Induction of tumor immunity following allogeneic stem cell transplantation
ABSTRACT The curative potential of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for many hematologic malignancies derives in large part from reconstitution of normal donor immunity and the development of a potent graft-versus-leukemia (GVL) immune response capable of rejecting tumor cell in vivo. Elucidation of the mechanisms of GVL by studies of animal models and analysis of clinical data has yielded important insights into how clinically effective tumor immunity is generated following allo-HSCT. These studies have identified NK cells and B cells as well as T cells as important mediators of the GVL response. A variety of antigenic targets of the GVL response have also been identified, and include tumor-associated antigens as well as minor histocompatibility antigens. The principles of effective GVL can now be applied to the development of novel therapies that enhance the therapeutic benefit of allogeneic HSCT while minimizing the toxicities associated with treatment. Moreover, many components of this approach that result in elimination of tumor cells following allogeneic HSCT can potentially be adapted to enhance the effectiveness of tumor immunity in the autologous setting.
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ABSTRACT: Purpose: The graft-versus-leukemia (GVL) reaction is an important example of immune-mediated tumor destruction. A coordinated humoral and cellular response accomplishes leukemia cell killing, but the specific targets remain largely uncharacterized. To learn more about the antigens that elicit antibodies during GVL reactions, we analyzed advanced myelodysplasia (MDS) and acute myeloid leukemia (AML) patients who received an autologous, granulocyte-macrophage colony stimulating factor (GM-CSF) secreting tumor cell vaccine early after allogeneic hematopoietic stem cell transplantation (HSCT). Experimental Design: A combination of tumor-derived cDNA expression library screening, protein microarrays, and antigen-specific ELISAs were employed to characterize sera obtained longitudinally from 15 AML/MDS patients who were vaccinated early after allogeneic HSCT. Results: A broad, therapy-induced antibody response was uncovered, which primarily targeted intracellular proteins that function in growth, transcription/translation, metabolism, and homeostasis. Unexpectedly, antibodies were also elicited against eight secreted angiogenic cytokines that play critical roles in leukemogenesis. Antibodies to the angiogenic cytokines were evident early after therapy, and in some patients manifested a diversification in reactivity over time. Patients that developed antibodies to multiple angiogenic cytokines showed prolonged remission and survival. Conclusions: These results reveal a potent humoral response during GVL reactions induced with vaccination early after allogeneic HSCT and raise the possibility that antibodies, in conjunction with NK cells and T lymphocytes, may contribute to immune-mediated control of myeloid leukemias. Copyright © 2014, American Association for Cancer Research.Clinical Cancer Research 12/2014; DOI:10.1158/1078-0432.CCR-14-1956 · 8.19 Impact Factor
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ABSTRACT: BACKGROUND Allogeneic stem cell transplantation (ASCT) has been a treatment option for patients with serious diseases of the blood and haematopoietic organs in Norway since 1985. Such treatment is potentially curative for selected patients who have a relatively short predicted survival with other treatment modalities. This article summarises the experience and results from ASCT at Oslo University Hospital Rikshospitalet.MATERIAL AND METHOD The study included all of the 734 adult patients who had undergone allogeneic stem cell transplantation at the Department of Haematology, Rikshospitalet, later Oslo University Hospital Rikshospitalet, from November 1985 to October 2012.RESULTS At the time of analysis, altogether 384 patients were alive, and the five and ten-year survival rates were 54 % and 48 % respectively. The median follow-up time was six years. A total of 339 patients (46 %) had developed acute graft-versus-host disease (GvHD), and 250 (73 %) of these had GvHD ≥ grade II. Altogether 280 out of 602 patients who lived ≥ 100 days after the transplantation (46.5 %) developed chronic GvHD. The most frequent causes of death included recurrence of the initial disease in 116 patients (33.1 %), multi organ failure after transplantation in 88 patients (25.4 %), infections in 54 patients (16 %) and GvHD in 33 patients (9.4 %).INTERPRETATION ASCT is a treatment option with a curative potential for patients with serious haematological diseases when other forms of treatment provide few prospects for recovery. The total survival rate in our study is in accordance with international results for the same time period, and the indications have consistently been in line with what is accepted internationally.
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ABSTRACT: Donor lymphocyte infusion (DLI) is an established and potentially curative immune therapy for relapsed leukemia after hematopoietic stem cell transplant (HSCT). Herein, we describe the utility of DLI as a tractable model system to glean fresh insights into understanding and predicting effective anti-leukemia immunity.OncoImmunology 03/2014; 3:e28187. DOI:10.4161/onci.28187 · 6.28 Impact Factor