OncoLog, Volume 61, Number 5, May 2016 Page: 2
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Intratumoral Therapies
[Continued from page 1]The phase I portion of the trial
found no dose-limiting toxic effects.
The main side effect was fever, which
was manageable, although one patient
experienced systemic inflammatory re-
sponse syndrome necessitating emer-
gency care.
Thus far, Dr. Subbiah said, analyses
of tumors injected with the vaccine
found increases in tumor- infiltrating
lymphocytes. However, in the current
trial, only one tumor per patient is in-
jected, and patients with multiple tu-
mors have had stable disease at best
in their noninjected tumors.
"Biopsies of noninjected tumors
showed some distant effects, but these
effects were weak," said Ravi Murthy,
M.D., a professor in the Department
of Interventional Radiology, who per-
forms the image-guided intratumoral
injections for patients in the trial. "In
the next study, we'll inject multiple tu-
mors-perhaps up to five sites-multi-
ple times."
Another strategy for future trials
might be to combine an intratumoral
vaccine with an inhibitor of an immune
checkpoint such as programmed cell
death protein 1 (PD-1) or the PD-1
ligand (PD-L1). Dr. Subbiah said that
such combination therapy might create
both local and systemic effects.
Oncolytic bacteria
The concept of using bacteria to
treat cancer may sound radical, but it
is hardly new. In the 1890s, William
B. Coley, a surgeon and pioneer of im-
munotherapy, observed that cancer
patients with bacterial infections some-
times experienced tumor regression.
But until recently the risks associated
with bacterial infection outweighed the
benefits of bacteria-based treatment for
cancer patients.
A nontoxigenic strain of bacteria,
Clostridium novyi-NT, was engineered
to be capable of germinating only in a
hypoxic environment such as that in
some tumors. "C. novyi-NT is not capa-
ble of germinating in normal tissue be-
cause the oxygen levels are too high,"
said Filip Janku, M.D., Ph.D., an assis-Intratumoral injections (other than those
for brain tumors) can be performed using
a multipronged array needle and a proce-
dure similar to that used for image-guided
biopsy. Inset: Computed tomography
shows the injection of a therapeutic agent
into a tumor. Images courtesy of Dr. Ravi
Murthy.
tant professor in the Department of In-
vestigational Cancer Therapeutics. "But
C. novyi-NT is capable of germinating
in hypoxic cancer tissue and causing
lysis-the destruction of the tumor."
Hypoxic tumors historically have
been difficult to treat. The limited
blood supply to the tumors hampers
the delivery of systemic agents. Also,
the lack of molecular oxygen, which
acts as a radiosensitizer, limits the effi-
cacy of radiation therapy against hy-
poxic tumors. Bacteria that target such
tumors could therefore be very useful.
In the first clinical trial of C. novyi-
NT, which was not conducted at MD
Anderson, the bacteria were injected
intravenously. "The theory was that
the bacteria would be selectively deliv-
ered to the tumor, which did occur;
however, the problem was that some
tumors were not accessible by surgery,
which made adverse events difficult to
manage," Dr. Janku said. "It was felt
that intratumoral injection would work
better because we can select a lesion
that is accessible so that we can con-
trol for potential collateral damage."C. novyi-NT is injected intratumor-
ally in an ongoing multicenter trial
(2013-0549) for which Dr. Janku is MD
Anderson's principal investigator. The
C. novyi-NT injection is an outpatient
procedure, but the study's protocol re-
quires patients to be hospitalized for 7
days after the injection so that immedi-
ate care can be given in case of adverse
events. As a precaution, all patients re-
ceive oral doxycycline starting on the
seventh day after C. novyi-NT injection.
Although preliminary data from the
current trial are not yet available, Dr.
Janku estimates that some level of local
response is seen in about one-third of
patients. Some of these responses have
been dramatic, with complete destruc-
tion of the tumor in a few days.
Side effects of the treatment can be
dramatic as well. For example, the first
patient treated in the trial had a tumor
surrounding the right humerus. The
tumor was injected with C. novyi-NT
and was destroyed, but the patient suf-
fered a right humerus fracture 2 months
later because the bone was too fragile
without support from the large sur-
rounding tumor. "We had a bad conse-
quence of a good effect," Dr. Janku said.
Other patients had systemic inflamma-
tory reactions that included fever, low
blood pressure, and coagulopathy; these
reactions were controlled by antibiotics
and other supportive measures. "The
reaction seems to be mediated by cyto-
kines rather than bacteremia because
we don't see bacteremia in these pa-
tients," Dr. Janku said.
Researchers think the bacteria works
through two mechanisms. The first, di-
rect lysis of the tumor, is very rapid.
The second is the abscopal effect: the
immune system is primed by the de-
struction of the tumor to recognize the
cancer. "It's still too early to tell, but
some patients seem to have signals of
a systemic response," Dr. Janku said.
"We see a slowdown in the growth of
the tumors that were not injected, but
that effect doesn't last very long. Data
suggest that this therapy can be even
more effective when combined with
some immune checkpoint inhibitors."2 OncoLog May 2016
FRI I
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University of Texas M.D. Anderson Cancer Center. OncoLog, Volume 61, Number 5, May 2016, periodical, May 2016; Houston, Texas. (https://texashistory.unt.edu/ark:/67531/metapth838991/m1/2/: accessed July 17, 2024), University of North Texas Libraries, The Portal to Texas History, https://texashistory.unt.edu.; crediting UNT Libraries Government Documents Department.