| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Investigations |
US Oncology, Dallas, Texas 75246[J. N., P. M.]; Baylor University Medical Center, Dallas, Texas [J. N., J. K., T. M., S. L.]; Beatson Cancer Institute, Glasgow, Scotland [I. G., S. K.]; M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030 [F. K.]; Albany Regional Cancer Center, Albany, New York [J. A.]; Onyx Pharmaceuticals Incorporated, Richmond, California [L. R., B. R., T. R., D. K.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Many of the same critical regulatory proteins that are inactivated during carcinogenesis are also inactivated by adenoviral gene products during replication (10, 11, 12, 13) . Because of this convergence, the deletion of viral genes that inactivate these cellular regulatory proteins can be complemented by genetic inactivation of these proteins within cancer cells. An E1B-55kDa gene-deleted adenovirus, ONYX-015 (dl1520), is currently being developed for the treatment of tumors lacking p53 function (11 , 14) . The p53 gene product is responsible for several growth-regulatory functions. One critical function includes induction of cell cycle arrest and/or apoptosis in response to foreign DNA synthesis (15, 16, 17) . p53 can induce either a G1 growth arrest by inducing cyclin-dependent kinase inhibitor p21/WAF1/Cip1 (18 , 19) , or apoptosis by inducing bax-1 (20) after a DNA virus infection. Because the E1B-55kD gene product is responsible for p53-binding and inactivation, it was hypothesized that an E1B-55kDa deletion mutant would be unable to inactivate p53 in normal cells and would, thus, be unable to replicate efficiently. In contrast, cancer cells lacking functional p53 (e.g., because of gene mutation) would hypothetically be sensitive to viral replication and subsequent CPE.2
The original article describing this approach reported that p53 mutant tumor cells could be destroyed in a replication-dependent fashion both in vitro and in vivo (21) . Many tumor cell lines with normal p53 gene sequences, however, were subsequently found to be relatively sensitive to the effects of ONYX-015 in vitro (7 of 10 tested; Ref. 14 ), and subsequent publications from several other groups suggest that the p53 gene sequence is a poor predictor of sensitivity to ONYX-015 in vitro (22, 23, 24, 25) . Given the numerous mechanisms by which p53 can be inactivated besides genetic mutation, this finding is not necessarily inconsistent with the original hypothesis (6 , 26) . Factors which inhibit p53 protein function, despite the presence of a normal p53 gene sequence, include expression of the human papillomavirus E6 protein or mdm-2 gene amplification (27) . Additionally, p14arf is known to be deleted in the vast majority of tumor cell lines with normal p53 gene sequences (28 , 29) . Even normal cells that are placed into tissue culture can rapidly select for a loss of p16 and p14arf during immortalization. Because the adenoviral E1A gene product can cause p53 induction through p14arf, the loss of p14arf may also reduce the ability of p53 to block ONYX-015 replication in some p53 wild-type tumor cells.3
One approach to studying the mechanism of ONYX-015 selectivity was to
compare its behavior in cell lines that are identical except for p53
function. Four matched pairs of cell lines have confirmed that ONYX-015
replication and/or CPEs are significantly inhibited by functional p53:
RKO (21)
, H1299 (30)
,
A2780,4
and U343.5
In contrast to these four cell lines, however, a fifth (U2OS) cell line
did not become significantly more sensitive to ONYX-015 after
transfection with dominant-negative p53 (31)
. Although it
is possible that as-yet-undetermined complementing mutations within
tumor cell lines may account for these differences in ONYX-015 effects,
most data confirm the selective replication capacity of ONYX-015. Some
of the controversy regarding ONYX-015 selectivity to p53 mutant targets
may be related to the multiplicity of infection used, the study
end points, and the time elapsed from infection to assessment of CPEs
(32)
.Overall, selectivity of ONYX-015 replication appears
to be most consistent at low multiplicities of infection (
1.0 pfu)
after prolonged observation of CPE assays.
We carried out initial clinical testing of ONYX-015 in patients with recurrent squamous cell carcinoma of the head and neck. Abnormalities in p53 function are common as a result of gene mutation or protein degradation attributable to human papillomavirus E6 protein expression (33 , 34) . Phase I investigation indicated good tolerability of ONYX-015 administered as a single intratumoral injection (doses up to 1011 pfu), and after a series of five daily consecutive intratumoral injections (doses up to 1010 pfu per injection (35) . Injections were done and the tumors were biopsied in an outpatient setting, which allowed clinical and histological assessment over time after tumor inoculation. Local-regional tumor progression was the cause of morbidity and death in the majority of cases. We, therefore, could obtain valuable biological data on viral presence, necrosis, and inflammation while attempting to benefit patients through local tumor control in Phase II testing.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
18
years old, had to have a Karnofsky performance status of 70%, and
life expectancy of 3 months. Normal hematological and renal function
were also required. This investigation was performed after approval by
the local Institutional Review Board at US Oncology (Dallas, TX). An
informed consent was obtained from each patient or from the patient’s
legal guardian prior to enrollment. The p53 gene status was
not used as an enrollment criteria. Institutional Review Board approval
of the protocol and consent form was required.
Baseline Assessment.
Baseline assessments were made prior to treatment, but these results
were not used as enrollment criteria. A biopsy sample was obtained for
p53 gene sequencing from the tumor to be injected (see
methods below). Baseline blood tests were performed as follows:
complete blood counts; CD3, CD4, and CD8 lymphocyte counts;
electrolytes; blood urea nitrogen; creatinine; and liver
function tests. In addition, baseline neutralizing antibody
titers to ONYX-015 were determined (most adults have neutralizing
antibodies to the adenovirus type 5 coat proteins that are present on
ONYX-015). In addition, delayed-type hypersensitivity skin testing
(Merieoux) and plain chest radiographs were performed.
ONYX-015.
ONYX-015 (dl1520) is a chimeric human group C adenovirus (Ad2 and Ad5)
that does not express the product of the E1B-55kDa gene; the virus was
constructed in the laboratory of Arnold Berk (Barker and Berk, Ref.
11
). The virus contains a deletion between nucleotides
2496 and 3323 in the E1B-55kDa region encoding the protein. In
addition, a C to T transition at position 2022 in E1B generates a stop
codon at the third codon position of the protein. These alterations
eliminate expression of the E1B-55kDa gene in ONYX-015 infected cells.
ONYX-015 was grown and titered on the human embryonic kidney cell line
HEK293 as described previously (14)
.
ONYX-015 Handling and Processing.
ONYX-015 is formulated as a sterile viral solution in TRIS buffer [10
mM TRIS (pH 7.4), 1 mM
MgCl2, 150 mM CaCl, and 10%
glycerol]. The solution is supplied frozen (-20°C) in single-use,
plastic screw-cap vials. Each vial contains 0.5 ml of virus solution at
a specified viral titer. Vialed virus solution was thawed and diluted
to the appropriate titer for dosing, and was then further diluted to a
final volume equivalent to 30% of the volume of the tumor to be
injected. Tumor volume was estimated by taking the product of the
maximal tumor diameter, its perpendicular and estimated depth, and
dividing by two. Vials of ONYX-015 were opened and diluted immediately
prior to injection in biological safety cabinets at the patient
treatment area. All of the waste items were disposed of in biohazard
containers and autoclaved or incinerated.
Treatment Regimen.
To ensure uniform dosing to the injected tumor in each patient, a
single tumor was identified for ONYX-015 injection in each patient. If
more than one injectable tumor was present, the most symptomatic and/or
largest tumor mass was injected with ONYX-015. The tumor was mapped
into five equally spaced and equally sized sections. Local anesthesia
was applied to the skin as needed. The tumor was injected with
1010 pfu following the template displayed in
Fig. 1
. The suspension volume of saline used for ONYX-015 administration was
normalized to 30% of the estimated volume of the tumor mass to be
injected (see above). During each treatment session, one puncture of
the skin was made at a site approximately 80% of the distance from the
tumor center out to the tumor periphery. Six to eight needle
tracts were made radially out from the puncture site; virus was
administered equally along the length of the needle tracks (25-gauge
needle). This approach was carried out each day from puncture sites
that were equiradially spaced out and that encompassed the entire tumor
mass. The majority of the viral dose was administered at the tumor
periphery and at the interface between normal tissue and tumor tissue.
This administration approach was used for two reasons. First, prior
studies have suggested improved efficacy with this administration
approach. Second, this technique allowed for assessment of the effects
of ONYX-015 injection on both normal tissues and tumor tissues in the
same patients.
|
Tumor Assessments.
Tumor masses were measured serially by either physical examination or
radiographic scanning (computed tomography or magnetic resonance
imaging), whichever the principal investigator deemed
most accurate for the measurement of the injected tumor mass. In
general, very superficial lesions were measured by physical
examination, and deeper tumors were measured most accurately by
radiographic scanning. Tumor measurements were determined either every
3 weeks (physical examination) or every 6 weeks (computed
tomography/magnetic resonance imaging scans) while patients were on
active study treatment. After treatment completion,
patient’s tumor(s) were assessed every 8 weeks or sooner if
signs/symptoms of progression became evident. Radiographic scans were
assessed by independent radiologists who were not investigators on the
study.
The degree of response within injected tumors was categorized as
follows: complete regression, complete disappearance of measurable
tumor; partial regression, 50% but <100% decrease in
cross-sectional tumor area; minor response, <50% but 25% decrease
in tumor area; stable disease, <25% decrease and
[mt]25% increase in tumor area; progressive
disease, 25% increase in tumor area versus the baseline
area. The time-to-injected tumor progression was defined as the time
from treatment initiation to an increase of 25% in the nonnecrotic
cross-sectional tumor area. To adequately assess the correlation
between the effects of ONYX-015 injection within the injected tumor and
predictive factors (e.g., p53 status), patients who received
less than two cycles of treatment because of either development of
comorbid medical conditions (n = 6) or
progression at noninjected sites (n = 7) were
not evaluable for this analysis. Investigators and radiologists were
blinded to the final p53 gene status and neutralizing
antibody titer of the patients at the time of tumor assessment.
Additional Follow-Up after Treatment Initiation.
Neutralizing antibody titers were repeated every 4 weeks. Injection
site biopsies between days 5 and 22 of the first treatment cycle were
optional, based on patient consent because of ethical considerations.
These biopsies were analyzed for E1A protein expression (the earliest
gene product expressed) and viral replication by in situ
hybridization. Routine blood testing (complete blood count,
electrolytes, blood urea nitrogen, creatinine, and liver
function tests) was repeated every 3 weeks.
p53 Gene Sequencing.
Pretreatment tumor biopsies were taken for p53 sequencing from the
recurrent tumor mass that was to be injected. Exons 5–9 were sequenced
completely during the first two-thirds of the trial. Mutations were
considered functionally significant if present in the Soussi database.
Exons 2–11 were assessed by p53 gene chip technology during the final
one-third of the trial. Because certain gene deletions can be missed by
gene chip analysis (i.e., a wild-type sequence is reported
despite a functionally significant mutation), wild-type p53 gene
sequences by gene chip analysis required confirmatory sequencing to be
validated.
In Situ Hybridization for Adenoviral DNA.
In situ hybridization for adenoviral DNA was carried out on
biopsy samples to determine the extent of replication of ONYX-015 in
both tumor and adjacent normal tissues as described previously
(14)
. Briefly, in situ hybridization was
performed on formalin-fixed, paraffin-embedded tissue, cut into 5-µm
sections. Slides were deparaffinized in xylenes, hydrated through
ethanols, digested with proteinase K, and postfixed in 4%
paraformaldehyde. Hybridization was carried out overnight at 37°C
with 0.5 µg/ml biotinylated adenovirus DNA probe (Enzo Diagnostics,
Inc., Farmingdale, NY). After three successive washes in 1x SSC at
55°C, an alkaline phosphatase conjugated-antibiotin antibody (Vector
Laboratories) was applied. NBT/BCIP was used as the chromagen, and
slides were counterstained with nuclear Fast Red.
E1A Immunohistochemistry.
Formalin-fixed, paraffin-embedded tissue sections were deparaffinized
and hydrated. Slides were subjected to antigen retrieval at 120°C for
10 min in citrate buffer and incubated with an adenovirus type-2 E1A
antibody (Clone M73; Calbiochem) for 90 min at room temperature. This
was followed by incubation with a biotinylated goat antimouse secondary
antibody, and streptavidin/horseradish peroxidase conjugate.
Determination of Neutralizing Antibody Titers.
Patient and control samples were incubated at 55°C for 30 min to
inactivate complement. Clinical plasma samples previously determined to
produce high, midrange, and negative titers were designated as plasma
controls. Each dilution was mixed with adenovirus stock at a titer
prequalified to produce 15–20 plaques per well of a 12-well dish in
DMEM growth medium. The patient’s samples and controls were inoculated
for 1 h at room temperature and applied to 70–80% confluent
JH393 cells in 12-well dishes. After 2 h of incubation at 37°C,
5% CO2 plasma-virus mix was removed and 2 ml of
1.5% Agarose in DMEM were added to each well. Plates were read on day
7 postinoculation by counting the number of plaque-forming units per
well. The titer of neutralizing antibody for each sample was reported
as the dilution of plasma that reduced the number of plaques to 60% of
the number of plaques in the virus control without antibody.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. Most patients were male (71%). The median age was 58.5 years, and
all of the patients had a Karnofsky performance status of 70.
Patients were heavily pretreated in most cases; 88% of patients had
received two or more previous therapeutic modalities, and 54% had
received three previous modalities. The most common site of the
patients’ injected recurrent tumor was the cervical area. Injected
tumors had a median diameter of 3.38 cm (range, 1–7 cm) and a median
cross-sectional area of 11 cm2
(range, 1.1–39
cm2
). Only one patient had a distant metastasis
present outside of the head and neck region. Patients were relatively
immunosuppressed. Delayed-type hypersensitivity skin-testing reactivity
to common antigens was below the normal range in 70% of patients, and
the median CD4 cell count was 339 (range, 126–1318).
|
Posttreatment Histology.
Tumor biopsies were obtained between day 5 and day 22 of the first
cycle of treatment (1–17 days after the final injection of ONYX-015).
Each patient (n = 24) evaluable for response
(received 2 cycles) underwent biopsy at varying time points. Time
points of biopsies were 1–3 days (n = 7
patients), 7–10 days (n = 4 patients), and
14–17 days (n = 10 patients) after the last
injection. Both tumor tissue and normal tissue were present in all of
the evaluable biopsies posttreatment. Viral presence was assessed by
in situ hybridization for adenoviral DNA (specific nuclear
staining was required) and by assessment of CPEs on H&E-stained slides
(Fig. 2, A and B)
.
|
. In contrast, normal
skin and mesenchymal tissue within the biopsies were uniformly negative
(n = 21) by in situ hybridization
(Fig. 2, C and D)
. Comparison of ONYX-015
presence in tumor tissue before day 14 (7 of 11 positive)
versus normal tissue (0 of 11 positive) was a significant
difference (P = 0.01). Immunohistochemical
staining for adenoviral E1A protein confirmed expression within
in situ hybridization-positive tumor cells (Fig. 2, E and F)
. Viral presence was further confirmed by
electron microscopy (Fig. 2, G and H)
. Areas of
viral presence within the tumors were associated with areas of CPEs and
necrosis as seen by neutrophil infiltrate (Fig. 2, A and B)
. CPEs were not seen within normal tissues. Thus, the high
concentration of ONYX-015 in malignant tissue 24 h after the last
injection is likely related to selective viral replication. Abnormalities in p53 were detected in all of the tumors demonstrating viral presence. On days 1–3 after the last injection, four of five p53 mutant biopsies showed viral presence. Two tumors without p53 mutation were biopsied; one was negative for viral presence, whereas the other showed very focal viral presence within an otherwise negative tumor specimen. p53 immunohistochemical staining of this tumor sample documented focal elevated expression within a small nest of tumor cells (<5% of the total), consistent with a p53 abnormality; therefore, focal replication or infection may have occurred within a small focus of cells with abnormal p53. p53 mutations may not be detected by DNA sequencing if present in less than 25% of the cells in the biopsy sample.6
Tumor-specific Response.
ONYX-015 injection induced a 25–100% response of the injected tumor
mass in 8 (33%) of 24 cases (Table 2)
: two complete (8.3%), three partial (12.5%), and three minor
(12.5%) regressions were observed. Normal peritumoral tissue did not
appear affected by physical exam in any case, despite direct injection
with ONYX-015 (Fig. 3)
. The intent-to-treat objective regression rate (50%) for all of the
37 patients receiving any treatment was
14%.7
|
|
Correlation of Tumor Response with p53 Gene Status.
A significant correlation was demonstrated between the induction of
tumor response after necrosis and the p53 gene status of the
tumor (Table 2)
. Seven (58%) of 12 p53 mutant tumors underwent
significant necrosis and achieved significant response, whereas none of
the 7 p53 wild-type tumors achieved a response (P = 0.017). An evaluable p53 gene sequence could not be
obtained from five tumors. Neither the baseline neutralizing antibody
status (positive or negative), nor exposure to prior radiotherapy, nor
the baseline tumor size (maximal diameter < or 3
cm.), nor Karnofsky performance status (90 versus <90)
correlated significantly with response (Table 2)
.
Time-to-Tumor Progression.
Tumor progression was rapid in most cases. The median time to
progression at the injected tumor site was 51 days (range, 21–114
days). Six (25%) of 24 patients were without progression of the
injected tumor after 3 months on study (Fig. 4)
. The time to progression of injected p53 mutant tumors (median, 56
days)was delayed compared with p53 wild-type tumors, although not
significantly (median, 21 days; Fig. 4
; P = 0.28).
|
. There was no correlation between baseline neutralizing antibody
titers and induction of tumor response (Table 2)
.
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The role of the immune response to replicating viral agents is unclear. This will best be answered in clinical trials because of the lack of an immunocompetent animal model that supports efficient adenoviral replication (40 , 41) . Neutralizing antibody titers either before or after treatment were not predictive for antitumor activity. Although encouraging, this finding does not rule out an inhibitory role for neutralizing antibodies during a longer-term treatment or after other routes of administration (e.g., i.v.). Future studies will be needed to better define the role of antibodies and whether their suppression would be beneficial. The role of cell-mediated immunity in either increasing or decreasing the antitumor activity in these patients is still unclear. These end-stage head and neck cancer patients were relatively immunosuppressed. CD4 cell counts were less than 500 (per µl) in 65% of the patients and less than 200 in 25%. Delayed-type hypersensitivity skin reactivity to common antigens was low in 70% of patients. Therefore, cell-mediated immunity may play less of a role than in more immunocompetent patient populations. The time course and magnitude of immune cell infiltration into tumors after injection will best be determined by histological assessment of the entire tumor mass (e.g., after surgical resection) at varied time points after treatment. On the basis of those results, immunomodulatory strategies might be developed. Finally, antiviral cytokines may also affect adenoviral replication and/or spread (42 , 43) .
Despite the encouraging biological activity demonstrated with ONYX-015 in this clinical trial, clinical benefit was not seen in the majority of patients. Tumor progression was rapid in the vast majority of patients, even for tumors that underwent substantial necrosis after treatment. These patients were heavily pretreated and were end-stage in most cases; the life-expectancy is 3–4 months in this patient population (44 , 45) . Additionally, because patients who progressed within two cycles at noninjected sites were excluded, these results cannot entirely rule out the possibility of a more beneficial response in patients with multiple slower-growing tumors. The true clinical benefit of intratumoral injection with ONYX-015 as a monotherapy will, therefore, need to be determined in randomized trials and, possibly, in earlier stage patients.
Future approaches also include the addition of therapeutic genes with antitumoral effects to ONYX-015 (i.e., using ONYX-015 as a delivery vehicle), so-called "armed therapeutic viruses." ONYX-015 has several favorable characteristics as a vector for gene delivery: inherent antitumoral activity and selectivity; potential amplification of the transgene leading to high level expression; and enhanced intratumoral spread versus nonreplicating vectors. If these approaches are successful, viral therapy with genetically engineered viruses may become a novel therapeutic platform for the treatment of cancer.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be
addressed, at US Oncology, 3535 Worth Street, Collins Building,
5th Floor, Dallas, Texas 75246. Phone: (214) 370-1822; Fax: (214)
370-1753; E-mail: John.Nemunaitis{at}USOncology.com 
2 The abbreviations used are: CPE, cytopathic
effect; pfu, plaque-forming unit(s).
3 M. Korn, personal communication.
4 I. Ganly, personal communication.
5 S. Freytag, personal communication.
7 J. Nemunaitis, F. Khuri, I. Ganly, J. Arseneau,
J. Kuhn, T. McCarty, S. Landers, L. Rommel, C. Heise, B. Randlev, T.
Reid, S. Kaye, and D. Kirn. A Phase II trial of intratumoral injection
of ONYX-015 in patients with refractory head and neck cancer. J. Clin. Oncol., in press.
Received 4/21/00. Accepted 9/19/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and p19ARF/p16ß is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. Oncogene, 17: 2779-2785, 1998.[Medline]
-primed macrophages is TNF- and contact-dependent. Cell. Immunol., 157: 223-238, 1994.[Medline]
This article has been cited by other articles:
|
|
 |
|
  A. N. Blackford and R. J. A. Grand Adenovirus E1B 55-Kilodalton Protein: Multiple Roles in Viral Infection and Cell Transformation J. Virol., May 1, 2009; 83(9): 4000 - 4012. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Schoder, M. Fury, N. Lee, and D. Kraus PET Monitoring of Therapy Response in Head and Neck Squamous Cell Carcinoma J. Nucl. Med., May 1, 2009; 50(Suppl_1): 74S - 88S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nakagawa, H. Tanaka, T. Shirakawa, A. Gotoh, Y. Hayashi, K. Hamada, M. Tsukuda, and K.-i. Nibu Cyclooxygenase 2 Promoter-Based Replication-Selective Adenoviral Vector for Hypopharyngeal Cancer Arch Otolaryngol Head Neck Surg, March 1, 2009; 135(3): 282 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. R. Paiva, C. Binny, S. C. Ferreira Jr., and M. L. Martins A Multiscale Mathematical Model for Oncolytic Virotherapy Cancer Res., February 1, 2009; 69(3): 1205 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Carlson, K. L. Classic, E. M. Hadac, D. Dingli, C. E. Bender, B. J. Kemp, and S. J. Russell Quantitative Molecular Imaging of Viral Therapy for Pancreatic Cancer Using an Engineered Measles Virus Expressing the Sodium-Iodide Symporter Reporter Gene Am. J. Roentgenol., January 1, 2009; 192(1): 279 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Su, H. Cao, S. Tan, Y. Huang, X. Jia, L. Jiang, K. Wang, Y. Chen, J. Long, X. Liu, et al. Toxicology Profiles of a Novel p53-Armed Replication-Competent Oncolytic Adenovirus in Rodents, Felids, and Nonhuman Primates Toxicol. Sci., November 1, 2008; 106(1): 242 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Huang, L. Zhuang, Y. Cao, Q. Gao, Z. Han, D. Tang, H. Xing, W. Wang, Y. Lu, G. Xu, et al. Biodistribution and kinetics of the novel selective oncolytic adenovirus M1 after systemic administration Mol. Cancer Ther., June 1, 2008; 7(6): 1624 - 1632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Choi and J.N. Myers Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy Journal of Dental Research, January 1, 2008; 87(1): 14 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Qiao, H. Wang, T. Kottke, C. White, K. Twigger, R. M. Diaz, J. Thompson, P. Selby, J. de Bono, A. Melcher, et al. Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus Clin. Cancer Res., January 1, 2008; 14(1): 259 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E Chisholm, U Bapat, C Chisholm, G Alusi, and G Vassaux Gene therapy in head and neck cancer: a review Postgrad. Med. J., December 1, 2007; 83(986): 731 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Advani, R. R. Weichselbaum, and S. J. Chmura Enhancing Radiotherapy With Genetically Engineered Viruses J. Clin. Oncol., September 10, 2007; 25(26): 4090 - 4095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Toyoda, J. Yin, S. Mueller, E. Wimmer, and J. Cello Oncolytic Treatment and Cure of Neuroblastoma by a Novel Attenuated Poliovirus in a Novel Poliovirus-Susceptible Animal Model Cancer Res., March 15, 2007; 67(6): 2857 - 2864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hiraoka, T. Kimura, C. R. Logg, and N. Kasahara Tumor-Selective Gene Expression in a Hepatic Metastasis Model after Locoregional Delivery of a Replication-Competent Retrovirus Vector Clin. Cancer Res., December 1, 2006; 12(23): 7108 - 7116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Cross and J. K. Burmester Gene therapy for cancer treatment: past, present and future. Clin. Med. Res., September 1, 2006; 4(3): 218 - 227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Friedman, J. P. Tian, G. Fulci, E. A. Chiocca, and J. Wang Glioma Virotherapy: Effects of Innate Immune Suppression and Increased Viral Replication Capacity Cancer Res., February 15, 2006; 66(4): 2314 - 2319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. P. Le, H. N. Le, I. P. Dmitriev, J. G. Davydova, T. Gavrikova, S. Yamamoto, D. T. Curiel, and M. Yamamoto Dynamic Monitoring of Oncolytic Adenovirus In Vivo by Genetic Capsid Labeling J Natl Cancer Inst, February 1, 2006; 98(3): 203 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou, Q. Gao, G. Chen, X. Huang, Y. Lu, K. Li, D. Xie, L. Zhuang, J. Deng, and D. Ma Novel Oncolytic Adenovirus Selectively Targets Tumor-Associated Polo-Like Kinase 1 and Tumor Cell Viability Clin. Cancer Res., December 1, 2005; 11(23): 8431 - 8440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Thomas and J. L. Abbruzzese Opportunities for Targeted Therapies in Hepatocellular Carcinoma J. Clin. Oncol., November 1, 2005; 23(31): 8093 - 8108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Marques, D. Rebouillat, C. V. Ramana, J. Murakami, J. E. Hill, A. Gudkov, R. H. Silverman, G. R. Stark, and B. R. G. Williams Down-Regulation of p53 by Double-Stranded RNA Modulates the Antiviral Response J. Virol., September 1, 2005; 79(17): 11105 - 11114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Jeeninga, B. Jan, B. van der Linden, H. van den Berg, and B. Berkhout Construction of a Minimal HIV-1 Variant that Selectively Replicates in Leukemic Derived T-Cell Lines: Towards a New Virotherapy Approach Cancer Res., April 15, 2005; 65(8): 3347 - 3355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. O. Kirby, A. Rivera, D. Rein, M. Wang, I. Ulasov, M. Breidenbach, M. Kataram, J. L. Contreras, C. Krumdieck, M. Yamamoto, et al. A Novel Ex vivo Model System for Evaluation of Conditionally Replicative Adenoviruses Therapeutic Efficacy and Toxicity Clin. Cancer Res., December 15, 2004; 10(24): 8697 - 8703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Chu, D. E. Post, F. R. Khuri, and E. G. Van Meir Use of Replicating Oncolytic Adenoviruses in Combination Therapy for Cancer Clin. Cancer Res., August 15, 2004; 10(16): 5299 - 5312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Hobom and M. Dobbelstein E1B-55-Kilodalton Protein Is Not Required To Block p53-Induced Transcription during Adenovirus Infection J. Virol., July 15, 2004; 78(14): 7685 - 7697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Morley, G. MacDonald, D. Kirn, S. Kaye, R. Brown, and D. Soutar The dl1520 Virus Is Found Preferentially in Tumor Tissue after Direct Intratumoral Injection in Oral Carcinoma Clin. Cancer Res., July 1, 2004; 10(13): 4357 - 4362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Davydova, L. P. Le, T. Gavrikova, M. Wang, V. Krasnykh, and M. Yamamoto Infectivity-Enhanced Cyclooxygenase-2-Based Conditionally Replicative Adenoviruses for Esophageal Adenocarcinoma Treatment Cancer Res., June 15, 2004; 64(12): 4319 - 4327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ganly and B. Singh Topical ONYX-015 in the Treatment of Premalignant Oral Dysplasia: Another Role for the Cold Virus? J. Clin. Oncol., December 15, 2003; 21(24): 4476 - 4478. [Full Text] [PDF]
|
|
|
|
|
|
B. Hann and A. Balmain Replication of an E1B 55-Kilodalton Protein-Deficient Adenovirus (ONYX-015) Is Restored by Gain-of-Function Rather than Loss-of-Function p53 Mutants J. Virol., November 1, 2003; 77(21): 11588 - 11595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Stubdal, N. Perin, M. Lemmon, P. Holman, M. Bauzon, P. M. Potter, M. K. Danks, A. Fattaey, T. Dubensky, and L. Johnson A Prodrug Strategy Using ONYX-015-Based Replicating Adenoviruses to Deliver Rabbit Carboxylesterase to Tumor Cells for Conversion of CPT-11 to SN-38 Cancer Res., October 15, 2003; 63(20): 6900 - 6908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q.-T. Le and A. J. Giaccia Therapeutic Exploitation of the Physiological and Molecular Genetic Alterations in Head and Neck Cancer Clin. Cancer Res., October 1, 2003; 9(12): 4287 - 4295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Noya, C. Balague, N. S. Banerjee, D. T. Curiel, T. R. Broker, and L. T. Chow Activation of Adenovirus Early Promoters and Lytic Phase in Differentiated Strata of Organotypic Cultures of Human Keratinocytes J. Virol., June 1, 2003; 77(11): 6533 - 6540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Wein, J. T. Wu, and D. H. Kirn Validation and Analysis of a Mathematical Model of a Replication-competent Oncolytic Virus for Cancer Treatment: Implications for Virus Design and Delivery Cancer Res., March 15, 2003; 63(6): 1317 - 1324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Yan, G. Kitzes, F. Dormishian, L. Hawkins, A. Sampson-Johannes, J. Watanabe, J. Holt, V. Lee, T. Dubensky, A. Fattaey, et al. Developing Novel Oncolytic Adenoviruses through Bioselection J. Virol., February 15, 2003; 77(4): 2640 - 2650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Hecht, R. Bedford, J. L. Abbruzzese, S. Lahoti, T. R. Reid, R. M. Soetikno, D. H. Kirn, and S. M. Freeman A Phase I/II Trial of Intratumoral Endoscopic Ultrasound Injection of ONYX-015 with Intravenous Gemcitabine in Unresectable Pancreatic Carcinoma Clin. Cancer Res., February 1, 2003; 9(2): 555 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. D. Davis, M. Jefford, P. Parente, and J. Cebon Rational approaches to human cancer immunotherapy J. Leukoc. Biol., January 1, 2003; 73(1): 3 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wadler, B. Yu, J.-Y. Tan, R. Kaleya, A. Rozenblit, D. Makower, M. Edelman, M. Lane, E. Hyjek, and M. Horwitz Persistent Replication of the Modified Chimeric Adenovirus ONYX-015 in both Tumor and Stromal Cells from a Patient with Gall Bladder Carcinoma Implants Clin. Cancer Res., January 1, 2003; 9(1): 33 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Edwards, B. R. Dix, C. J. Myers, D. Dobson-Le, L. Huschtscha, M. Hibma, J. Royds, and A. W. Braithwaite Evidence that Replication of the Antitumor Adenovirus ONYX-015 Is Not Controlled by the p53 and p14ARF Tumor Suppressor Genes J. Virol., November 13, 2002; 76(24): 12483 - 12490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Reid, E. Galanis, J. Abbruzzese, D. Sze, L. M. Wein, J. Andrews, B. Randlev, C. Heise, M. Uprichard, M. Hatfield, et al. Hepatic Arterial Infusion of a Replication-selective Oncolytic Adenovirus (dl1520): Phase II Viral, Immunologic, and Clinical Endpoints Cancer Res., November 1, 2002; 62(21): 6070 - 6079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W. van Beusechem, P. B. van den Doel, J. Grill, H. M. Pinedo, and W. R. Gerritsen Conditionally Replicative Adenovirus Expressing p53 Exhibits Enhanced Oncolytic Potency Cancer Res., November 1, 2002; 62(21): 6165 - 6171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. O. Freytag, M. Khil, H. Stricker, J. Peabody, M. Menon, M. DePeralta-Venturina, D. Nafziger, J. Pegg, D. Paielli, S. Brown, et al. Phase I Study of Replication-competent Adenovirus-mediated Double Suicide Gene Therapy for the Treatment of Locally Recurrent Prostate Cancer Cancer Res., September 1, 2002; 62(17): 4968 - 4976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-W. Peng, C. J. TenEyck, E. Galanis, K. R. Kalli, L. C. Hartmann, and S. J. Russell Intraperitoneal Therapy of Ovarian Cancer Using an Engineered Measles Virus Cancer Res., August 15, 2002; 62(16): 4656 - 4662. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Bergsland and A. P. Venook Shedding Old Paradigms: Developing Viruses to Treat Cancer J. Clin. Oncol., May 1, 2002; 20(9): 2220 - 2222. [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. A. Ring Cytolytic viruses as potential anti-cancer agents J. Gen. Virol., March 1, 2002; 83(3): 491 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Geoerger, J. Grill, P. Opolon, J. Morizet, G. Aubert, M.-J. Terrier-Lacombe, B. Bressac de-Paillerets, M. Barrois, J. Feunteun, D. H. Kirn, et al. Oncolytic Activity of the E1B-55 kDa-deleted Adenovirus ONYX-015 Is Independent of Cellular p53 Status in Human Malignant Glioma Xenografts Cancer Res., February 1, 2002; 62(3): 764 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Adachi, P. N. Reynolds, M. Yamamoto, M. Wang, K. Takayama, S. Matsubara, T. Muramatsu, and D. T. Curiel A Midkine Promoter-based Conditionally Replicative Adenovirus for Treatment of Pediatric Solid Tumors and Bone Marrow Tumor Purging Cancer Res., November 1, 2001; 61(21): 7882 - 7888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. DeWeese, H. van der Poel, S. Li, B. Mikhak, R. Drew, M. Goemann, U. Hamper, R. DeJong, N. Detorie, R. Rodriguez, et al. A Phase I Trial of CV706, a Replication-competent, PSA Selective Oncolytic Adenovirus, for the Treatment of Locally Recurrent Prostate Cancer following Radiation Therapy Cancer Res., October 1, 2001; 61(20): 7464 - 7472. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Koch, J. Gatfield, C. Lober, U. Hobom, C. Lenz-Stoppler, J. Roth, and M. Dobbelstein Efficient Replication of Adenovirus Despite the Overexpression of Active and Nondegradable p53 Cancer Res., August 1, 2001; 61(15): 5941 - 5947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yver, J. J. Nemunaitis, and C. Cunningham Does Detection of Circulating ONYX-015 Genome by Polymerase Chain Reaction Indicate Vector Replication? J. Clin. Oncol., June 15, 2001; 19(12): 3155 - 3157. [Full Text] [PDF]
|
|
|
|
|
|
B. R. Dix, S. J. Edwards, and A. W. Braithwaite Does the Antitumor Adenovirus ONYX-015/dl1520 Selectively Target Cells Defective in the p53 Pathway? J. Virol., June 15, 2001; 75(12): 5443 - 5447. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
