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

Abstract

© 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 ...

Potential and clinical translation of oncolytic measles viruses

“…These include: adult acute lymphoblastic leukemia and chronic lymphocytic leukemia [58,59], adult T cell leukemia/lymphoma [60], atypical teratoid rhabdoid tumor [61], breast cancer [44,62], cholangiocarcinoma [63], colorectal cancer [64], cutaneous T cell lymphoma [65], gliomas [66], head and neck squamous cell cancer [67], hepatoblastoma [68], hepatocellular cancer [51], lung cancer [64,69,70], malignant peripheral nerve sheath tumor [71], mantle cell lymphoma [72], medulloblastoma [53,73,74], melanoma [75,76], mesothelioma [77,78], multiple myeloma [47,79], non-Hodgkin’s lymphoma [80], osteosarcoma [81], ovarian cancer [52,82,83], pancreatic cancer [49,50,84], prostate cancer [45,85], renal cell carcinoma [86], rhabdomyosarcoma [87], and splenic marginal zone lymphoma [88]. …”

“…To date, there have only been two oncolytic viruses that have achieved regulatory approval worldwide, based on phase III data; both involved intratumorally injected attenuated viruses. H101, an E1B attenuated adenovirus, was approved in 2005 in China after demonstrating superior response rates in combination with chemotherapy over chemotherapy alone in patients with squamous cell cancer of the head and neck or esophagus [5,6]. Similarly, talimogene laherparepvec (T-VEC), an oncolytic herpes virus (HSV1) engineered to produce granulocyte macrophage colony-stimulating factor (GM-CSF), demonstrated a superior durable response rate and promising overall survival in patients with melanoma, becoming the first oncolytic virus approved in the USA and Europe in 2015 [7].…”

Induction of Cell Death in the Human Acute Lymphoblastic Leukemia Cell Line Reh by Infection with Rotavirus Isolate Wt1-5

“…Within the rapid progress of new therapeutic strategies for the treatment of hematological malignancies, OVs continue to be a promising tool for effective treatments. Attempts to treat hematological malignancies with OVs have also included vesicular stomatitis virus (VSV) [ 40 , 41 ], live attenuated measles virus (MV) [ 42 , 43 ], oncolytic parvovirus [ 44 ], myxoma virus (MYXV) [ 45 , 46 ], and oncolytic poxvirus [ 47 , 48 ]. OVs have shown both advantages and limitations as therapy tools, including challenges and opportunities to improve treatment tolerability.…”

Signaling lymphocytic activation molecules Slam and cancers: friends or foes?

“…Studies employing MV as an oncolytic virotherapy agent have suggested that SLAMF1 is a therapeutic target in certain hematological diseases. For instance, in mouse models, this therapeutic strategy has been evaluated using attenuated MV to target certain acute lymphoblastic leukemia (ALL) [ 27 ]. Attenuated MV efficiently killed leukemia cells without affecting normal human blood cells and progenitors.…”

“…Attenuated MV efficiently killed leukemia cells without affecting normal human blood cells and progenitors. A few intravenous injections of attenuated MV were able to eradicate leukemic blasts [ 27 ]. Takeda et al reported higher susceptibility of lymphoma cells to attenuated therapeutic MV vaccine strain (CAM-70)-induced cytolysis due to elevated expression of SLAMF1 in these cells.…”