Page 79 - Read Online

are testing the RRV suicide gene therapy in recurrent Perhaps one solution would be to offer immunotherapy
glioma patients (www.clinicaltrials.gov, NCT01156584; upfront, or integrate it with standard of care treatments.
NCT01470794; NCT01985256).
Therapeutically, the chronic inflammation that
Most recently, our attention has turned to preclinical develops and worsens in correlation with glioma
studies examining a more aggressive combined grade promotes a skewed “type 2” inflammatory
immunogene therapy approach. RRV-transduced state, both in the local tumor microenvironment and
alloCTL have effector and delivery functions. If combined systemically. [40] Once gliomas are in the progression
with pro-drug administration, the immunogene therapy phase (i.e. pro-wound repair) deactivation of
is more efficacious in vivo than the individual therapies T cell-mediated immune response occurs. To effectively
and control groups. Better extension was obtained in mount a host-generated, anti-tumor response immune
the survival of mice bearing orthotopic intracranial homeostasis must be “reset” and skewed towards a
implants of breast carcinoma. [109,110] The immunogene “type 1” inflammatory state. An interesting possibility
therapy is similarly being tested in a syngeneic mouse to generate a (Type 1) inflammatory response is
glioma model. If the data look as promising in this the administration of attenuated microbes. Indeed,
model after optimizing doses and timing, combining Bacillus Calmette Guérin (BCG) is effectively used
the therapies should be easily translatable since both for immunotherapy of superficial bladder cancer. [111]
are being individually tested now in the clinic. The success of BCG as a therapeutic modality for
low-grade bladder cancer can be effectively attributed
Challenges in immunotherapy to two characteristics: immunogenicity and anti-tumor
Immunotherapeutics do not always robustly provide targeting. In BCG tumor models, the initial presence
efficacious treatment for gliomas. This may be of both Th1 and Th2 inflammatory cytokines was
due to the concurrent activation of both pro- and also observed, but then later skewed towards Th1
anti-inflammatory responses and this may have clinical cytokines that in particular involved the up-regulation
and therapeutic consequences [Figure 3]. Clinically, of IFN-γ. [112] However, the situation is complicated
immunotherapy entails protracted treatments. While for the treatment of high-grade glioma. Studies of
manageable in theory, maintaining patients on immune immunosuppression have shown that once “type 2”
treatments over the extended period necessary to inflammation has been activated, challenge with a
effect a cell-mediated immune response has proven bacterial lipopolysaccharides fails to skew the cytokine
difficult. [102] Furthermore, inflammation associated expression towards “type 1” in a time-dependent
with immune therapy is indistinguishable from tumor manner. Thrombospondin receptor (CD36) expressed
[29]
progression on follow-up magnetic resonance images; on macrophages among other cell types formed a
a clinician must give benefit of doubt and recommend “molecular bridge” between anionic sites on apoptotic
other treatments inhibiting possible tumor growth. The cells and CD36. This cell-cell signaling interaction was
immunotherapy is unfortunately either interrupted or sufficient to signal the resolution of inflammation and
incompletely tested. With the inability to distinguish activation of “type 2” inflammation. Further, antibodies
pseudo- from tumor- progression, completion of trials is against thrombospondin prevented its binding to CD36
difficult, especially with the availability of drugs such as receptor leading to a decrease of IL-10 and restored
Avastin, Temodar, or other chemo- or radio-therapeutics TNF-α, IL-1β, and IL-12 in the presence of apoptotic
for use at recurrence. Developing an appropriate set of cells. Thus, it appears that immune homeostasis must
neuroimaging parameters to distinguish inflammation first be restored for high-grade tumors that are driven
from tumor growth would help advance this field. by “type 2” inflammation before further intervention

Figure 3: Activation of pro- and anti-inflammatory responses in glioma patients. The flowcharts illustrate (a) the “normal” physiologic processes in the inflammatory
response and its resolution; (b) the physiologic processes occurring when glioma-secreted factors influence a state of chronic inflammation resulting in glioma
progression; and (c) how rapid glioma growth creates a necrotic/hypoxic environment supporting tumor proliferation and immunosuppression

72 Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014