed for low grade lymphomas.

High risk leukemia and myelodysplasia (MDS)

It may be difficult to maintain remission in patients with fast pace disease, such as acute leukemia in relapse or transformed MDS. Indeed there are little data available for these indications, and disappointing results were also presented at ASH.12 Some of these patients were included in the TBI 200 cGy regimens, in the BU 8 mg/kg or the THIO 10 mg/kg regimens. There was no specific program described for patients with acute lymphoblastic leukemia.

Myeloma

Ghosta Gahrton presented the outcome of allogeneic HSCT in myeloma: results have improved considerably with time, such that mortality has now been halved to less than 25%. An EBMT study was presented in which patients are first autografted with melphalan 200 mg/m2, and then, in the presence of an HLA-identical sibling, they are offered an allograft using the TBI 200 cGy + FLU regimen. This program derives from the Seattle program for patients with myeloma. It was not entirely clear which patients would be eligible for this trial: the protocol reads 18–65 years of age. Whether a 35-year-old patient with myeloma should undergo a conventional allogeneic HSCT or an autograft with melphalan 200 followed by an allograft with TBI 200

Specific transplant procedures and GVHD

Allogeneic transplants after RI conditioning are designed to reduce toxicity and exploit the immune effect of the graft: for this reason many programs call for discontinuation of in vivo immunosuppression as early as day +60 after HSCT, and/or infusion of donor lymphocytes (DLI) to maximize this effect. The difficulty of bringing this into practice is shown by the TBI 200 cGy regimen which was designed to give DLI to all patients, but which ended up by infusing lymphocytes in only approximately 10% of

Bone Marrow Transplantation

Second EBMT Workshop on RI-HSCT

A Bacigalupo

194

the patient population. This is mainly due to the fact that older age and early discontinuation of CsA cause severe acute GVHD in 15–20% of all cases and makes DLI impossible. The factors in PB allografts also induce extensive chronic GVHD in approximately half of patients, which is good for disease control, but less so for quality of life. In a study of the French group SFGM, early discontinuation of CsA had a significant negative impact on survival.
Programs involving CAMPATH 1H in conditioning were followed by little or no acute or chronic GVHD: whether this is desirable remains to be determined. However, prevention seems the most effective way to manage GVHD, since treatment is currently unsatisfactory. or melphalan 140 mg/m2, most of them in combination with fludarabine. Variations of these four regimens are described.
(6) Extensive chronic GVHD is seen in a considerable proportion of patients and should be carefully monitored: guidelines for long-term effects have been developed by EBMT and should be followed.
(7) Reduced intensity programs are being optimized and tested in selected indications including unrelated donor transplants.
(8) The comparison with conventional programs will probably be tested.
(9) As in 1999, it was agreed that the term ‘minitransplant’ is misleading for patients and physicians: we may want to refer to this procedure as an allogeneic hematopoietic stem cell transplant (HSCT) and the conditioning regimen may be further classified.
(10) Donor complications were not described, although older age calls for particular care.

Unrelated donor transplants

The largest series reported is from Seattle/ Leipzig with 41 patients receiving TBI 200 cGy + FLU 90 mg/m2. Median age was 48 (6–65), 34 were PB and seven BM transplants. Engraftment was achieved in 37 patients. Acute GVHD grade II–IV was seen in 62% and TRM in 7/41 patients (17%) at a median follow-up of 185 days (5–471). The median duration of CsA treatment was 6 months. Recently, the BU 8 + FLU 125 + ATG regimen of Shimon Slavin has also been explored in 16 young patients (median age 17) grafted from unrelated donors:13 three patients developed grade III–IV acute GVHD, and three died of transplant-related complications. Although these are relatively early results, they indicate that alternative transplants can be performed in some patients with reduced intensity conditioning. This may be particularly appealing in patients with non-malignant diseases. An ongoing program of the EBMT Severe Aplastic Anemia Working Party calls for FLU 120 mg/m2 + CY 1200 mg/m2 + ATG followed by unmanipulated marrow and CsA + MTX post transplant: it has enrolled 12 patients and eight are alive and well, with full donor chimerism, and little or no GVHD.
(11) The next Workshop in 2003 will bring further results and indications on best strategies.

Finally, reducing the intensity of the conditioning regimen is one way of minimizing toxicity. Other ways are being explored, among which is graft engineering with expanded cell sub-populations (such as mesenchymal stem cells) which may then be infused in conjunction with hemopoietic stem cells, following conventional or intensified conditioning regimens. We will also be awaiting results of these studies, some of which seem promising.14

Acknowledgements

This Workshop was organized with an unrestricted educational grant from AMGEN Europe. I am grateful to my co-chairpersons Shimon Slavin and Francesco Frassoni for their contribution, as well as to all discussants: Jane Apperley, Paolo Corradini, Ghosta Gahrton, Anthony Goldstone, Mauricette Michallet, Dietger Niederwieser, Felipe Prosper, Olle Ringden, Giovanni Rosti, Norbert Schmitz, Shimon Slavin, Alvaro Urbano Ispizua.

Lessons from the 2001 Workshop
References

Some tentative conclusions from the 2001 Workshop are as follows:

1 Bacigalupo A. Hematopoietic stem cell transplants after reduced intensity conditioning regimen (RI-HSCT): report of a workshop of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 2000; 25: 803–805.
2 Khouri IF, Keating M, Korbling M et al. Transplant lite: induction of graft versus malignancy using fludarabine based non ablative chemotherapy and allogeneic blood progenitor cell transplantation as treatment for lymphoid malignances. J

Clin Oncol 1998; 16: 2817–2824.

3 Storb R, Yu C, Sanmeier BM et al. Mixed hemopoietic chimerism after marrow allografts. Transplantation in the ambulatory care setting. Ann NY Acad Sci 1999; 872: 372–375.
4 Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

(1) Reduced intensity allogeneic HSCT can now be performed with relatively low toxicity in patients over the age of 50.
(2) There is, however, an ‘age effect’ in almost all programs, when reported, and patients above 50 do worse than patients below 50 years.
(3) The preferred stem cell source is peripheral blood: a prospective randomized trial is under way to compare blood and marrow in this setting.
(4) The preferred GVHD prophylaxis is CsA + MTX or
CsA + MMF. ATG or CAMPATH antibodies are used in some programs, and reduce the risk of GVHD.
(5) There are four major conditioning regimens based on
TBI 200 cGy, busulfan 8 mg/kg, thiotepa 10 mg/kg

Recommended publications
  • Reduced Intensity Conditioning Allogeneic Stem

    Reduced Intensity Conditioning Allogeneic Stem

    Brief Report Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation Mohamad Mohty,1 Myriam Labopin,2 Reza Tabrizzi,3 Niklas Theorin,4 Axel A Fauser,5 Alessandro Rambaldi,6 Johan Maertens,7 Shimon Slavin,8 Ignazio Majolino,9 Arnon Nagler,10 Didier Blaise,11 and Vanderson Rocha2,12 on behalf of the Acute Leukemia Working Party 1Service d’Hématologie Clinique, CHU Hôtel Dieu, Université de Nantes, Nantes, France; 2European Group for Blood and Marrow Transplantation (EBMT), Acute Leukemia Working Party, Hopital Saint-Antoine, Assistance Publique des Hôpitaux de Paris and Université de Paris 6, Pierre et Marie Curie, Paris, France; 3Centre Hospitalo-Universitaire de Bordeaux, Hôpital Haut-Leveque, Pessac, France; 4University Hospital, Dept. of Hematology, Linköping, Sweden; 5Klinik fuer Knochenmarktransplantation und Haematologie/Onkologie, Idar-Oberstein, Germany; 6Ospedale Bergamo, Divisione di Ematologia, Bergamo, Italy; 7University Hospital Gasthuisberg, Dept. of Hematology, Leuven, Belgium; 8Hadassah University Hospital, Department of Bone Marrow Transplantation, Jerusalem, Israel; 9Ospedale S. Camillo-Forlanini, Dept. of Hematology and BMT, Rome, Italy; 10Tel-Aviv University, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 11Unité de Transplantation et de Thérapie Cellulaire, Institut Paoli-Calmettes, Marseille, France and 12Department of Hematology, Hopital Saint-Louis, Assistance Publique Hopitaux de Paris, Paris, France Citation: Mohty M, Labopin M, Tabrizzi R, Theorin N, Fauser AA, Rambaldi A, Maertens J, Slavin S, Majolino I, Nagler A, Blaise S, and Rocha V on behalf of the Acute Leukemia Working Party. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation.
  • Induction of Early Post-Transplant Graft-Versus-Leukemia Effects

    Induction of Early Post-Transplant Graft-Versus-Leukemia Effects

    Research Article 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 Iris Yung, Lola Weiss, Ali Abdul-Hai, Judith Kasir, Shoshana Reich, and Shimon Slavin Department of Bone Marrow Transplantation and Cancer Immunotherapy, Cell Therapy and Transplantation Research Center, Hadassah University Hospital, Jerusalem, Israel Abstract Using NST, the primary goal is to achieve engraftment of donor Graft-versus-leukemia (GVL) effects can be induced in tolerant stem cells thus establishing host-versus-graft unresponsiveness, mixed chimeras prepared with nonmyeloablative conditioning. and consequently, durable engraftment of donor immune system GVL effects can be amplified by post-grafting donor lymphocyte cells (8–10). However, in the absence of T-cell depletion, severe infusion (DLI). Unfortunately, DLI is frequently associated with acute and especially extensive chronic graft-versus-host disease graft-versus-host disease (GVHD). We investigated the feasibil- (GVHD) caused by alloreactive T lymphocytes still remain major ity of induction of potent GVL effects by DLI using intentionally obstacles. Over the years, several approaches have been proposed mismatched lymphocytes followed by elimination of alloreac- to prevent or at least control GVHD. Slavin et al. (11–13) and Sykes tive donor T cells by cyclophosphamide for prevention of and Sachs (14, 15) have documented in preclinical animal models lethal GVHD following induction of very short yet most potent that establishing a state of mixed chimerism was associated with a reduced risk of GVHD. Slavin et al. (12) and Weiss et al. (16) GVL effects.
  • IL-2-Targeted Therapy Ameliorates the Severity of Graft

    IL-2-Targeted Therapy Ameliorates the Severity of Graft

    BIOLOGY IL-2–Targeted Therapy Ameliorates the Severity of Graft-versus-Host Disease: Ex Vivo Selective Depletion of Host-Reactive T Cells and In Vivo Therapy Shai Yarkoni,1 Tatyana B. Prigozhina,2 Shimon Slavin,3 Nadir Askenasy4 T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2- cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical trans- 1 plants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3 ; 1 1 50%) and CD25 FoxP3 T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro 1 2 1 1 apoptosis in both CD4 CD25 and CD4 CD25 subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2- cas–pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of 1 CD25highFoxP3 T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2–targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploident- ical GVHD.
  • NIH Public Access Author Manuscript Arch Neurol

    NIH Public Access Author Manuscript Arch Neurol

    NIH Public Access Author Manuscript Arch Neurol. Author manuscript; available in PMC 2011 February 9. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Arch Neurol. 2010 October ; 67(10): 1187±1194. doi:10.1001/archneurol.2010.248. Safety and Immunological Effects of Mesenchymal Stem Cell Transplantation in Patients With Multiple Sclerosis and Amyotrophic Lateral Sclerosis Dr. Dimitrios Karussis, MD, PhD, Dr. Clementine Karageorgiou, MD, Dr. Adi Vaknin- Dembinsky, MD, PhD, Dr. Basan Gowda-Kurkalli, PhD, Dr. John M. Gomori, MD, Mr. Ibrahim Kassis, MSc, Dr. Jeff W. M. Bulte, PhD, Dr. Panayiota Petrou, MD, Dr. Tamir Ben- Hur, MD, PhD, Dr. Oded Abramsky, MD, PhD, and Dr. Shimon Slavin, MD Department of Neurology, Laboratory of Neuroimmunology and Agnes Ginges Center for Neurogenetics and Multiple Sclerosis Center (Drs Karussis, Vaknin-Dembinsky, Petrou, Ben-Hur, and Abramsky and Mr Kassis), Department of Bone Marrow Transplantation (Drs Gowda-Kurkalli and Slavin), and Unit of Neuroradiology, Department of Radiology (Dr Gomori), Hadassah Hebrew University Hospital, Jerusalem, Israel; Department of Neurology, Gennimatas General Hospital, Athens, Greece (Dr Karageorgiou); and Russell H. Morgan Department of Radiology and Radiological Science, Department of Biomedical Engineering, and Department of Chemical and Biomolecular Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland (Dr Bulte) Abstract Objective—To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Design—A phase 1/2 open-safety clinical trial.
  • Tumor Effect

    Tumor Effect

    Biology of Blood and Marrow Transplantation 10:40-48 (2004) ᮊ 2004 American Society for Blood and Marrow Transplantation 1083-8791/04/1001-0004$30.00/0 doi:10.1016/j.bbmt.2003.09.013 Allogeneic versus Syngeneic Killer Splenocytes as Effector Cells for the Induction of Graft-versus- Tumor Effect Shoshana Morecki, Elena Yacovlev, Yael Gelfand, Anna Vilensky, Shimon Slavin Department of Bone Marrow Transplantation & Cancer Immunotherapy, Cell Therapy & Transplantation Research Center, Hadassah University Hospital, Jerusalem, Israel Correspondence and reprint requests: Shoshana Morecki, PhD, Department of BMT, Hadassah University Hospital, Jerusalem 91120, Israel (e-mail: [email protected]). Received August 8, 2003; accepted September 22, 2003 ABSTRACT The effect of allogeneic versus syngeneic killer cells derived from normal or severe combined immunodefi- ciency disease (SCID) mice was evaluated for induction of antitumor reaction in a murine model of mammary carcinoma. Tumor cells of H-2d origin were injected intravenously into H-2d/b mice 24 hours after total body irradiation (4 Gy). On the following day, lymphokine-activated killer (LAK) splenocytes, derived from either minor (H-2d) or major (H-2b) histocompatibility complex (MHC)–mismatched parental normal mice or MHC (H-2b)–mismatched SCID mice, were given intravenously. LAK cells of H-2d normal or SCID mice, syngeneic to the tumor, were inoculated in parallel. The results show that LAK cells derived from minor histocompat- ibility complex–mismatched or MHC-mismatched parental normal mice improved the probability of tumor- free survival as compared with LAK cells syngeneic to the tumor cells, but they aggravated the severity of graft-versus-host disease.
  • Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells

    Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells

    SPLIT IMMUNITY: IMMUNE INHIBITION OF RAT GLIOMAS BY SUBCUTANEOUS EXPOSURE TO UNMODIFIED LIVE TUMOR CELLS. Ilan Volovitz †,* , Yotvat Marmor *, Meir Azulay *, Arthur Machlenkin *, Ofir Goldberger * , Felix Mor *, Shimon Slavin ‡, Zvi Ram †, Irun R. Cohen *and Lea Eisenbach * † The Cancer Immunotherapy lab, the Dept. of Neurosurgery. The Tel-Aviv Sourasky Medical Center. * The Dept. of Immunology. The Weizmann Institute of Science. ‡ The International Center for Cell Therapy & Cancer Immunotherapy, The Tel-Aviv Medical Complex, Tel-Aviv. ABSTRACT Gliomas, which appear to grow uninhibited in the brain, almost never metastasize outside the CNS. The rare occurrences of extracranial metastasis are usually associated with an immune compromised status of the host. This observation raises the possibility that some gliomas might not grow outside the CNS due to an inherent immune response. We now report that the highly malignant F98 Fischer rat undifferentiated glioma, which grows aggressively in the brain, spontaneously regresses when injected live subcutaneously (sc). We found that this regression is immune-mediated and that it markedly enhances the survival, or cures rats challenged with the same tumor intracranially (ic) either before or after the sc live-cell inoculation. Adoptive transfer experiments showed the effect was immune-mediated, and that the CD8 T-cell fraction, which exhibited direct tumor cytotoxicity, was more effective than the CD4 T-cell fraction in mediating resistance to intracranial challenge of naïve rats. The results in the F98 model were corroborated also in the Lewis rat CNS-1 astrocytoma model. In both tumor models the unprecedented survival results using live-cell immunization were significantly better than those achieved using immunization with irradiated cells.
  • Induction of Early Post-Transplant Graft-Versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Eliminatio

    Induction of Early Post-Transplant Graft-Versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Eliminatio

    Research Article 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 Iris Yung, Lola Weiss, Ali Abdul-Hai, Judith Kasir, Shoshana Reich, and Shimon Slavin Department of Bone Marrow Transplantation and Cancer Immunotherapy, Cell Therapy and Transplantation Research Center, Hadassah University Hospital, Jerusalem, Israel Abstract Using NST, the primary goal is to achieve engraftment of donor Graft-versus-leukemia (GVL) effects can be induced in tolerant stem cells thus establishing host-versus-graft unresponsiveness, mixed chimeras prepared with nonmyeloablative conditioning. and consequently, durable engraftment of donor immune system GVL effects can be amplified by post-grafting donor lymphocyte cells (8–10). However, in the absence of T-cell depletion, severe infusion (DLI). Unfortunately, DLI is frequently associated with acute and especially extensive chronic graft-versus-host disease graft-versus-host disease (GVHD). We investigated the feasibil- (GVHD) caused by alloreactive T lymphocytes still remain major ity of induction of potent GVL effects by DLI using intentionally obstacles. Over the years, several approaches have been proposed mismatched lymphocytes followed by elimination of alloreac- to prevent or at least control GVHD. Slavin et al. (11–13) and Sykes tive donor T cells by cyclophosphamide for prevention of and Sachs (14, 15) have documented in preclinical animal models lethal GVHD following induction of very short yet most potent that establishing a state of mixed chimerism was associated with a reduced risk of GVHD. Slavin et al. (12) and Weiss et al. (16) GVL effects.
  • The Second International Meeting on Allogeneic Transplantation in Solid Tumors

    The Second International Meeting on Allogeneic Transplantation in Solid Tumors

    Bone Marrow Transplantation (2006) 38, 527–537 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt MEETING REPORT The Second International Meeting on Allogeneic Transplantation in Solid Tumors M Bregni1, NT Ueno2 and R Childs3 1Oncology-Hematology-Bone Marrow Transplant Unit, Department of Oncology, Istituto Scientifico San Raffaele, San Raffaele Hospital, Milan, Italy; 2Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 3NHLBI, National Institutes of Health, Bethesda, MD, USA In October 2005,the second international meeting on convened in Stresa (Italy) by Marco Bregni, Naoto Ueno, allogeneic transplantation in solid tumors was convened in and Richard Childs under the auspices of the European Stresa (Italy). The aim of this second meeting was to Group for Blood and Marrow Transplantation (EBMT) share clinical experiences of allografting in solid tumors, Solid Tumor Working Party. The first meeting took to discuss preclinical data on the mechanisms of graft- place in Milano, Italy, in June 2002, and was a chance versus-tumor (GVT) effect,and to review methods for for people involved to communicate and discuss initial more efficacious transplant approaches. On the first day, clinical and biological studies of reduced-intensity allo- the most recent results in cancer immunotherapy were grafting in solid tumors.1 The aim of this second meeting reviewed; head-to head comparisons of clinical results was to share experiences of allografting for solid tumors, achieved by standard therapy and by allografting in renal, update data accumulated in this field over the past 3 years, breast,and ovarian cancer were presented.
  • A Patient's Path Through the Maze of Stem Cell Transplantation

    A Patient's Path Through the Maze of Stem Cell Transplantation

    CY OCA AW V A D R A D < > W O T R 20 10 I L D M M S U T E S M C E L L A PAtient’s PATH THROUGH THE MAZE OF STEM CELL TRANSPLANTATION AN INTRODUCTION TO THE STEM CELL The first true stem cell was discovered and named in 1908 by the Russian scientist, Alexander Maksimov, A CLOSER LOOK who found that certain cells could generate blood cells. In 1963, Canadian researchers Earnest McCullough and James Till described the self- renewing nature of transplanted mouse mesenchymal cells. In 1998, Dr. James Thomson and his colleagues from the University of Wisconsin - Madison announced the successful AT STEM CELLS, extraction of stem cells from human embryos in the laboratory. Enormous excitement surrounds these and related discoveries because stem cells have the potential to develop into many different cells, which means they can serve as an internal repair system. When a stem cell divides, it has the potential to either continue PROCEDURES, functioning as is or to become another type of cell with a more specialized function, such as muscle, red blood or brain cell. The most important characteristic of stem cells is their ability to renew, repair or replace worn out or damaged tissue. FACILITIES AND An Introduction to Stem Cells We are now in 2010, faced with a multitude of potential stem cell therapy opportunities for those with ALS and other debilitating diseases and injuries. As a result, an entirely new and complicated collection of terms has emerged in the process. The terminology includes embryonic, adult, fetal, mesenchymal, umbilical cord THE EMERGENCE blood, amniotic, olfactory ensheathing cells, autologous, allogeneic and a whole host of other substrata of OF ALS WORLDWIDE stem cells, enough to confuse any patient and possibly even some of the scientists.
  • New Jersey Commission on Cancer Research

    New Jersey Commission on Cancer Research

    New Jersey Commission on Cancer Research 2000 Annual Report "Dedicated to Conquering Cancer Through Scientific Research" The Honorable Donald T. DiFrancesco Acting Governor Dear Governor DiFrancesco: As the newly elected Chairman of the New Jersey Commission on Cancer Research, I am honored to present to you the Commission's report for the Year 2000. Consistent with its legislative mandate, the Commission focused its efforts during the past year on basic research directed to increase our understanding of this disease and reduce morbidity and mortality related to the disease. Toward this goal, the Commission awarded twelve grants for basic, clinical, and psychosocial research,seven pre-doctoral and post-doctoral research fellowships, and fifteen summer research fellowships, designed to encourage college students to pursue careers in cancer research. This year, the Commission began a more formal tracking program for past award recipients, and we continue to find that their productivity supports our contention that the monies expended have been a superb investment in the future of New Jersey's research infrastructure and institutions of higher learning. Past investigators supported by the Commission have, in large part, remained within New Jersey, contributed to a significant increase in research dollars flowing into the State, and provided an invaluable resource to research, educational, and corporate entities. The Commission has long recognized that research carried out in a vacuum has reduced value, and in this regard, we continue to serve as a catalyst and supporter of educational and research meetings. This year, the International Conference on Advances in Cancer Immunology, the Annual Retreat on Cancer Research in New Jersey and the Conference on Cancer Survivorship Throughout the Life-span, brought together hundreds of consumers, educators and scientists, in an atmosphere conducive to networking and program development, and in a way designed to highlight New Jersey's strengths in these programs.
  • Immune Inhibition Of

    Immune Inhibition Of

    Split Immunity: Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells This information is current as Ilan Volovitz, Yotvat Marmor, Meir Azulay, Arthur of February 27, 2013. Machlenkin, Ofir Goldberger, Felix Mor, Shimon Slavin, Zvi Ram, Irun R. Cohen and Lea Eisenbach Downloaded from J Immunol 2011; 187:5452-5462; Prepublished online 12 October 2011; doi: 10.4049/jimmunol.1003946 http://www.jimmunol.org/content/187/10/5452 http://jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2011/10/12/jimmunol.100394 Material 6.DC1.html References This article cites 56 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/187/10/5452.full#ref-list-1 at Weizmann Institute of Science on February 27, 2013 Subscriptions Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscriptions Permissions Submit copyright permission requests at: http://www.aai.org/ji/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/cgi/alerts/etoc The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Split Immunity: Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells Ilan Volovitz,*,† Yotvat Marmor,* Meir Azulay,* Arthur Machlenkin,* Ofir Goldberger,* Felix Mor,* Shimon Slavin,‡ Zvi Ram,† Irun R. Cohen,* and Lea Eisenbach* Gliomas that grow uninhibited in the brain almost never metastasize outside the CNS.
  • Split Immunity: Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells

    Split Immunity: Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells

    Split Immunity: Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells This information is current as Ilan Volovitz, Yotvat Marmor, Meir Azulay, Arthur of September 27, 2021. Machlenkin, Ofir Goldberger, Felix Mor, Shimon Slavin, Zvi Ram, Irun R. Cohen and Lea Eisenbach J Immunol 2011; 187:5452-5462; Prepublished online 12 October 2011; doi: 10.4049/jimmunol.1003946 Downloaded from http://www.jimmunol.org/content/187/10/5452 Supplementary http://www.jimmunol.org/content/suppl/2011/10/12/jimmunol.100394 Material 6.DC1 http://www.jimmunol.org/ References This article cites 56 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/187/10/5452.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Split Immunity: Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells Ilan Volovitz,*,† Yotvat Marmor,* Meir Azulay,* Arthur Machlenkin,* Ofir Goldberger,* Felix Mor,* Shimon Slavin,‡ Zvi Ram,† Irun R.