Graft Versus Leukemia in Humans

Butturini, Anna; Gale, Robert Peter

doi:10.1007/978-1-4615-2013-9_14

Cited by 7 publications

(3 citation statements)

References 73 publications

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“…8 Allogeneic blood and marrow transplantation is an active form of such treatment frequently used in younger patients. 9,10 Graft versus leukemia (GVL) effects have been documented in animal and human settings to be mediated by both antigen specific cytotoxic lymphocytes 11,12 and by NK cells. 13 As might be expected, these activities operate most efficiently when the burden of residual leukemia in patients is small, as in patients who are in complete remission but are expected to experience disease relapse.…”

Section: A Non-coding Cationic Lipid Dna Complex Produces Lasting Antmentioning

confidence: 99%

A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects

Keasey

Herse

Chang

et al. 2010

Cancer Biology & Therapy

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Cationic lipid DNA complex (CLDC) is an immunostimulatory preparation that has significant anti-leukemic effects in multiple murine models of leukemia: BCR-ABL(+) myelogenous leukemia in C3H/HeJ animals and myelomonocytic leukemia in BALB/c mice. Following leukemic challenge, CLDC treatment inhibits tumor cell growth in vivo and extends survival, sometimes resulting in apparent eradication of tumor cells. CLDC induces multiple cytokines including interferon-gamma (IFNγ), and intravenous treatment results in a more rapid and robust response than subcutaneous treatment. IFNγ is induced in a dose-dependent manner, and tachyphylaxis results from repeated doses of CLDC. Tachyphylaxis of therapeutic effects is exacerbated at higher doses, thus the optimal survival benefits are seen at intermediate doses. Animals whose leukemia has been successfully treated with CLDC exhibit a survival advantage when faced with a secondary leukemic challenge, suggesting the existence of an adaptive anti-leukemic response. This work demonstrates the effectiveness of CLDC in multiple experimental leukemias and is consistent with a stimulation of a lasting TH(1) anti-leukemic immune response.

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Section: A Non-coding Cationic Lipid Dna Complex Produces Lasting Antmentioning

confidence: 99%

A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects

Keasey

Herse

Chang

et al. 2010

Cancer Biology & Therapy

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“…Increasing evidence has indicated that the immune system can play a role in the destruction of leukemic cells if immune system is stimulated appropriately by cytokines such as interleukin-2 and GM-CSF, which can lead to an improvement of overall survival of leukemic patients (Rojas et al, 2003;Fujimura et al, 2004). The fact that bone marrow transplantation with allogeneic cells causes graft versus leukemia provides strong evidence that the host immune system is capable of controlling leukemia (Butturini and Gale, 1995;Platzbecker et al, 2004). These and other findings (O'Keefe et al, 2004) suggest that impairment of leukemia-specific immune responses occurs in leukemia patients, and this abnormality may be due to oncoproteins, such as BcrAbl in chronic myeloid leukemia, which cause immune dysfunction in hematopoietic cells (Dong et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Vaccination with leukemia cells expressing cell-surface-associated GM-CSF blocks leukemia induction in immunocompetent mice

et al. 2006

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The fundamental basis for immunotherapy of leukemia is that leukemic cells express specific antigens that are not expressed by normal hematopoietic cells. However, the host immune system appears to be tolerant to leukemia cells. To overcome this tolerance, we vaccinated immunocompetent mice with murine leukemia cells (WEHI-3B and BCR-ABL þ 32D cells) transduced with a specifically constructed transmembrane form of granulocytemacrophage colony-stimulating factor (tmGM-CSF). The transduced cells expressed tmGM-CSF on the cellsurface. To determine whether tmGM-CSF-expressing WEHI-3B leukemia cells would prevent leukemia formation as a vaccine, immunocompetent mice (BALB/c and C3H/HEJ) were immunized with lethally irradiated murine leukemia cells expressing cell-surface tmGM-CSF before challenging mice with murine leukemia cells. Two immunocompetent mouse models were investigated, either WEHI-3B cells in BALB/c mice or BCR-ABL þ 32D cells in C3H/HEJ mouse. The results showed that 100% of WEHI-3B/tmGM-CSF-vaccinated BALB/c mice and about 65% of 32D þ BCR-ABL/tmGM-CSFvaccinated C3H/HEJ mice were protected from leukemia after leukemia cell challenge, whereas all non-vaccinated mice succumbed to leukemia. Spleen and marrow cell suspensions from vaccinated mice challenged with WEHI-3B cells lacked detectable GFP þ WEHI-3B cells at 82 days post-challenge. A significant delay of death was observed in C3H/HEJ mice challenged with the very aggressive DA-1 cell line expressing BCR-ABL. Vaccination of mice with WEHI-3B/CD40L cells protected 80% of the mice from the WEHI-3B challenge. Notably, 60% of the WEHI-3B/BALB/c mice were also protected from leukemia when WEHI-3B/tmGM-CSF vaccination was carried out after the leukemia challenge. In order to determine whether cellular immunity is involved in this vaccine-mediated protection, either CD4 þ or CD8 þ T cells were depleted from mice after the WEHI-3B/tmGM-CSF vaccination. The results indicate that CD8 þ T-cells mediated the protective immune response provided by the irradiated tmGM-CSF-expressing WEHI-3B cells.In addition, vaccination of nude mice did not provide protection from WEHI-3B leukemia induction. Importantly, 80% of non-vaccinated mice were also protected from a WEHI-3B cell challenge after receiving spleen cells from vaccinated mice 1 day before challenge with leukemia cells. These results indicate that overexpression of tmGM-CSF on the leukemia cell-surface can enhance the recognition of leukemic cells by CD8 þ T cells, and can either prevent or significantly delay leukemia induction. These findings suggest that injection of irradiated leukemia cells expressing cell-surface-bound GM-CSF has the potential as an immunological approach to treat leukemia.

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“…3,4 T-cell depletion (TCD) effectively prevents GVHD, but increases the risk of graft failure and leukemic relapse. 5,6 One method of decreasing the risk of graft failure with TCD is to increase the immunosuppression of the preparative regimen. Thus, most preparative regimens for MUD BMT include total body irradiation (TBI).…”

mentioning

confidence: 99%

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens

Kalaycio¹,

Rybicki²,

Pohlman³

et al. 2004

Bone Marrow Transplant

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Summary:The role of T-cell depletion (TCD) to prevent graftversus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and VP-16 50 mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8 þ T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67% of evaluable patients developed acute GVHD, severe grade III-IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8 þ TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8 þ TCD for AML is a potentially curative treatment option.

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Graft Versus Leukemia in Humans

Cited by 7 publications

References 73 publications

A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects

A non-coding cationic lipid DNA complex produces lasting anti-leukemic effects

Vaccination with leukemia cells expressing cell-surface-associated GM-CSF blocks leukemia induction in immunocompetent mice

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens

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