Immunological Effects of Interferon-alpha on Chronic Myelogenous Leukemia

Castro, Fabíola Attié de; Palma, Patrícia Vianna Bonini; Morais, F. R.; Simões, Belinda Pinto; Carvalho, Paulo V. B.; Ismael, Sebastião José; Lima, Carmen Passos; Voltarelli, Júlio César

doi:10.1080/1042819031000110973

Cited by 29 publications

(18 citation statements)

References 21 publications

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“…IFN is known to normalize some activities of the immune system that are otherwise impaired in patients with CML. For example, IFN alpha restores NK and T-cell function in patients with CML 46,47 and induces CML mononuclear cells to differentiate toward antigen-presenting dendritic cells. 46 Our findings, together with the prior clinical observation that ICSBP levels are restored in patients with CML who respond to IFN alpha, suggest a key role for ICSBP and CCL15 and CCL23, the human orthologues of CCL6 and CCL9, respectively, in mediating the therapeutic effects of IFN alpha in CML.…”

Section: Discussionmentioning

confidence: 99%

ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

Nardi

Naveiras

Azam

et al. 2009

Blood

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Section: Discussionmentioning

confidence: 99%

ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

Nardi

Naveiras

Azam

et al. 2009

Blood

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“…We chose to focus on hIFN-␤ because of its reported stronger antiproliferative activity against other tumor types. [11][12][13][14] The use of our immunodeficient model offers an opportunity to selectively assess the antiproliferative effects of hIFN-␤ in the absence of its immunomodulatory 15 and direct antiangiogenic properties, 16 because hIFN-␤ does not cross-react with its cognate murine receptor. 17 In our initial experiments, recombinant hIFN-␤ was administered either subcutaneously (2000 IU per mouse thrice weekly) or intravenously (60 000 IU per mouse daily) into cohorts of ␤2m null NOD/SCID mice a week after intravenous injection with HL-60 cells with an additional untreated cohort (n ϭ 10) serving as controls.…”

Section: Effects Of Ifn-␣ and ␤ On Aml Cell Lines In Vitro And In Vivomentioning

confidence: 99%

Continuous delivery of human type I interferons (α/β) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model

Benjamin

Khwaja

Singh

et al. 2006

Blood

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IntroductionDespite significant advances in the treatment of acute myeloid leukemia (AML), long-term survival is limited to about 30% of patients; hence the urgent need for alternative treatment strategies. 1 Type I IFNs (IFN-␣ and IFN-␤) have shown considerable promise in the treatment of many solid tumors 2 and have proven to be highly effective in several hematologic malignancies, including chronic myeloid leukemia. 3 Although in vitro studies with type I IFNs have shown impressive cytotoxicity against AML cells, 4 their antitumor efficacy in vivo remains largely untested in animal models or in patients with AML, except for the United Kingdom Medical Research Council (UK MRC) AML 11 trial, in which maintenance treatment with IFN-␣ failed to prevent relapse or improve overall survival. 5 However, it remains unclear whether this lack of efficacy was related to poor antileukemic effect in vivo or a failure to maintain stable therapeutic IFN-␣ levels because of its short half-life. 6 In this study, we compare the antileukemic effects of IFN-␣ and ␤ against a variety of AML cell lines in a xenograft model. Two different schedules of administration were used: the traditional high-dose multiple bolus injection approach using recombinant IFN-␤, as well as continuous low-dose delivery, achieved here through gene transfer with adenoassociated virus (AAV) vectors. Materials and methods Cell culture and cell proliferation assaysThe AML cell lines HL-60, KG1␣, AML193, and OCI AML5 were cultured in RPMI medium with 10% fetal calf serum. GM-CSF at 100 pg/mL was added to the medium for AML193 and OCI AML5 cells. Frozen AML cells obtained from leukopheresis of patients with poor-risk AML were used for our primary AML experiments. Cell lines were seeded in 96-well plates at 20 000 cells per well to which varying concentrations of recombinant human IFN␤-1a or IFN␣-2b were added. Following stimulation for 3 or 5 days, cells were pulsed with 3 H-thymidine (0.5 Ci [0.0185 MBq] per well) for 4 hours, harvested, and 3 H-thymidine incorporation measured by scintillation counting. AAV2/8 hIFN-␤ and AAV2/8 hFIX vector productionAs previously described, recombinant AAV vectors pseudotyped with serotype 8 capsid were generated by transient transfection of 293T cells using either the pAV2 CAGG hIFN-␤ or pAV2 CAGG human factor IX (hFIX) control vector plasmids together with pAAV2/8 packaging and pHTGI adeno helper plasmids. 7 The AAV2/8 vectors were purified using an ion exchange chromatography method, and slot blot analysis was used to determine the titer of the vectors. Human IFN␣-2b and IFN␤-1a bioassayPlasma levels of human IFN-␣ and IFN-␤ were determined using a validated antiviral assay with a sensitivity of 0.5 IU/mL as described before. 8

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“…In part, this may be due to the capacity of interferon-a to modify host responses that support tumor growth as well as host immunity. 2,4,54,55 Additional evidence for hybrid IFNa2a1 induced stimulation of immune cells could be discerned in the differential effect on tumors in immunocompetent BALB/c mice versus immunocomprimised SCID-BEIGE mice. Expression in BALB/c mice after four i.t.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, this rAd vector effect is augmented by systemic exposure to IFNa2a1 (Figure 2b and c), which has immunostimmulatory function. 2,4,54,55 However, immune responses to adenovirus also limit transgene expression. 57,58 The limitation of immune clearance may be overcome with new less immunogenic generation of vectors.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus delivery provides extended interferon-α exposure and augments treatment of metastatic carcinoma

Brin¹,

Atencio²,

Helmich³

et al. 2006

Cancer Gene Ther

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Type I interferons (e.g. IFNa2b) have been successfully used to treat a variety of hematological malignancies, but have not been efficacious for treatment of most solid tumors. We tested the hypothesis that delivery of type I interferon utilizing recombinant adenovirus (rAd) vectors may improve treatment efficacy of metastatic carcinomas by providing increased interferon exposure resulting from continuous transgene expression. Treatment of mice with a rAd-vector expressing hybrid-IFN (rAd-IFNa2a1) inhibited 4T1 mammary carcinoma tumor growth and induced tumor regression in a dose-dependent manner. Moreover, rAd-IFNa2a1 treatment reduced hepatic and pulmonary metastatic burden. A comparison of local and systemic routes of administration demonstrated that intratumoral delivery of rAd-IFNa2a1 was sufficient for inhibition of tumor growth. Moreover, it reduced toxicity associated with high-dose systemic IFNa2a1 exposure. Interestingly, antitumor activity following intratumoral treatment was due, in part, to the immunostimulatory capacity of the rAd vector component. Furthermore, systemic administration of rAd-IFNa2a1 potentiated the immunotherapeutic effect induced by local intralesional delivery of empty-rAd vector. These results suggest continuous interferon-a exposure may provide improved antitumor responses for metastatic carcinomas. Additionally, immunostimulatory responses induced by rAd-IFNa2a1 may mitigate the immune-evasive tumor microenvironment.

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Immunological Effects of Interferon-alpha on Chronic Myelogenous Leukemia

Cited by 29 publications

References 21 publications

ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

Continuous delivery of human type I interferons (α/β) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model

Adenovirus delivery provides extended interferon-α exposure and augments treatment of metastatic carcinoma

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