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At least 19 recordsLinked to original sources
PubMed1993

The graft-vs.-leukemia effect. Implications for post-marrow transplant antileukemia treatment.

PURPOSE: Over the past 30 years, evidence supporting the existence of an antileukemic effect of allogeneic bone marrow has rapidly expanded. Early animal studies demonstrated this "graft-vs.-leukemia" (GVL) effect in association with graft-vs.-host disease (GVHD). PATIENTS, METHODS, AND RESULTS: Clinical evidence for the GVL effect derived from experience in allogeneic bone marrow transplantation (BMT) includes the following: the association of GVHD, both acute and chronic, with a decreased rate of leukemic relapse, the occurrence of a higher relapse rate following identical twin transplants compared to allogeneic major histocompatibility complex-matched sibling transplants, the decrease of GVHD and increase of leukemic relapses with T-cell depletion of donor bone marrow, and that allogeneic marrow transplants without GVHD have a lower leukemic relapse rate compared to identical twin transplants and T-cell depleted transplants. In addition, some reports indicate that modifying the immunosuppressive regimens (consisting of cyclosporine A or methotrexate) that are aimed at prevention of GVHD can affect leukemic relapse rates. Although the mechanism of this GVL effect is poorly understood, there are several favored hypotheses. Cytotoxic T cells, which may mediate GVH effects, could also mediate a GVL effect. There may also be T cells with specificity for destroying leukemic blasts alone. The natural killer/lymphokine-activated killer cytotoxic cell may play a role in the GVL effect. These nonspecific cytotoxic cells can be activated with cytokines induced in the transplant setting. Finally, the GVL effect could be secondary to the in vivo induction of various cytokines that either have direct antileukemic effects or that induce leukemic differentiation. Advances in our basic understanding of the immune system and its activation, and the availability of purified immunoregulatory cytokines, have revealed new ways to induce GVL-like effects. Promising results with therapy based on use of interleukin-2 in solid tumors have been seen. It is hoped that these advances will enable the "antileukemic" components of the GVL effect to be prospectively controlled (as part of the technique of marrow transplant) and intentionally used as leukemic therapy in patients undergoing bone marrow transplantation.

Animals↗
PubMed2001

Identification of T-cell clones showing expansion associated with graft-vs-leukemia effect on chronic myelogenous leukemia in vivo and in vitro.

Although the graft-vs-leukemia (GVL) effect induced by donor leukocyte infusion (DLI) is thought to be mediated by T cells, their features, as well as target molecules, remain unknown. To characterize T cells that mediate the GVL effect on chronic myelogenous leukemia (CML), we studied T-cell repertoire in peripheral blood (PB) of two patients treated with DLI for relapsed CML after allogeneic bone marrow transplantation. Peripheral blood mononuclear cells (PBMCs) were obtained at 2-week intervals following DLI and examined for the presence of antigen-driven T-cell proliferation using complementarity-determining region (CDR) 3 size spectratyping of T-cell receptor beta chain subfamilies. Both patients exhibited transient proliferation of a limited number of T cells at a certain point in time (day 132 for patient 1 and day 75 for patient 2) after DLI in association with a decrease in the proportion of Philadelphia chromosome (Ph)-positive cells. In patient 2, who showed expansion of a BV16(+) T cell in PB, expansion of BV16(+) T cells with a similar CDR3 motif containing QDR to that of PB was demonstrated in the bone marrow (BM) sampled on day 33 and in the buccal mucosal tissue, showing chronic graft-vs-host disease (GVHD) on day 138 after DLI. When PBMCs obtained from patient 2 in remission were cultured with cryopreserved CML cells for 2 weeks, proliferation of a BV16(+) T cell with a CDR3 motif of QIR was induced in vitro. These findings indicate that transient proliferation of a limited number of T cells detected in PB 3-5 months after DLI probably reflects the GVL response against CML cells and may serve as a marker for the appearance of the GVL effect induced by DLI.

Adult↗
PubMed2002

Induction of a transient graft vs. leukemia effect following unrelated cord blood transplantation.

Umbilical cord blood (UCB) has become a frequent source of allogeneic hematopoietic stem cells for transplantation. Of theoretical concern is a potential decrease in the graft vs. leukemia (GvL) effect, given the lesser degree of graft vs. host disease (GvHD) with this donor source. We report a case of recurrent acute non-lymphoblastic leukemia (ANLL) following stem cell transplantation with unrelated mismatched UCB, which responded to the induction of GvHD. The response was documented both morphologically and by evaluation of chimeric engraftment by molecular DNA techniques. In addition, WT-1, a purported marker of minimal residual disease in acute leukemia, correlated with remission status in this patient. In summary, the GvL effect is seen with allogeneic UCB transplantation and has the potential to be induced along with GvHD.

Child, Preschool↗
PubMed2003

CD40 ligand-specific antibodies synergize with cyclophosphamide to promote long-term transplantation tolerance across MHC barriers but inhibit graft-vs-leukemia effects of transplanted cells.

OBJECTIVES: We previously demonstrated that allogeneic bone marrow transplantation (BMT) after low-dose total lymphoid irradiation (200 cGy) and depletion of donor-reactive cells with cyclophosphamide (Cy) converted recipients to graft-vs-host disease (GVHD)-free chimeras tolerant to donor skin grafts. BMT also generated strong graft-vs-leukemia (GVL) response. However, clinical application of the protocol was hampered by the requirement for a relatively high dose of Cy (200 mg/kg). In this study we have tried to minimize the Cy dose by a concomitant blockade of CD40-CD40L interaction. MATERIALS AND METHODS: Mildly irradiated BALB/c mice were primed with C57BL/6 BM cells (BM(1)) and skin graft on day 0, injected with Cy (200 mg/kg or less) on day 1, and transplanted with a second C57BL/6 BM cell inoculum (BM(2)) on day 2. CD40L-specific antibody (MR1) was given with BM(1), BM(2), and 2 days later. Treated animals were monitored for survival, chimerism, and skin allograft rejection. The GVL potential of transplanted cells was examined in mice inoculated with BCL1 leukemia cells before irradiation. RESULTS: Blocking CD40-CD40L interaction with MR1 mAb allowed the reduction of a tolerance-generating Cy dose by 50%. Unfortunately, adding MR1 to the protocol reduced the GVL potential of the transplanted cells. Neither low-dose Cy nor antibodies alone could downregulate donor or recipient immune response. CONCLUSIONS: CD40L-specific antibodies synergize with Cy to induce bilateral transplantation tolerance. Therefore, their use may be beneficial for safer allogeneic BMT for nonmalignant indications. However, due to MR1-associated reduction of GVL effects, MR1 should be considered with caution as conditioning for BMT for leukemia-bearing recipients.

Abatacept↗
PubMed2003

Emergency living related liver transplantation for fulminant reactivation of hepatitis B virus after unrelated marrow transplantation.

We report a unique case of emergency living related donor orthotopic liver transplantation (OLT) for late fulminant reactivation of hepatitis B virus (HBV) after matched unrelated bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Cessation of lamivudine after BMT for HBV positive patients may carry risks of late fatal HBV reactivation. Similar to fulminant HBV reactivation in the general population, OLT under resumption of lamivudine can be life saving. In our case, concomitantly molecular relapse of CML at the time of liver failure was also cleared by OLT, possibly via a 'liver-graft vs. leukemia' effect. Liver rejection (graft vs. graft disease) was mild due to inherent immunocompromise of the marrow graft. Hence BMT recipients in stable remission should not be denied the opportunity for life-saving solid organ transplantation. A choice of marrow and liver donors with innate HBV immunity may be needed to give the additional advantage of long-term HBV clearance.

Adult↗
PubMed2004

The Mortimer M. Bortin Lecture: to destroy by the reaction of immunity: the search for separation of graft-versus-leukemia and graft-versus-host.

The graft-versus-leukemia effect of allogeneic blood or marrow transplantation is a dramatic example of the power of the immune system to eradicate malignant disease. In this personal essay, adapted from the inaugural Mortimer M. Bortin Lecture presented at the 2004 Tandem BMT Meetings, the author recounts early efforts by Bortin and others to manipulate the graft-versus-leukemia effect and separate it from the potentially fatal complications of graft-versus-host disease.

Animals↗
PubMed2001

Graft-vs-leukemia activity and graft-vs-host disease induced by allogeneic Th1- and Th2-type CD4+ T cells in mice.

INTRODUCTION: The transfer of allogeneic lymphocytes contained in a hematopoietic stem cell graft confers an immune-mediated antileukemic effect, termed the graft-vs-leukemia (GVL) effect. Graft-vs-host disease (GVHD), the most detrimental complication of allogeneic BMT, largely resides within the same lymphocyte population. Therefore, separation of GVL- and GVH-reactions is a long-standing goal of experimental studies dealing with allogeneic transplantation of hematopoietic stem cells. MATERIALS AND METHODS: The objective of the current study was to assess the potential of Th1- and Th2-type CD4+ T cells in mediating GVHD and GVL effects in a fully allogeneic murine transplant model. BALB/c (H-2d) mice were given a dose of A20 (H-2d, B-cell leukemia) cells two days prior to lethal total body irradiation (TBI) and transplantation of fully mismatched (C57BL/6, H-2b) T-cell depleted (anti-Thy1.2, CD90) bone marrow (TCD-BM) cells. Graded numbers of either unmanipulated, Th1- or Th2-polarized highly enriched CD4+ donor type T cells (10(6) or 10(7)) were administered 2 h posttransplant. Infusion of 10(6) of unmanipulated, Th1-, or Th2-primed CD4+ T cells resulted in moderate GVHD-related mortality (40%, 50%, 10%) and significantly improved long-term survival (50%, 45%, 46% surviving the observation period of 120 days) as compared to animals receiving TCD-BM alone (18%). RESULTS: The administration of 10(7) unmanipulated or Th1-type CD4+ T cells given shortly after transplantation led to death of all mice within 50 days due to fatal acute GVHD. In contrast, the adoptive transfer of 10(7) Th2-primed CD4+ T cells resulted in significant improvement of long-term survival (80%) compared to the TCD-BM group. This powerful GVL effect was associated with a substantially lower incidence of lethal acute GVHD (10%) if compared to the results of transplantation of Th1-type CD4+ T cells. CONCLUSION: These results demonstrate that allogeneic Th2-type CD4+ T cells given post BMT can induce GVL effects in a cell-dose-dependent manner without increasing the risk of severe acute GVHD.

Adoptive Transfer↗
PubMed2002

Reliable engraftment, low toxicity, and durable remissions following allogeneic blood stem cell transplantation with minimal conditioning.

OBJECTIVE: Allogeneic blood stem cell transplantation (BSCT) can cure patients with hematologic malignancies by high-dose chemotherapy and allogeneic graft-vs-tumor (GvT) reactions. To avoid high-dose conditioning and evaluate engraftment, toxicity, and GvT reactions, we treated a group of high-risk patients with a minimal intensive conditioning regimen followed by allogeneic BSCT. MATERIALS AND METHODS: Thirty-four patients with lymphoma (11), myeloma (10), chronic myeloid leukemia (4), myelodysplastic syndrome (5), and acute myeloid leukemia (4) were treated with fludarabine (3 x 30 mg/m(2)) and 200 cGy total-body irradiation followed by the infusion of peripheral blood stem cells from related (28) or unrelated (6) donors. Cyclosporine or tacrolimus and mycophenolate mofetile were given posttransplant. Most patients had advanced disease, were intensively pretreated, and had contraindications against conventional myeloablative transplantation. RESULTS: Thirty-two patients (94%) had engraftment of donor cells. Patients with lymphatic malignancies developed complete donor chimerism significantly faster than patients with myeloid malignancies (p < 0.05). Clinical responses were observed in 16 of 27 patients (59%) who had active disease at transplantation. Of 7 patients who were treated in remission, 5 remain free of disease. After a median follow-up of 325 days (range 100-844) 22 patients are alive (65%, 14 CR, 4 PR, 4 PD). Two patients (6%) died of treatment-related complications and 10 patients (29%) died of progressive disease. Acute graft-vs-host-disease (GvHD) of grade II or more developed in 17 patients (50%). Chronic GvHD is present in 10 of 22 patients (45%) who are alive beyond day 100. CONCLUSIONS: Toxicity and survival in this group of high-risk patients are superior to those expected with conventional allogeneic transplantation. GvT reactions frequently occur in conjunction with GvHD and can induce durable remissions in patients with advanced hematologic malignancies.

Adult↗
PubMed2006

[Transplant of hemopoietic progenitors].

In the second half of the XX century, the transplant of hemopoietic progenitors ceased to be a desperate treatment with a high incidence of complications implying a high mortality, and became a curative treatment for thousands of patients with hematological neoplasias and other diseases. Since then understanding of the hemopoietic stem cells has increased, peripheral blood has replaced bone marrow as a source of progenitors, cord blood has been established as a viable source of progenitors and the realisation of unrelated transplants is a reality for many patients. The improvement of conditioning regimes and the introduction of new non-myeloablative treatments have reduced relapses. The new diagnostic techniques and the new anti-microbial treatments have reduced infectious complications and their mortality. There has been an advance in knowledge in determining minimal residual disease and the anti-tumour effect of the lymphocytes of the donor, which has made it possible to widen the indications. Besides, new understanding of the immunobiology of the transplant has, on the one hand, improved the options for controlling one of the principal complications, the graft-versus-host disease, and, on the other, a better use is made of the immunotherapeutic effect of the transplant.

Adult↗
PubMedDate not supplied

Allogeneic hematopoietic cell transplantation as immunotherapy for solid tumors: current status and future directions.

Although myeloablative conditioning can cytoreduce or debulk malignancies, the curative antitumor effects of allogeneic hematopoietic stem cell transplantation (HCT) are mostly mediated by transplanted donor immune cells. A heightened awareness and appreciation of the immune-mediated anticancer effects that occur after allogeneic transplantation has led to the increasing use of reduced-intensity stem cell transplantation (RIST) approaches to treat advanced malignancies. The graft-versus-leukemia effects that occur against hematologic cancers after RIST have recently attracted oncologists to explore the therapeutic potential of allogeneic HCT for treatment-refractory solid tumors. Delayed tumor regression after RIST in a subset of patients with metastatic renal cell, breast, ovarian, pancreatic, and colon carcinoma has recently been reported, confirming the existence of a graft-versus-tumor effect in solid tumors. Advanced disease states, rapidly growing tumors, and accrual of patients with extremely short survival are factors that have been identified to limit the efficacy of allogeneic immunotherapy. This review discusses results of allogeneic HCT for solid tumors and the development of newer transplant strategies to optimize the potential of the graft-versus-tumor effect.

Breast Neoplasms↗
PubMed2005

Selective elimination of alloreactivity from immunotherapeutic T cells by photodynamic cell purging and memory T-cell sorting.

Allogeneic stem cell transplantation (alloSCT), especially in the mismatched setting, carries a high risk of life-threatening GvHD because of activation of donor T cells by Ag present on host cells. Removal of mature donor T cells can prevent GvHD but leads to delayed immune reconstitution, and an increased incidence of opportunistic infections and disease relapse. These findings demonstrate the vital role of donor T cells in providing graft-versus-tumor (GvT) and anti-pathogen effects as well as facilitating immune reconstitution. It has been well documented that GvHD can be separated from GvT effects, making it possible potentially to eliminate GvHD while preserving the immunotherapeutic benefits of donor T cells. Over the past decade, major attempts have been made to reduce GvHD incidence without loss of GvT effect, especially in the haplo-identical setting. Novel techniques to deplete host-reactive donor T cells selectively have been explored. This review focuses on the use of the photodynamic cell purging (PDP) process and of sorting memory T cells for the selective elimination of alloreactivity. Minimizing the threat of GvHD while maximizing the beneficial GvT effect would broaden the scope and effectiveness of alloSCT.

Cell Separation↗
PubMed2004

Kinetics of in vivo elimination of suicide gene-expressing T cells affects engraftment, graft-versus-host disease, and graft-versus-leukemia after allogeneic bone marrow transplantation.

Suicide gene therapy is one approach being evaluated for the control of graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We recently constructed a novel chimeric suicide gene in which the entire coding region of HSV thymidine kinase (HSV-tk) was fused in-frame to the extracellular and transmembrane domains of human CD34 (DeltaCD34-tk). DeltaCD34-tk is an attractive candidate as a suicide gene in man because of the ensured expression of HSV-tk in all selected cells and the ability to rapidly and efficiently purify gene-modified cells using clinically approved CD34 immunoselection techniques. In this study we assessed the efficacy of the DeltaCD34-tk suicide gene in the absence of extended ex vivo manipulation by generating transgenic animals that express DeltaCD34-tk in the peripheral and thymic T cell compartments using the CD2 locus control region. We found that DeltaCD34-tk-expressing T cells could be purified to near homogeneity by CD34 immunoselection and selectively eliminated ex vivo and in vivo when exposed to low concentrations of GCV. The optimal time to administer GCV after allogeneic BMT with DeltaCD34-tk-expressing transgenic T cells was dependent on the intensity of the conditioning regimen, the leukemic status of the recipient, and the dose and timing of T cell infusion. Importantly, we used a controlled graft-vs-host reaction to promote alloengraftment in sublethally irradiated mice and provide a graft-vs-leukemia effect in recipients administered a delayed infusion of DeltaCD34-tk-expressing T cells. This murine model demonstrates the potential usefulness of DeltaCD34-tk-expressing T cells to control GVHD, promote alloengraftment, and provide a graft-vs-leukemia effect in man.

Animals↗