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alone. Ad5 co-treated with radiation and Ad5 co-treated
with surgery both had a statistically significant increase of
grade 3 AE (radiation-6.7% vs. 3.3%,p= 0.04 and surgery
8.2% vs. 3.3%, p= 0.03).
In the trials that reported only drug-related AE, the only
statistically significant difference was Ad5 co-treated with
chemotherapy in grade 3 AE compared to Ad5 alone(8.6%
vs. 4.7%, p= 0.01). There was no significant difference in
the comparison of the other co-treatment arms.
Trials that reported only the most frequent AE, Ad5 cotreated
with radiation had statistically significant fewer
grade ‡3 (5.9% vs. 15.6%,p= 0.00) and grade 3 (5.9% vs.
15.1%, p= 0.00) AE than Ad5 alone. Ad5 co-treated with
surgery also had significantly fewer grade ‡3 AE than Ad5
alone (7.5% vs. 15.6%, p= 0.00).
Results by grade of AE. Table 3 reports grade ‡3
AE with the highest frequency. Overall, lymphopenia was
the most common serious (grade ‡3) AE (20.6%), followed
by dyspnea (8.7%), neutropenia (8.6%), nausea
(7.1%), hyponatremia (7.1%), transaminitis (6.8%), anemia
(6.1%), headache (5.7%), and weakness (5.7%).
The most frequent grade 3 AE were lymphopenia
(17.2%), dyspnea (7.7%), and nausea (7.1%). Ad5 cotreated
with chemotherapy was statistically increased in
grade 3 leukopenia compared to Ad5 (11.1% vs. 0%). Ad5
co-treated with radiation was statistically increased in
grade 3 lymphopenia (25.4% vs. 7%p= 0.02) and grade 3
hypernatremia (9.1% vs. 0% p= 0.05) compared to Ad5
alone. Ad5 co-treated with radiation was statistically decreased
in grade 3 weakness compared to Ad5 alone (0%
vs. 9.6% p= 0.00). Ad5 co-treated with surgery was statistically
increased in grade 3 transaminitis compared to
Ad5 alone (25% vs. 2.4% p= 0.00).
The most frequent grade 4 AE were neutropenia
(4.6%), lymphopenia (3.3%), and leukopenia (3.1%). Ad5
co-treated with chemotherapy had statistically increased
grade 4 neutropenia compared to Ad5 alone (19% vs. 0%
p= 0.02). Ad5 co-treated with surgery was statistically
increased in grade 4 anemia compared to Ad5 alone (8.3%
vs. 0% p= 0.04). Common grade 4 AE reported in <10
trials were hyperbilirubinemia (4.4%), pneumonia (3.1%),
and pulmonary emoblism (6.7%).
Multiple dosing and replication characteristic outcomes.
Trials which dosed with either single or multiple
injections (range 1-25 doses) and reported a total
number of AE (grade 1-5) were compared to one another
(Supplementary Table S1). The average number of doses
in trials with multiple injections was calculated by using
the minimum and maximum number of possible doses to
determine a range (overall 4.4-6.2 doses). Overall, the
multiple dosed trials had statistically significant more
grade ‡3 (12.4% vs. 8.2%,p= 0.00) and grade 4 (2.2% vs.
0.3%, p= 0.00) AE when compared to single-dosed trials.
Trials that reported unedited AE had an average multiple
dose range between 2.4 and 4.4. There was a statistically
significant increase with multiple compared to
single dosing in grade 4 AE (2.4% vs. 0.6%, p= 0.01). In
drug-related trials, there was an average multiple dose
range between 4 and 6.4. There was a statistically significant
decrease with multiple compared to single dosing in
grade 3 AE (5.6% vs. 13.3%, p= 0.02).
In trials reporting most frequent AE, the average dose
range was between 7.8 and 8.7. With multiple compared to
single dosing, there was a statistically significant increase
in grade ‡3 (19.4% vs. 5.8%,p= 0.00), grade 3 (19.8% vs.
5.8%, p= 0.00), and grade 4 (2.5% vs. 0%, p= 0.00) AE.
AE were compared by replication-competent versus
replication-incompetent Ad5 as replication-competent
Ad5 continues to proliferate in the tumor cells and could
be expected to cause more AE (Supplementary Table S2).
The mechanism of action of replication-competent therapeutics
was mainly oncolytic, except for 2 suicide drugs
and 4 drugs, which were combinations of oncolytic with
other mechanisms.
In trials reporting their total (grade 1-5) AE, there was
a statistically significant increase of grade ‡3AE(11.6%
vs. 8.8%, p = 0.02) and grade 3 AE (10.7% vs. 7.6%,
p = 0.01) in replication-competent Ad5 when compared
to replication incompetent. In trials that reported only
unedited AE, there was a statistically significant increase
with replication competent in grade 4 (2.7% vs. 1.1%,
p = 0.05) AE compared to replication incompetent. There
was no other significant difference between replicationcompetent
and replication-incompetent arms when
comparing trials reporting drug-related or most frequent
AE.
DISCUSSION
Gene therapy has the potential to revolutionize cancer
treatment as we know it. To fulfill this promise, in addition
to a sound experimental drug, an optimal delivery vector
needs to be available. The use of adenovirus vectors will
certainly expand the tool box for drug development.
However, it is important that we critically evaluate all
aspects of any innovation, especially its safety. A real
safety concern about Ad5 as a viral vector was raised
following the death of a young patient who was treated for
an inherited enzyme deficiency.
Following this tragic event, there was reasonable cause
for concern about the safety of Ad5 as a viral vector.1
Multiple publications have investigated this specific incident
and many questions were raised about the cause of the
patient's death, including the possibility that the cytokine
storm was a result of adenovirus exposure. The other
possible causes were the administration of the clinical trial
or drug. In brief, certain modifications to the protocol of
that trail did not undergo IRB approval/review and there
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