Anti-leukemic activity of Lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

Sutherland, May Kung; Yu, Changpu; Lewis, Timothy S.; Miyamoto, Jamie B.; Morris-Tilden, Carol A.; Jonas, Mechthild; Sutherland, Jennifer; Nesterova, Albina; Gerber, Hans‐Peter; Sievers, Eric L.; Grewal, Iqbal S.; Law, Che‐Leung

doi:10.4161/mabs.1.5.9288

Cited by 38 publications

(32 citation statements)

References 55 publications

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“…While no preclinical or clinical data on the former strategy are yet available, the latter has already been tested in clinical studies, in which it showed a moderate success, 39,40 and its mechanisms of action are currently under analysis. 41 We believe, however, that a T-cell-based, CAR-mediated targeting of AML might be a potentially better approach. T cells, in fact, might have superior homing capabilities, can amplify the anti-tumor immune responses through targetspecific cytokine release, and, last but not the least, can proliferate after contact with tumor cells, thus ensuring a boosted and persistent anti-tumor activity and, perhaps, complete eradication of the disease.…”

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confidence: 99%

Cytokine-induced killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors

Marin¹,

Pizzitola²,

Agostoni³

et al. 2010

Haematologica

104

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The online version of this article has a Supplementary Appendix. BackgroundCytokine-induced killer cells are ex vivo-expanded cells with potent antitumor activity. The infusion of cytokine-induced killer cells in patients with acute myeloid leukemia relapsing after allogeneic hematopoietic stem cell transplant is well tolerated, but limited clinical responses have been observed. To improve their effector functions against acute myeloid leukemia, we genetically modified cytokine-induced killer cells with chimeric receptors specific for the CD33 myeloid antigen. Design and MethodsSFG-retroviral vectors coding for anti-CD33-ζ and anti-CD33-CD28-OX40-ζ chimeric receptors were used to transduce cytokine-induced killer cells. Transduced cells were characterized in vitro for their ability to lyse leukemic targets (4-hour 51 chromium-release and 6-day co-cultures assays on human stromal mesenchymal cells), to proliferate ( 3 H-thymidine-incorporation assay) and to secrete cytokines (flow cytomix assay) after contact with acute myeloid leukemia cells. Their activity against normal CD34 + hematopoietic progenitor cells was evaluated by analyzing the colony-forming unit capacity after co-incubation. ResultsCytokine-induced killer cells were efficiently transduced with the anti-CD33 chimeric receptors, maintaining their native phenotype and functions and acquiring potent cytotoxicity (up to 80% lysis after 4-hour incubation) against different acute myeloid leukemia targets, as also confirmed in long-term killing experiments. Moreover, introduction of the anti-CD33 chimeric receptors was accompanied by prominent CD33-specific proliferative activity, with the release of high levels of immunostimulatory cytokines. The presence of CD28-OX40 in chimeric receptor endodomain was associated with a significant amelioration of the anti-leukemic activity of cytokine-induced killer cells. Importantly, even though the cytokine-induced killer cells transduced with anti-CD33 chimeric receptors showed toxicity against normal hematopoietic CD34 + progenitor cells, residual clonogenic activity was preserved. ConclusionsOur results indicate that anti-CD33 chimeric receptors strongly enhance anti-leukemic cytokine-induced killer cell functions, suggesting that cytokine-induced killer cells transduced with these molecules might represent a promising optimized tool for acute myeloid leukemia immunotherapy.Key words: chimeric T-cell receptor, acute myeloid leukemia, CD33, cell therapy, gene therapy. Haematologica 2010;95(12):2144-2152. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n

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confidence: 99%

Cytokine-induced killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors

Marin¹,

Pizzitola²,

Agostoni³

et al. 2010

Haematologica

104

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“…33 In a previous study, we reported that lintuzumab significantly prolonged the survival of mice in multiple models of AML. 34 Additionally, lintuzumab interacts with effector cells to mediate tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities. In the current study, experiments were undertaken to assess the impact of 5-azacytidine on the ability of lintuzumab to effect anti-leukemic activity.…”

Section: -Azacytidine Enhances the Anti-leukemic Activity Of Lintuzumentioning

confidence: 99%

“…34 In the current study, an aggressive HL60cy model of AML was used to assess the effect of 5-azacytidine on the in vivo activity of lintuzumab. In the HL60cy model, the mice displayed signs of disease (scruffy coat, significant weight loss, hind limb paralysis, buffalo head and presence of palpable tumors) almost three times faster (within 20-30 d) than the HL60 model we reported (40-80 d for disease symptoms to develop).…”

Section: -Azacytidine Enhances the In Vivo Activity Of Lintuzumab Inmentioning

confidence: 99%

“…In the HL60cy model, the mice displayed signs of disease (scruffy coat, significant weight loss, hind limb paralysis, buffalo head and presence of palpable tumors) almost three times faster (within 20-30 d) than the HL60 model we reported (40-80 d for disease symptoms to develop). 34 The results of dosing tumor-bearing mice with lintuzumab and 5-azacytidine Fig. 1A).…”

Section: -Azacytidine Enhances the In Vivo Activity Of Lintuzumab Inmentioning

confidence: 99%

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5-Azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

Sutherland

Anderson

et al. 2010

mAbs

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“…CD33 is frequently overexpressed on leukemic blasts, including the stem cell fraction, suggesting it may be an effective therapeutic target (93). Early studies evaluated unconjugated or naked anti-CD33 monoclonal antibodies (mAbs) in AML and reported preclinical efficacy in vivo due to antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent phagocytosis, and modulatory effects on cytokines in the tumor microenvironment (94). Although effective in preclinical models, unconjugated anti-CD33 was only modestly active in phase 1 and 2 clinical trials.…”

Section: Monoclonal Antibodies and Antibody-drug Conjugatesmentioning

confidence: 99%

Emerging therapies for acute myeloid leukemia: translating biology into the clinic

Kavanagh¹,

Murphy²,

Law³

et al. 2017

JCI Insight

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Anti-leukemic activity of Lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

Cited by 38 publications

References 55 publications

Cytokine-induced killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors

Cytokine-induced killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors

5-Azacytidine enhances the anti-leukemic activity of lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

Emerging therapies for acute myeloid leukemia: translating biology into the clinic

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