Attenuated, Oncolytic, but Not Wild-Type Measles Virus Infection Has Pleiotropic Effects on Human Neutrophil Function

Zhang, Yu; Patel, Bijendra; Dey, Aditi; Ghorani, Ehsan; Rai, Lena; Elham, Mohammed; Castleton, Anna; Fielding, Adele K.

doi:10.4049/jimmunol.1102262

Cited by 23 publications

(18 citation statements)

References 47 publications

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“…Interestingly, in the current model, metastases rarely were found in the axillary lymph nodes (which drain the trunk), a location sited in previous studies. 48,49 Instead, the primary sight of metastatic disease was the renal lymph node, which drains the lumbar area, kidney, and perirenal area, as well as the iliac and paraaortic lymph nodes that drain the gluteal area. 48 …”

Section: Discussionmentioning

confidence: 99%

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

Doty¹,

Liu²,

McFadden³

et al. 2013

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Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15]) were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred- and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral replication of recombinant MXYV contributes to the antitumoral effect of MYXV treatment in this melanoma model. These findings support the inclusion of neutrophil chemotaxins in recombinant poxvirus oncolytic virotherapy.

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Section: Discussionmentioning

confidence: 99%

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

Doty¹,

Liu²,

McFadden³

et al. 2013

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“…12 Furthermore, ALL-infiltrating neutrophils may become activated to secrete antitumor cytokines and TRAIL, a notion supported by a recent proof of principle study. 51 A further factor-enhancing efficacy of MV-Edm against ALL in the mouse model was efficient intraleukemic viral spread. The absence of immunity against measles virus in mice favored intraleukemic spread and thus leukemolytic efficacy of MV-Edm in vivo.…”

Section: Discussionmentioning

confidence: 99%

Attenuated measles virus controls pediatric acute B-lineage lymphoblastic leukemia in NOD/SCID mice

Lühl¹,

Zirngibl²,

Dorneburg³

et al. 2014

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nproducts inhibit replication and spread of MV. Deficiency in suppression of the type I IFN response in normal cells is part of the attenuated phenotype of vaccine strains of MV. 40,41 Many solid cancer cells are known to have a decreased IFN response (reviewed by Pitha 42 ), which can be exploited for oncolytic virotherapy. 43,44 It is unknown whether ALL cells have a deficient type I IFN response impacting on their response to viral infection, whether they harbor defects in the RIG-I/MDA-5 pathway or whether other mechanisms of increased susceptibility to attenuated MV are operative in ALL cells.In this study, we set out to investigate the hitherto unknown susceptibility of pediatric ALL to attenuated MV. Using our large collection of primary pediatric ALL propagated in immunodeficient mice 45 we show that MVEdm is remarkably effective against acute B-lineage ALL in the pre-clinical setting. Methods ALL cell lines, xenografts and patient samplesThe ALL cells lines Jurkat, CCRF-CEM, MOLT-4, REH, RS4;11 and NALM-6 were purchased. ALL cells from patients propagated in non-obese diabetic/severe combined immunodeficient mice (NOD/SCID) mice were procured from spleen tissue at a purity of above 90%. Primary patient ALL samples were obtained at diagnosis from pediatric patients with de novo ALL. Most patients were enrolled in the ALL-BFM study protocols. Patients' characteristics for the xenografts are listed in the Online Supplementary Table S1. The human study protocol was approved by the Ethical Review Board of the University Medical Center Ulm in accordance with the Declaration of Helsinki. Cell lines, xenografts and primary ALL cells were cultured in RPMI 1640 with 10% fetal calf serum, L-glutamine, penicillin and streptomycin. Human ALL NOD/SCID mouse modelNOD/SCID mice at a median age of 8-10 weeks (w) were used. Housing and treatment of animals were in accordance with state guidelines. ALL cells were injected into a lateral tail vein. After grafting, blood samples were evaluated at 1-w or 2-w intervals for human leukemia cells by determining CD45 + Ly5 -cells using flow cytometry. At necropsy cell suspensions from spleen, bone marrow and meninges were prepared and brains were procured. The presence of leukemic cells in the suspensions was determined by FACS analysis. Virus infectionEx vivo cells were infected with MV-Edm at a MOI of 1. ALL cell lines, xenografts, patient samples, peripheral blood mononuclear cells (PBMC), B and T cells were infected in serum-free RPMI 1640 medium at 37°C for 3 hours (h). For hematopoietic stem cells (HSC) serum-free IMDM medium was used. Medium was changed depending on the experiment. Replication of MV-Edm in Jurkat cells and PBMCTo quantitate viral replication in Jurkat cells, lysates were harvested 3, 24, 48 and 72 h after infection and added to Vero indicator cells. Syncytia were determined 72 h later. To compare replication in Jurkat cells to PBMC, lysates of PBMC were collected 72 h after infection and added to Vero ...

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“…Notably, cell death mediated by OVs seems to receive a significant contribution from neutrophils and has been reported and reviewed elsewhere [68,69,70]. In fact, often observed following therapy, neutrophils could be even more important than CTLs in driving OV-mediated cell death [69,71,72].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

From Benchtop to Bedside: A Review of Oncolytic Virotherapy

et al. 2016

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Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not fully understood, major advances have been made in our understanding of how OVs function and interact with the host immune system, resulting in the recent FDA approval of the first OV for cancer therapy in the USA. This review provides an overview of the history of OVs, their selectivity for cancer cells, and their multifaceted mechanism of antitumor action, as well as strategies employed to augment selectivity and efficacy of OVs. OVs in combination with standard cancer therapies are also discussed, as well as a review of ongoing human clinical trials.

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Attenuated, Oncolytic, but Not Wild-Type Measles Virus Infection Has Pleiotropic Effects on Human Neutrophil Function

Cited by 23 publications

References 47 publications

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

Attenuated measles virus controls pediatric acute B-lineage lymphoblastic leukemia in NOD/SCID mice

From Benchtop to Bedside: A Review of Oncolytic Virotherapy

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