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SHELDON ET AL.
The decision to examine only AE reported in 10 or
more trials was to aid in limiting the number of cancerspecific
AE; however, there were still several AE that
appeared to be disease related, such as headache, which
occurred in glioma and head and neck cancer trials. Another
AE of interest was transaminitis as liver toxicity is a
known effect of Ad553; however, the majority of cases
were mild with only three grade 4 AE (2 in head and neck
cancer trials and 1 in glioma). The only statistically significant
transaminitis occurred in a single pancreatic trial,
which co-treated with surgery, making it difficult to separate
the disease and the treatment.
When comparing single versus multiple dosed trials,
there was an increase in AE with multiple doses, except in
drug-related AE. There was a significantly higher rate of
grade 4 AE across all, except the drug-related subgroup.
Interestingly, the drug-related subgroup had less
overall grade £3 AE with a significant decrease in grade 3
AE. While an increase in AE with multiple doses and interventions
would be expected, it is unclear why the drugrelated
subset had the opposite trend. One possibility is that
the single dosed arm in the drug-related subgroup reported
the fewest number of AE categories (12.7) compared to the
other subgroups (28, 32, and 31 AE categories). In addition,
there were only three trials with 26 patients in the drugrelated
AE single dose arm compared to 116 patients in the
multiple-dose arm.
Ad5 can be engineered to be replication competent (i.e.,
oncolytic) or incompetent depending on the design of the
experimental drug. When comparing these drugs, there
appears to be an increase in AE with replication competent
when comparing grade ‡3 and grade 3 AE across all
studies, which is not repeated in subgroup analysis and is
of unclear significance. There is also an increase of grade 4
AE in replication competent compared to replication incompetent
in the unedited subgroup. The difference between
these AE mainly comes from one study of
metastatic sarcoma co-treated with chemotherapy.
In this one study, there were 9 (8.7%) grade 4 AE out of
a total 104 AE in only 6 patients, compared to all the other
studies that had a combined grade 4 AE rate of<2%. If this
one study was excluded, the average grade 4 AE would
drop to 1.3%, in line with the remainder of the trials. It is
unclear why this one study has a higher rate of AE. More
importantly, there does not seem to be any significant
difference in AE when comparing drug-related studies,
indicating that replication-competent Ad5 experimental
drugs do not inherently indicate a higher risk.
In undertaking any comparison of multiple trials, the
main difficulty is ensuring an equal comparison across
studies. While the most accurate way would be to compare
patients affected, only a small percent (34%) of trials provided
these data. Therefore, the analysis mainly compared
the proportion of serious AE across studies, which still
provided a risk of AE, although not an absolute number.
In addition, while all trials used CTCAE to report their
AE, varying number of categories were reported in each
trial. While most articles specified the subtype of AE reported
(unedited vs. drug-related vs. most frequent), those
that did not specify were assumed to be unedited. However,
the broad range of AE categories reported (5-69
categories) make it likely that even the unedited trials still
reported AE with some amount of author discretion.
Another limitation is that most trials treated at multiple
dose levels, but did not separate their AE by level, making
it impossible to determine if the dose of Ad5 had an effect
on the AE. Trials also did not specify their specific chemotherapy
or radiation dosages or regimens, making this
impossible to analyze. Additional studies reporting these
data points will help to further study the safety profile of
Ad5, as well as allow differentiation by invasiveness of
procedure and stage of disease.
CONCLUSION
While there are still questions to be answered, the
overall picture of this broad analysis supports the continued
use ofAd5 as a safe delivery vector for oncologic gene
therapy with relatively few AE, especially in terms of
mortalities and life-threatening AE.
ACKNOWLEDGMENTS
The authors acknowledge Dr. Kelly Banas for gene
therapy writing support.
AUTHORS' CONTRIBUTIONS
Y.S.: conceptualization (lead), formal analysis (lead),
and writing original draft (lead). G.T.: writing original
draft (supporting), and reviewing and editing original draft
(lead). B.C.Y.: edited and reviewed (equal). E.K.: edited
and reviewed (equal). N.P.: edited and reviewed (equal).
S.W.: edited and reviewed (equal), and final approval of
version to be published.
AUTHOR DISCLOSURE
No competing financial interests exist.
FUNDING INFORMATION
No funding was received for this article.
SUPPLEMENTARY MATERIAL
Supplementary Table S1
Supplementary Table S2
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