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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Division of Medical Oncology and 2 Centre for Cancer Therapeutics, Ottawa Hospital Regional Cancer Centre, University of Ottawa, Ottawa, Ontario, Canada and 3 Wellstat Biologics Corp., Gaithersburg, Maryland
Requests for reprints: Scott A. Laurie, Division of Medical Oncology, Ottawa Hospital Regional Cancer Centre, University of Ottawa, 503 Smyth Road, Ottawa, Ontario, Canada K1H 1C4. Phone: 613-737-7700, ext. 70173; Fax: 613-247-3511; E-mail: slaurie{at}ottawahospital.on.ca.
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Abstract |
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Experimental Design: Sixteen adults with incurable solid tumors were enrolled. Cycles consisted of six PV701 doses over 2 weeks followed by a 1-week rest. Doses 1 to 2 were 1 and 12 x 109 plaque-forming units (pfu)/m2, respectively, whereas doses 3 to 6 were escalated by cohort from 24 to 120 x 109 pfu/m2.
Results: No dose-limiting toxicities were observed, permitting dose escalation through cohort 4 (1, 12, 120, 120, 120, 120 x 109 pfu/m2). Mild flu-like symptoms were common following the first infusion, diminished with repeated dosing, and were less pronounced than those seen previously. Tumor regression was observed in a patient with anal carcinoma who enrolled with stable disease following palliative radiotherapy. Four patients with clearly progressing cancer before enrollment had disease stabilization of 
6 months.
Conclusions: This novel two-step desensitization improved patient tolerability compared with the previous regimen. Toxicities were predictable and manageable. PV701, the first oncolytic virus to enter phase 1 i.v. testing, continues to show single-agent activity, warranting planned phase 2 trials.
80%) of diverse human cancer cell lines tested in vitro (3). Most tumor cells are at least 1,000-fold more sensitive to PV701 cytolysis than normal cells (3). PV701 is selectively cytotoxic, exploiting defects in IFN antiviral responses common in tumor cells (6). Such defects are believed to confer a growth advantage but also lead to impaired antiviral defenses, rendering cancer cells especially sensitive to infection by and replication of viruses (7–10). PV701, when given via i.t., i.p., or i.v. routes, had activity against human tumor xenografts in athymic mice (3, 4). The mechanisms mediating efficacy and toxicity appear distinct, with efficacy due to viral replication and cell lysis and toxicity due to the production of inflammatory cytokines (4, 5). Repeat dosing widens the therapeutic index of PV701; with repeat dosing in tumor-bearing mice, efficacy increased, whereas the toxicity lessened with each successive dose (4, 5). The term desensitization refers to the phenomenon by which, following the first PV701 dose, the toxicities of subsequent doses are reduced, allowing a 5- to 10-fold increase in the maximum tolerated dose of those subsequent doses compared with the first dose. Desensitization occurred in severe combined immunodeficient mice, indicating that it is an antibody-independent phenomenon.
In the first phase 1 trial of i.v. administration of PV701, 79 patients with advanced solid tumors were treated on various schedules to determine the maximum tolerated dose of both single-dose and multiple-dose regimens (1). Three categories of adverse events of PV701 were observed: flu-like symptoms arising from the induction of proinflammatory cytokines; tumor site-specific adverse events; and adverse events during infusion (1, 5). Tumor site-specific adverse events were associated with peritumoral inflammation, such as erythema, edema, and/or pain of palpable metastases, elevation of hepatic transaminases over 200 units/L only in those with hepatic metastases, and severe dyspnea, including one fatality, in those with large pulmonary tumors and baseline compromised lung function (1). Adverse events during infusion were observed at higher doses, included lower back and chest pain, and were controlled by analgesics and slowing the PV701 infusion rate. Based on the lack of ECG changes, the chest pain was labeled as noncardiac in nature.
In contrast to chemotherapy in which toxicity tends to increase with successive doses, most adverse events, principally flu-like symptoms (e.g., fever, chills, malaise, nausea, vomiting, and diarrhea), only occurred following the first infusion of PV701 (1). These were generally manageable with prophylactic antipyretics and antiemetics. Desensitization reduced the frequency and severity of these symptoms even when subsequent PV701 doses were up to 10-fold higher. Thus, whereas the maximum single dose of bolus PV701 was 12 x 109 plaque-forming units (pfu)/m2, in multidose regimens subsequent doses of up to 120 x 109 pfu/m2 could be given safely and tolerably. Cumulative toxicity was not observed.
Signs of efficacy seen in the first phase 1 trial of PV701 included a complete response in a patient with tonsillar carcinoma and a partial response in a patient with colorectal carcinoma (1). Several patients had minor responses or prolonged disease stabilization, including one patient with chemorefractory mesothelioma who had disease stabilization for 3.5 years while remaining on PV701 therapy.
Although comparing favorably to many chemotherapeutics in terms of tolerability, the single-step desensitization regimen (a low initial dose followed by five identical higher doses, all given over a 2-week period every 21 days) resulted in one third of patients developing grade 3 fatigue following the first dose of cycle 1 and improving during repeat dosing. In mice, using an additional desensitization step, a low first dose protected against the toxicity of a moderate second dose that in turn protected against toxicity of higher doses.4 This second phase 1 trial of i.v. PV701 was designed to test if a two-step desensitization could improve patient tolerability.
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Patients and Methods |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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18 years, a life expectancy of 3 months, Karnofsky performance status of 70, presence of at least one bidimensionally measurable lesion, and normal organ function, including a serum creatinine <1.5 times the upper limit of normal, bilirubin <1.5 times upper limit of normal, serum transaminase levels <2.5 times upper limit of normal or <5 times upper limit of normal in the presence of hepatic metastases, leukocyte count of >3,000/µL, neutrophils of >1,500/µL, platelets of >100,000/µL, and hemoglobin of >9 g/dL. Patients were not eligible if they had egg hypersensitivity, were receiving systemic corticosteroids, had an autoimmune disease, HIV, hepatitis B or C infection, or uncontrolled cardiac disease, or had any uncontrolled bacterial infection. Given the known occurrence of tumor site-specific inflammation, patients with brain metastases, abdominal tumors that had previously caused bowel obstruction, pulmonary metastases >5 cm or causing impaired pulmonary function (FEV1 of <75% of that predicted for age and height and/or a resting pulse oximetry of <90% oxygen saturation), or tumor at any site judged to be dangerous if peritumoral edema occurred were excluded. Pregnant or nursing women were excluded as were patients with a past or current history of working with poultry, as these patients may have preexisting anti–Newcastle disease virus antibodies. Although no human-to-human transmission has been documented with Newcastle disease virus, as a precaution, patients were instructed to avoid infants ages <1 month, pregnant women, and those with immunodeficiency until 3 weeks following discontinuation of study therapy. This trial was approved by Health Canada and the research ethics boards of the Ottawa Regional Cancer Centre and the Ottawa Hospital, and all patients provided written informed consent.
PV701. PV701 is a naturally attenuated, triple-plaque purified isolate from the MK107 mesogenic vaccine strain of Newcastle disease virus. The virus is grown in specific pathogen-free embryonated chicken eggs and purified from the allantoic fluid. Doses are expressed in pfu using the plaque assay described by Pecora et al. (1). The ratio of infectious particles (pfu) to total particles was determined to be 1. PV701 was formulated in an aqueous mannitol-lysine solution and stored below –65°C. For administration, vials were thawed at room temperature and diluted into i.v. saline bags.
Treatment plan. Table 1 schematically illustrates the treatment plan. Each 21-day cycle consisted of six infusions of PV701 over a 15-day period followed by 6-day rest. PV701 was given on days 1, 4, 8 ± 2, 10 ± 2, 12 ± 2, and 15 ± 2. For each patient, there were at least 2 days between doses. Each PV701 dose was given as an i.v. infusion over 30 minutes for the first two cycles and then over 1 hour for all subsequent cycles. For all patients, the first dose of each cycle was 1 x 109 pfu/m2 and the second dose was 12 x 109 pfu/m2. The third to sixth doses of each cycle were kept constant for each patient but were escalated by cohort. Based on the previous phase 1 experience with this agent, four cohorts were planned for study. For the first cohort, the dose of PV701 for the third to sixth infusions was 24 x 109 pfu/m2. Subsequent cohorts escalated these doses to 48, 96, and 120 x 109 pfu/m2.
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Toxicity assessment and dose escalation. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria version 2.0 (Bethesda, MD). Dose-limiting toxicity (DLT) was defined as any clinically significant hematologic toxicity of grade 4 (except for lymphopenia and except for leukopenia or neutropenia lasting <5 days) or any clinically significant nonhematologic toxicity of grade 3 (except for fatigue, fever, chills, myalgia, and reversible elevations of liver enzymes in a patient with known hepatic metastases) that occurred during the first cycle of therapy. Symptoms clearly attributable to disease progression were not considered DLT. Three patients were enrolled per cohort, and if one episode of DLT was observed, the cohort would have been expanded to six patients. Dose escalation to the next cohort was permitted if DLT was seen in fewer than two patients per dose level. Dose escalation involved only the third and subsequent doses, up to the previously determined repeat dose maximum tolerated dose of 120 x 109 pfu/m2 (1). The maximum tolerated dose was defined as the dose level below which DLT was observed in two or more patients per cohort.
Patient assessment. After obtaining informed consent, the following evaluations were done to determine eligibility: a complete medical history and physical examination, hematology and biochemistry panel, urinalysis, electrocardiogram, and tumor imaging studies. Additionally, pulmonary function tests and pulse oximetry were done in those with lung or pleural involvement from their malignancy. These evaluations were repeated before each dose of PV701. Blood was drawn for antibodies against PV701, and urine samples were obtained for viruria assessment. Vital signs were monitored every 15 minutes throughout each PV701 infusion and for 1 hour following infusion.
Disease response was assessed after two treatment cycles. Patients with a response, those with stable disease, or those who were felt by the investigator to have a clinical benefit (e.g., improvement in performance status) could continue to receive therapy on an extension protocol at the same dose and schedule.
Anti-PV701 IgG antibody enzyme immunoassay. Serum samples for antibody levels were drawn before doses 1, 3, and 6 of cycle 1, doses 1 and 6 of cycle 2, and before dose 1 of subsequent cycles and stored at below –65°C. After thawing, serial dilutions of heat-inactivated serum samples were added to 96-well assay microplates coated with PV701 (500 ng protein/well) and incubated for 90 minutes at room temperature. Plates were then washed to remove unbound antibody, incubated at room temperature for 60 minutes with horseradish peroxidase–conjugated goat anti-human IgG (
chain specific; Rockland Immunochemicals, Gilbertsville, PA), washed again, and then incubated with a solution of TMB for 10 minutes. After the reaction was stopped with a solution of 1 N HCl and 3N H2SO4, the absorbance at 450 nm was measured. The antibody concentration of each sample was determined from a standard curve using a four-variable logistic curve fit with SoftmaxPro version 4.0 (Molecular Devices Corp., Sunnyvale, CA). This immunoassay had a limit of detection of 0.03 mg/mL and a lower limit of quantification of 0.09 mg/mL for anti-PV701 IgG.
Neutralizing antibody to PV701. Serial 2-fold dilutions of heat-inactivated patient serum were mixed with a PV701 preparation that contained 300 pfu/mL in a total volume of 2 mL. After incubation for 1 hour at room temperature, the serum-virus mixture was tested for infectivity using a plaque assay (1). The neutralizing antibody titer of the serum sample was expressed as the last dilution resulting in 80% reduction in the number of plaques compared with a nonneutralized virus control.
Viruria. During the first two cycles of therapy before each infusion of PV701 and before dose 1 of each subsequent cycle, urine samples were collected and stored at below –65°C. After thawing, samples were diluted with an equal volume of M4RT viral transport/preservation medium (Remel, Lenexa, KS) and then passed through a 10DG desalting column (Bio-Rad, Hercules, CA) to separate toxic urine constituents from any virus in the sample. Serial dilutions of the samples were done (with eight replicates per dilution) across a 96-well microtiter plate. HT1080 fibrosarcoma cells (2.5 x 104 per well in DMEM supplemented with 2% FCS, 100 units/mL penicillin, 100 µg/mL streptomycin, 50 µg/mL gentamicin, and 1.25 µg/mL amphotericin B) were added. A standard of known virus concentration was included. Following 68 hours of incubation at 37°C, cytopathic effects of any virus in the sample were determined by standard assay using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt. Logit analysis was used to determine the TCID50 dilution at which 50% of the wells showed cytopathic effects. The amount of virus in the samples was determined by establishing a relative potency for each sample compared with the standard. This viruria assay had a limit of detection of 70 pfu/mL and a lower limit of quantification of 600 pfu/mL. Patient urine output was not quantified, however; therefore, the results represent a semiquantitative assessment of viral shedding.
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Results |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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Dose escalation and toxicity. No DLTs were observed in this trial, permitting dose escalation to cohort 4 (first dose per cycle of 1 x 109 pfu/m2, second dose per cycle of 12 x 109 pfu/m2 followed by four doses of 120 x 109 pfu/m2). Thus, cohort 4 was determined to be safe and tolerable for outpatient administration.
Flu-like symptoms, such as fever, chills, fatigue, and headache, were observed in all patients during the initial three or four doses of the first cycle. These were mild to moderate (grade 
2) and most common and pronounced following the first dose, decreasing in intensity and frequency with subsequent doses of the first cycle (Fig. 1
). Likewise, mild gastrointestinal symptoms, such as nausea and anorexia, were common, whereas vomiting and diarrhea of grade <2 severity were observed in roughly one-half to two-thirds of patients. PV701 caused mild hypotension in two patients. The frequency of these flu-like symptoms was markedly reduced in the second cycle of PV701 (Table 3
) and was similar across all cohorts (Table 4
).
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Infusion-related adverse events were dose dependent and consisted principally of noncardiac chest and/or back pain (Table 3). These were observed in seven patients (Table 4), five of whom were treated at the highest dose level (cohort 4), and in all cases occurred during the infusion of the third to sixth doses in a cycle (i.e., the highest doses given during a cycle). Episodes were transient and brief, with a median duration of 15 minutes, and of grade 1 or 2 in severity. They were managed with an interruption of the PV701 infusion and with analgesics. In all cases, the remainder of that PV701 dose was given without recurrence of pain by slowing the rate of infusion of the agent. In no case did these infusion-related events preclude further therapy with PV701. No evidence of myocardial ischemia was observed.
Transient elevations in liver transaminases were observed in almost all patients, and, except in one case of a patient with liver metastasis, were all <200 units/L. No other significant biochemical or laboratory findings were observed. Six episodes of transient mild dyspnea were observed, with three of these occurring in patients with pulmonary metastases.
One patient, enrolled in cohort 3, received only the first dose (1 x 109 pfu/m2) of cycle 1 of therapy. This 66-year-old woman with ovarian carcinoma had a 7-cm pelvic mass, baseline tumor-related pelvic pain (grade 2), and a Karnofsky performance status of 70. She was admitted to hospital for observation 24 hours following dose 1 of the first PV701 cycle with a worsening of her pelvic tumor pain (grade 3), fever (grade 1), chills (grade 1), nausea (grade 2), vomiting (grade 2), and dehydration (grade 3). She did not take antipyretics as per study procedures, and she and her treating physician decided to discontinue study therapy. Given the tolerability of the same initial dose of 1 x 109 pfu/m2 in the previous six patients and the known tolerability of a first dose of 12 x 109 pfu/m2 when using appropriate prophylactic medication (1), this was not considered a DLT, and an additional subject was enrolled to cohort 3 to replace this patient. Three other patients recruited to this cohort had no toxicity of greater than grade 2; thus, dose escalation to cohort 4 was permitted.
Absence of cumulative toxicity. Following the first two cycles of therapy, a total of an additional 49 cycles of PV701 were given to eight patients who had stable disease [median number of additional cycles beyond cycle 2 is 4 (range, 1-14)]. No cumulative toxicities were observed. Following the first two cycles, improved tolerability was noted with no incidence of grade 3 toxicity deemed at least possibly related to PV701. The incidence of fever, fatigue, and all other flu-like symptoms lessened during additional cycles of treatment (e.g., fatigue was seen at incidences of 88%, 69%, 44%, and 16% for cycles 1-4, respectively). One patient (enrolled in cohort 4) continued to have infusion-related back pain despite an attempt to prevent them by commencing all further PV701 infusions at half-rate; premedication with narcotic analgesics before each infusion prevented further episodes.
Virology. During the first two cycles of therapy, urine samples were taken for viruria testing before each dose. Viruria was seen in 19% of cycle 1 samples with the incidence dropping to 7% in cycle 2 and 0% in cycles 3 and beyond. Levels of shed virus in positive urine samples were modest, with a median of 6.6 x 103 pfu/mL (range, 600-1.4 x 105 pfu/mL). Day 11 was the median day of onset for viruria (range, days 7-21), which lasted a median duration of 4 days (range, 1-14 days). There was no evidence of persistent shedding.
Only one patient had measurable levels of anti–Newcastle disease virus IgG at baseline; this patient had undetectable neutralizing antibody titers. Nine of 15 patients remained seronegative at day 8 (dose 3), but all patients had detectable anti-PV701 antibodies by day 15 (dose 6 of cycle 1). During the first few months, antibody levels (anti–Newcastle disease virus IgG and neutralizing antibody) continued to increase with repeated exposure to PV701 (Fig. 2 ). However, in the two patients treated for >10 months, antibody levels reached a plateau with maximal neutralizing titers of 1:1,280 and 1:5,120. Total PV701 IgG antibodies followed a parallel course with neutralizing antibodies (Fig. 2) and there was no apparent relationship to dose level (data not shown).
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0.8 mg/mL and 1:1,280, respectively, for the duration of his therapy. Tumor regression of >90% was noted during PV701 treatment in a 67-year-old woman with anal carcinoma who was enrolled to cohort 3. At study entry, her only confirmed disease site was a palpable 4.5 cm inguinal lymph node metastasis that had recurred following initial radiotherapy 2 years before enrollment. This mass had stabilized clinically following palliative radiotherapy (3,000 cGy) completed 2 months before initiation of PV701. She subsequently went on to receive a total of 16 cycles of PV701 and had a progression-free duration of 13 months. During her first 4 months of treatment, the mass remained stable. However, after her seventh cycle, the node was no longer palpable and by computed tomography scan changed from soft-tissue density to that of fat density, a radiographic change that was maintained 3 months later and confirmed by an independent radiologist. As there was no clear evidence of disease progression in this previously irradiated node before study entry, a contribution of radiation to this delayed regression after 5 months of PV701 treatment and 7 months following completion of palliative radiotherapy cannot be ruled out. During her 16 cycles of treatment, her antibody levels initially rose and then reached a plateau (for neutralizing antibodies at 1:2,560 after 3 cycles and for total anti-PV701 IgG antibodies at 3 mg/mL after 10 cycles).
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Discussion |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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Infusion reactions, consisting of back and/or noncardiac chest pain, were particularly noted at the highest given dose of 120 x 109 pfu/m2 and never occurred during the first two doses. Generally, these adverse events responded to interruption and/or slowing of the rate of infusion and did not preclude further therapy. In one patient for whom slowing the rate of infusion did not prevent further reactions, prophylactic analgesics were effective. Before study initiation, the protocol specified that all patients were to have their PV701 infusion time increased from 30 minutes to 1 hour beginning with the third cycle of therapy. This slower infusion rate was associated with a significant reduction in the incidence of infusion reactions (1 of 62 doses when 120 x 109 pfu/m2 was given over 1 hour compared with 12 of 44 doses given over 30 minutes). The cause of these reactions is unclear; similar reactions are occasionally seen with other agents, especially other biologics. These reactions were notable in that they did not respond to antihistamines and did not include hypotension as can be seen, for example, with paclitaxel (11).
Tumor site-specific adverse events were rare in this trial in contrast to the frequency with which they were observed in the previous trial. Tumor site-specific adverse events may be dependent on the initial doses of PV701 used, which were significantly lower in this trial. In the previous phase 1 trial, severe dyspnea was observed in nine patients with extensive involvement of the lungs by tumor (1). In the current trial, patients with large lung tumors and those with baseline pulmonary compromise were excluded, and all patients with any lung involvement from their malignancy were required to pass pulmonary functions tests before study entry. With these criteria, there were no cases of severe dyspnea, including in those who had lung involvement with tumor. The one patient with ovarian cancer who suffered an increase of baseline grade 2 pelvic pain at her tumor site to grade 3 following the first dose of PV701 did not receive the appropriate nonsteroidal anti-inflammatory medication, and it could be hypothesized that use of these medications may help to prevent or reduce tumor site-specific adverse events. Additional methods to minimize the peritumoral inflammation, such as the use of corticosteroids, could be studied to broaden the range of patients who may receive PV701. Rather than being an "adverse event," however, tumor inflammation or tumor swelling may be a desirable consequence of virus administration, indicating activity at the tumor site (12).
In contrast to chemotherapy and importantly for long-term administration, patients received therapy with PV701 for extended periods without the development of cumulative toxicities. Additionally, there were no unexpected toxicities nor was there any sign of immune-complex disease during extended treatment.
PV701, a live attenuated virus, is safe to administer from an occupational health and a public health perspective. The virus is not a human pathogen (2), and no contacts of the patients enrolled to this trial developed any infectious illness potentially related to PV701. The levels of virus shed in the urine and the incidence of positive samples were similar to that seen previously (1). Levels of viruria diminished with repeated dosing, with no indication of persistent shedding.
Almost all patients were seronegative at the start of the current study, consistent with general surveys of the extremely low prevalence of anti–Newcastle disease virus antibodies in the general human population (13, 14) and unlike the situation with other oncolytic viruses in clinical development, such as adenovirus and herpesvirus (15–17). After treatment, all patients developed antibodies to PV701 despite the potential immunosuppression from their disease and prior treatments. Neutralizing antibody titers, even with multiple cycles, reached a moderate plateau level of 1:1,280. These levels seem significantly lower than those reported for patients treated intravascularly with adenoviruses (18–20). Recent testing of viremia samples from another phase 1 study indicated that PV701 clearance during a second cycle was not significantly affected by antibodies.5 Of potential clinical significance in our study, continued disease stabilization was observed in patients long after antibody formation. However, understanding the effects that the host humoral and cell-mediated immunity has on PV701 antitumor efficacy requires further study. There is recent speculation that therapeutic viruses might escape antibody neutralization by binding to blood cells or through the administration of quantities of viruses greatly in excess of the neutralizing antibody titers (21). For oncolytic herpesvirus, preclinical studies suggest antitumor activity may be in part mediated by the acquired immune response (22, 23).
Antitumor activity of PV701 was suggested by the prolonged disease control seen in several patients. A contribution of palliative radiotherapy given 7 months before the tumor regression observed in the patient with anal carcinoma cannot be excluded, but this may suggest a beneficial sensitizing effect of radiation to subsequent PV701 treatment. Support for such an interaction has been observed in the other phase 1 studies in which two major responses were observed in patients treated with PV701 after having failed radiotherapy: one complete response in a patient with squamous cell carcinoma of the tonsil and a durable near-complete response in a patient with cervical carcinoma. Alternatively, cancers associated with human papillomavirus, such as squamous cell carcinomas of the anal canal, cervix, or tonsil (24–26), may be particularly sensitive targets for therapy. Human papillomavirus makes two oncogenic proteins, E6 and E7, which both disrupt IFN response pathways in infected cells (27–29). These cancers may therefore be especially susceptible to oncolytic viruses like PV701.
Phase 2 testing of PV701 in patients with colorectal cancer should be considered. Among six colorectal cancer patients in this trial, two experienced prolonged disease stabilization for 6 and 11 months. In the previous phase 1 trial of PV701, a colorectal cancer patient had a partial response lasting 10 months and two other patients had stable disease lasting at least 4 months (1). Additional encouraging signs of activity in colorectal cancer have been noted recently in another phase 1 trial of PV701 (30).
In conclusion, PV701 is a novel oncolytic virus that shows antitumor activity when given i.v. as a single agent. It has predictable first-dose toxicity that can be managed on an outpatient basis. The two-step desensitization methodology resulted in improved tolerability compared with the one-step desensitization regimen used in the previous trial and compares favorably with chemotherapy. Decreasing the infusion rate of high PV701 doses markedly reduced the incidence of infusion reactions (e.g., back and noncardiac chest pain). Other toxicities were generally mild. Long-term administration of PV701 seems feasible because no cumulative toxicities were observed. Given the observed tolerability and signs of efficacy, phase 2 trials of this novel oncolytic agent are planned.
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Presented in part at the 14th European Organization for Research and Treatment of Cancer-National Cancer Institute-AACR Symposium on "Molecular Targets and Cancer Therapeutics" Frankfurt, Germany, November 2002.
4 R.M. Lorence, unpublished results. 
5 S.J. Hotte et al., in preparation.
Received 9/21/05; revised 1/31/06; accepted 2/16/06.
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B-responsive genes in cervical keratinocytes. J Virol 2001;75:4283–96.This article has been cited by other articles:
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  S. J. Goebel, J. Taylor, B. C. Barr, T. E. Kiehn, H. R. Castro-Malaspina, C. V. Hedvat, K. A. Rush-Wilson, C. D. Kelly, S. W. Davis, W. A. Samsonoff, et al. Isolation of Avian Paramyxovirus 1 from a Patient with a Lethal Case of Pneumonia J. Virol., November 15, 2007; 81(22): 12709 - 12714. [Abstract] [Full Text] [PDF]
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 S. J. Hotte, R. M. Lorence, H. W. Hirte, S. R. Polawski, M. K. Bamat, J. D. O'Neil, M. S. Roberts, W. S. Groene, and P. P. Major An Optimized Clinical Regimen for the Oncolytic Virus PV701 Clin. Cancer Res., February 1, 2007; 13(3): 977 - 985. [Abstract] [Full Text] [PDF]
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