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Access this article on Remission of Disseminated Cancer After Systemic Oncolytic Published Online: May 13, 2014 Publication stage: In Press Corrected Proof No data is available Need help playing this video? Supplemental Video AbstractMV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored bynoninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 10 TCID tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reductionand resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at alldisease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infectedplasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses oﬀer a promising new modalityfor the targeted infection and destruction of disseminated cancer.
Abbreviations and Acronyms: Oncolytic viruses (OVs) are promising experimental anticancer agents that, because of their complexity and diversity, canincorporate a variety of novel tumor-targeting and cell-killing eady shown clinical promise as immunotherapeutic agents, driving immune-mediated tumor destruction after intratumoral administration inpatients with metastatic e have been reports of localized tumors responding to an intravenously administered , the "oncolytic paradigm," whereby a systemically administered OV targets a disseminatedcancer and initiates a spreading infection that mediates the cancer's destruction, has not yet been clinically Multiple myeloma (MM) is a malignancy of terminally diﬀerentiated plasma cells that diﬀusely infiltrate the bone marrow aswell as form skeletal and/or soft tissue plasmacytomas (focal lesions). Multiple myeloma typically responds well toalkylator-, corticosteroid-, and immune-modulatory drugs and proteasome inhibitors but eventually becomes refractory tothese treatments and is rarely cur eatment modalities such as oncolytic virotherapy are therefore being MV-NIS is a recombinant oncolytic measles virus (MV) derived from an attenuated Edmonston lineage vaccine strain (MV-Edm) that was adapted to grow on human cancer (HeLa) cells, then engineered to express the human thyroidal sodiumiodide symporter (NIS) so that its in vivo spread can be noninvasively monitored by radioiodine single-photon emissioncomputed tomography (SPECT)–computed tomography (CT) imaging. paramyxovirus with a negative-sense RNA genome whose surface glycoproteins not only mediate the entry of the virus intosusceptible target cells but also drive the fusion of infected cells with adjacent uninfected measles, MV-Edm, and hence MV-NIS, targets CD46 as a cell-entry and cell-fusion receptor complement regulatory protein that, fortuitously, is highly expressed on human myeloma cells, making them abnormallysusceptible to MV-NIS infection, syncytium formation, and cell killing.
The antimyeloma eﬃcacy of systemic MV-NIS therapy was found to be dose dependent when the virus was administeredintravenously in myeloma xenograft models. e passively immunized with antimeasles -NIS toxicities were not encountered in preclinical dose-finding studies in CD46 transgenicmice and nonhuman primates, even at the maximum feasible intravenous initiated to determine the maximum tolerated dose of intravenously administered MV-NIS in patients with advanced,refractory eported in detail elsewhere, has a standard cohorts- of-3 design with a first dose level of 6 (50% tissue cultur e infectious dose) of MV-NIS, increasing by 10-fold dose increments to a maximum feasible dose of 50 Eligible patients had relapsing myeloma refractory to approved In this current report, we provide preliminary data on 2 patients from the phase 1 trial. These patients were selected forimmediate reporting because (1) they were the first 2 patients studied at the highest feasible dose level who were alsoseronegative for prior measles exposure and (2) they both had no response to multiple rounds of conventional therapy forMM and were therefore at risk for imminent death. Thus, these 2 patients provided a unique opportunity to determine thesystemic adverse eﬀects of oncolytic virotherapy in the absence of a preexisting antiviral immune response, as well as theresulting eﬀect on tumor burden. Collectively, these patients provided heretofore unreported insights into the feasibility andrisk-to-benefit profile of this novel approach to cancer therapy.
Patients and Methods Selected Study Patients Patient 1 was a 49-year-old woman with heavily pretreated light chain MM who experiencedrelapse while receiving no therapy 9 months after her second autologous stem cell transplant (ASCT). Multiple myelomahad been diagnosed 9 years earlier and treated with thalidomide and dexamethasone followed by consolidative lenalidomide and cyclophosphamide, bortezomib, and and a second ASCT.
Immediately before receiving MV-NIS, she had a rapidly enlarging firm, nontender 3-cm-diameter plasmacytoma emanatingfrom the left frontal bone. The serum λ free light chain level had increased substantially from 2.5 to 8.0 mg/dL (to convert tomg/L, multiply by 10) since her previous clinic visit 2 months earlier. Positron emission tomography (PET)–CT revealedmultifocal osseous progression of her MM when compared with the previous scan obtained immediately before her secondASCT, with enlargement of the glucose-avid lesion in the left frontal bone and new glucose-avid lesions in the left sternalmanubrium, right frontal bone, medial right clavicle, and T11 vertebral body. Bone marrow biopsy, which had yieldedcompletely negative results on day 100 following the ASCT, revealed 3% infiltration with λ light chain–restricted clonalplasma Patient 2 was a 65-year-old woman with relapsing IgA κ MM refractory to all approvedantimyeloma drugs who experienced disease progression while receiving carfilzomib, pomalidomide, and dexamethasonetherapy. Her MM had been diagnosed 7 years earlier and had been treated with local radiotherapy; high-dosedexamethasone; lenalidomide and dexamethasone; single-agent bortezomib; cyclophosphamide, bortezomib, anddexamethasone; ASCT; lenalidomide, bendamustine, and dexamethasone; bortezomib, cyclophosphamide, lenalidomide,and dexamethasone; carfilzomib plus dexamethasone; bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin,cyclophosphamide, and etoposide; and several experimental therapies. Before MV-NIS therapy, she had innumerablepalpable (firm, nontender) soft tissue plasmacytomas, especially in the muscles of her lower extremities, ranging indiameter from 2 to 7 cm. Her hemoglobin level was 8.9 g/dL (to convert to g/L, multiply by 10), and her serum κ free lightchain value had increased from 6.5 mg/dL to 31.1 mg/dL (to convert to mg/L, multiply by 10) over the previous month.
PET-CT revealed numerous fluorodeoxyglucose (FDG)–avid nodules and mass lesions, most prominent below the level ofthe diaphragm and especially in the soft tissues of the legs. Several of these lesions had increased in size and FDG activitysince the previous scan 6 weeks earlier. The largest lesion, located in the left hamstring musculature, measured 74 × 46mm with a maximum standard uptake value of 8.0. Bone marrow biopsy revealed 1% infiltration with κ light chain–restricted clonal plasma cells.
Virus Dose and Location of InfusionIn both patients, the virus, at a dose of 10 TCID , was infused into a superficial arm vein in 100 mL of normal saline over Assessment of Response to Oncolytic VirotherapyThe following methods were used to assess the immediate and delayed eﬀects of the virotherapy as well as itspharmacokinetic profile and its ability to target sites of tumor growth.
Measurement of Temperature, Heart Rate, and Blood Pressure Measurement of physiologic variables during and immediately after virus infusion was performedwith the patient in the sitting position. Heart rate was determined from the radial pulse, and blood pressure was determinedfrom a mechanically cycled Philips IntelliVue MP50 sphygmomanometer. Sublingual temperature was measured using aWelch Allyn SureTemp Plus 690 Device.
Pharmacokinetic Studies Blood samples for early pharmacokinetic studies were obtained at baseline, at 1, 30, 60, 120, and240 minutes after completion of the MV-NIS infusion, and again on days 3, 8, 15, and 42. RNA was extracted and analyzedby quantitative reverse transcription–polymerase chain reaction to determine the number of circulating viral genomes (earlytime points) or N gene messenger RNA transcripts (later time points) in the blood at each time Antimeasles Antibody Titers Neutralizing antimeasles antibody titers were determined using a standard plaque reductionneutralization assay in which serial dilutions of serum were mixed with 250 infectious units of an indicator virus (MV SPECT-CT Imaging Studies Radioiodine uptake was visualized on SPECT-CT obtained 6 hours after oral administration of 5mCi of iodine 123. The scans were obtained at baseline and on days 8, 15, and 28 after virus administration using a PhilipsBrightView SPECT-CT scanner. To suppress thyroidal NIS expression, liothyronine sodium (25 μg, 3 times daily) wasadministered orally for 4 days before the first (baseline) scan and was continued until completion of the day 28 scan.
Eight-Color Plasma Cell Flow Cytometry Mononuclear cells isolated from aspirated bone marrow by Ficoll gradient were stained withantibodies to CD38 (APC), CD138 (PerCP-Cy5.5), CD19 (PE-Cy7), and CD45 (APC-Cy7). They were then fixed-permeabilized and treated with RNAse, followed by staining with antibodies to κ (FITC) and λ (PE) immunoglobulin lightchains and a 15-μM solution of 4′,6′-diamidino-2-phenylindole. A total of 500,000 events were collected on BDFACSCanto II instruments (BD Biosciences) and analyzed using BD FACSDiva software (BD Biosciences) for surfaceimmunophenotype, cytoplasmic immunoglobulin light chain restriction, and DNA content and S phase through analysis of4′,6′-diamidino-2-phenylindole staining.
Systemic Response to Virus Infusions MV-NIS was infused into a superficial vein on the left forearm. The infusion time of 60 minutesincluded a brief interruption for severe headache that responded to diphenylhydramine and acetaminophen. Two hourslater, the patient became febrile (temperature, 40.5 C), tachycar dic (maximum heart rate, 175 beats/min), and hypotensive (minimum blood pressure, 73/33 mm Hg) with severe nausea and vomiting that responded to acetaminophen, meperidine,metoclopramide, lorazepam, and a cooling blanket. Fever recurred over the next few days, and a superficial venousthrombosis extending from the wrist to the upper humerus was detected. The thrombosis was managed conservatively andresolved over the ensuing weeks. At no time following administration of MV-NIS, nor for the preceding 9 months, did shereceive corticosteroids or any drug with known antimyeloma activity.
MV-NIS was infused into a superficial forearm vein. Two hours after infusion, the patient becamefebrile (maximum temperature, 40.0 C), tachycar dic (maximum heart rate, 119 beats/min), and hypotensive (minimum blood pressure, 85/44 mm Hg). The fever responded to acetaminophen. The hypotension was attributed to dehydration and waseﬀectively treated with intravenous hydration. Headache without neurologic deficit responded to intravenous morphine.
Recurrences of fever during the first week after virus infusion resolved spontaneously within a few hours.
Antiviral Antibody ResponseNeither of the patients had detectable neutralizing antimeasles antibodies before therapy, but both of them had high serumtiters 6 weeks after virus administration ( TableMeasles Genome Copy Numbers in Peripheral Blood After MV-NIS MV-N RNA copy number (×10 /
Time from infusion Post-MV (day 42) MV = measles virus; MV-N = measles virus N gene; ND = not done; PRN = plaque reduction neutralization.
Antimeasles antibody titers were determined by PRN assay. The reciprocal of PRN titers is shown for before and after MV treatment.
Effect on Tumor BurdenResponse data are summarized in The level of the involved serum free light chain decreased considerably in bothpatients , A). In patient 1, the λ free light chain level declined rapidly into the reference range; it remained normal at7 months after therapy but was minimally increased (2.9 mg/dL) 9 months posttherapy. In patient 2, the κ free light chainlevel decreased rapidly to 25% of its initial value, but this decline was not maintained at the 6-week time point. Bonemarrow aspirates and biopsies were obtained 6 weeks after therapy and were compared with baseline samples ,B). In both patients, the bone marrow plasmacytosis resolved completely, leaving no morphologic or immunophenotypicevidence of a plasma cell proliferative disorder in the posttherapy bone marrow samples. Thirty-six hours after MV-NISinfusion, patient 1 noted that the plasmacytoma on her left forehead had softened and started to shrink, and by 6 weeks, itwas no longer palpable. Patient 2 also had the early impression that her plasmacytomas were shrinking, having becometender and painful 1 week after therapy, but by 6 weeks, there was no objective change in their size. Six weeks aftertherapy, FDG PET-CT scans were compared with baseline pretherapy scans ( C). The scan in patient 1 showedsubstantial improvement in all 5 previously noted lesions. There was almost complete resolution of the FDG-avid soft tissuemass occupying the lytic lesion in the left frontal bone. Further, there was a considerable reduction of maximum standarduptake value in the lytic lesions in the right frontal bone, medial right clavicle, and sternum and resolution of the focus invertebra T11. A repeated scan 6 months after therapy revealed minimal FDG uptake in the right frontal lesion and nodiscernible uptake in the remaining lesions. By 9 months after therapy, there was increasing FDG uptake in the right frontallesion. Local radiotherapy was administered because the remainder of the skeletal lesions were FDG negative and onrepeated bone marrow biopsy, results remained morphologically and immunophenotypically negative by flow cytometry.
The 6-week posttherapy scan in patient 2 revealed increased size and FDG uptake in most of the soft tissue lesions,although a few lesions did have varying degrees of improvement, including resolution of a focus of uptake adjacent to thedescending aorta and another in the lateral aspect of the right Figure 1Clinical response to systemically administered MV-NIS. A, Serial free light chain (FLC)measurements in patients 1 and 2 as a surrogate of myeloma tumor burden, increasing atmyeloma relapse and decreasing after successful therapy. Asterisks indicate the timing ofrelevant bone marrow (BM) and positron emission tomography–computed tomography(PET-CT) examinations. B, High-sensitivity 8-color plasma cell (PC) flow cytometryperformed on pretherapy BM samples from both patients (left panels) shows CD38- andCD138-positive, CD19-negative monoclonal PCs (λ-restricted in patient 1, κ-restricted inpatient 2) with hyperdiploid DNA content. In these same studies performed on BMsamples obtained 6 weeks after therapy (right panels), the abnormal PCs are not present.
C, Alternate coronal PET-CT sections at the level of the left frontal plasmacytoma in patient 1 before and 7 weeks afterMV-NIS therapy. Far right panel shows higher magnification of the middle sections, focusing on the plasmacytoma.
Note the pretherapy cerebral compression and altered skin contour that normalize after therapy. ASCT = autologousstem cell transplant; DAPI = 4′,6′-diamidino-2-phenylindole; MV = measles virus; UNL = upper normal limit.
SPECT-CT Imaging Studies to Monitor Virus SpreadMV-NIS–infected cells express the thyroidal sodium iodide symporter (NIS) and therefore concentrate radioactive iodide.
Radioiodine SPECT-CT scans from patients 1 and 2 provided clear evidence of tumor-targeted MV-NIS infection (Radioiodine uptake in the left frontal plasmacytoma of patient 1 was increased above background on the day 8 scan andwas further increased on the day 15 scan , A), indicating propagation of the MV-NIS infection. However, there wasno evidence for virus spread from plasmacytomas to adjacent normal tissues. In patient 2, the day 8 scan revealed striking radioiodine uptake in several plasmacytomas that was not present at baseline. Uptake diminished considerably by day 15and was no longer detectable on day 28 posttherapy , B). Comparing day 8 radioiodine SPECT-CT and baselineFDG PET-CT scans, there was variable uptake of radioiodine by tumors of similar size ( C), indicatingheterogeneity of viral propagation in diﬀerent plasmacytomas in the same Figure 2Intratumoral propagation of systemically administered MV-NIS. A, Serial single-photonemission computed tomography (SPECT)–computed tomography (CT) images from patient1 at baseline (d-1) and on days 8 (d8) and 15 (d15) after MV-NIS infusion at the level of theleft frontal plasmacytoma. Two adjacent transaxial slices from 6 hours after isotopeadministration are shown for each time point. There is a small area of increased uptake inthe plasmacytoma visible in the lower slice on the day 8 scan (circle). This area ofincreased uptake is more extensive, and visible in both slices (circles), on the day 15 scan.
B, Serial SPECT-CT images from patient 2 at baseline and on days 8, 15, and 28 (d28) afterMV-NIS infusion at the level of the inguinal region. Compared with the baseline images, there is greatly increased radioiodine uptake in a deep-seated intramuscular plasmacytoma in the right hemipelvis onday 8 after MV-NIS administration, which is diminishing by day 15 and is back to baseline by day 28 (arrows). On thesame transaxial slices, there is moderately increased radioiodine uptake in the large left inguinal lymph node on day 8,which again is diminishing by day 15 and back to baseline by day 28 (arrowheads). C, Anteroposteriorfluorodeoxyglucose positron emission tomography (PET)–CT image obtained before MV-NIS administration and thecorresponding iodine 123 SPECT-CT images obtained 8 days and 28 days after virus administration. All areas ofintense radioiodine uptake (aside from the bladder) in the day 8 SPECT-CT scan are seen to correspond to glucose-avid plasmacytomas in the PET-CT image (circles).
DiscussionWe report the tumor-specific infection and clinical responses of the first 2 measles-seronegative patients with treatment-refractory myeloma to be treated intravenously with the oncolytic measles virus MV-NIS at the maximum feasible doselevel. Targeted infection of virus-infected plasmacytomas was clearly documented (using SPECT-CT imaging in bothpatients) by the appearance and later disappearance of NIS-mediated radioiodine uptake signals that were absent atbaseline. After virotherapy, NIS expression was heterogeneous among the plasmacytomas of patient 2. Resolution of bonemarrow plasmacytosis and regression of identifiable plasmacytomas in patient 1 led to complete disease remission thatlasted 9 months. This response occurred after only a single intravenous administration of the virus. Bone marrowplasmacytosis resolved in patient 2 and remained undetectable at 6 weeks after therapy, but her plasmacytomas wereprogressing by that time, and her free light chain level was increasing.
Despite the long history of the field of oncolytic virotherapy, complete remission of a disseminated malignancy mediated bya systemically administered virus has not previously been documented in a human subject, nor has the specific targeting ofOV infection to sites of tumor growth. Although there have been many well-documented immune-mediated completeremissions (most frequently of metastatic MM) after intratumoral OV intravenous virotherapy ecently recovered from biopsied tumors following intravenous delivery in a phase 1 clinical esponse at a single tumor site was seen at the highest dose level (approximately 9 50) in that study, and virus biodistribution was not evaluated because, unlike MV-NIS, the virus was not designed for noninvasive imaging. The current report is therefore the first to establish feasibility of thesystemic oncolytic virotherapy In contrast to conventional drug therapies, OVs are designed to self-amplify at sites of tumor growth, which greatlycomplicates the study of their pharmacology. In the case of MV-NIS, this concern was addressed by engineering the virusto drive high-level NIS reporter gene expression in infected target cells such that its biodistribution and pharmacokineticscan be noninvasively monitored by radioiodine eclinical studies have also found that the antimyeloma potency of MV-NIS can be synergistically boosted by appropriately timed administration of iodine 131, which localizes tointratumoral sites of virus propagation depositing a tissue-destructive dose of beta outcome and imaging data, particularly from patient 2, there is now a strong rationale for combining MV-NIS with iodine131 (radiovirotherapy) in a future clinical One key factor that may have contributed to the successful outcome in these 2 patients was their low pretreatment serumtiters of antimeasles antibodies.
obable relevance was the high dose of virus administered.
Dose-response relationships for antitumor eﬃcacy and virus delivery have been well documented in previous virotherapystudies, eshold eﬀect can be mathematically pr detectable in the circulating cells of patient 1 at 6 weeks after virus infusion, by which time there had been a substantialboost to her antimeasles antibody titer, suggesting the possibility of continuing ongoing oncolytic activity even at that late ConclusionOn the basis of this demonstration of tumor-selective MV-NIS replication and, in one case, durable tumor regression inheavily pretreated patients who have myeloma with bulky disease, OVs oﬀer a promising new modality for the targetedinfection and destruction of disseminated cancer. Additional MV-NIS is now being manufactured to support a plannedphase 2 expansion of the clinical trial in measles-seronegative patients.
AcknowledgmentsWe thank Kaaren K. Reichard, MD, for flow cytometric analysis of bone marrow.
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Grant Support: This work was supported by funds from the National Institutes of Health/National Cancer Institute (grants
R01CA125614 and R01CA168719 ), Al and Mary Agnes McQuinn, the Harold W. Siebens Foundation, and the Richard M.
Schulze Family Foundation. The National Cancer Institute RAID (Rapid Access to Intervention Development) Programsupported MV-NIS manufacture and toxicology/pharmacology studies.
Potential Competing Interests: Drs Russell, Federspiel, and Peng and Mayo Clinic have a financial interest in the technology
used in this research.
2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
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