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cytokines in response to lipopolysaccharide stimuli. [94] of the experimental agent. Surgical resection serves
This attribute is most likely an evolutionarily hard-wired multiple purposes. Importantly, resection reduces tumor
negative feedback mechanism to preserve the cyclic burden and the immunosuppressive factors present in
response curve characteristic in NF-κB signaling. [95] the tumor microenvironment that will enhance the
We propose that the presence of IL-10 in the glioma effectiveness of the immunotherapy. Also, the degree
microenvironment substantially dampens the transient of the mobilized inflammatory response is minimized.
pro-inflammatory activating pulse delivered by The tumor specimens are valuable since they serve as
tumor-lysate activated DCs and booster injection of a source of tumor associated antigens to make vaccines.
TLR agonist. This mechanism is circumvented in NF-1 Likewise, tumor specimens can be processed and placed
heterozygous microglia through deregulated Ras/Rac1/ into culture where the cells can serve in in vitro studies
JNK/c-Jun/AP-1 signaling, which operates in parallel and and as target cells for cytotoxicity testing. [98]
independent of the NF-κB signaling pathway [Figure 2].
Deactivating antibodies against IL-10 may restore the We have successfully used tumor-lysate pulsed DC
formation of the NF-κB heterodimer ultimately leading vaccines that are given with or without TLR agonist;
to a M1 microglia phenotype without overshooting the they represent an active immunotherapy strategy
pro-inflammatory response, which may have detrimental designed to enhance cell-mediated immunity. [99]
effects on patients. Then, effectors cells mobilized by The conclusion of a phase II clinical trial has shown
the vaccine can operate and maintain functionality by the vaccine treatment to extend median survival
encountering a skewed microenvironment to a “type 1” to 34 months. It appears that the treatment has a
pro-inflammatory state. Ultimately tumor regression relevant role in flagging the tumor cells remaining
may lead to a natural resolution of the inflammatory after surgical resection. [100] We have also examined
phase mediated in large part by IL-10. a passive immunotherapy approach that utilizes
effector alloreactive cytotoxic T lymphocytes (alloCTL)
IMMUNE AND GENE THERAPEUTICS THAT that are intratumorally implanted with low doses of
ENGENDER INFLAMMATION Interleukin-2. [101] The allogeneic CTL are trained in vitro
to target patient human leukocyte antigens that are
Our translational immunotherapy research team has present on glioma cells but not on normal neuroglia.
a long-standing interest in the development of novel A pilot clinical study described at www.clinicaltrials.
therapeutic options for brain tumor patients. Our group gov (NCT00068510), [102,103] suggested a clinical response
and others have preclinically explored active and in recurrent WHO grade III gliomas. These studies led
passive immune and gene therapy approaches, some to a second phase I dose escalation trial that is currently
of which are translated to the clinic. [96,97] The therapies open for patient enrollment at University of California,
are generally designed as adjuvant treatments and Los Angeles (www.clinicaltrials.gov; NCT01144247).
entail tumor resection followed by administration
In another gene therapy approach, transduction of
glioma cells with retroviral replicating vectors (RRV)
coding for pro-drug activating enzymes followed by
their exposure to non-toxic pro-drug has also proven to
be another potent cancer therapy strategy. Non-cytolytic
RRV are particularly well suited for the treatment of
primary or metastatic brain tumors. In the CNS, normal
brain neuroglial cells are relatively quiescent, thus,
the dividing glioma cells are selectively targeted by
the RRV. After achieving genomic integration, the
viral constructs can stably seed the tumor mass and
replicate within the tumor cells even as they infiltrate
in vivo. Pro-drug administration results in targeted
destruction of the cells harboring the RRV. Such
an approach utilizes RRV coding for yeast cytosine
deaminase. Upon administration of the pro-drug,
Figure 2: Signaling imparted through interactions of advanced glycation end
products (AGE) with the receptors for AGE (RAGE) versus interactions of 5-fluorocytosine, the drug is converted to its toxic
pathogen associated molecular pattern (PAMP) or damage associated molecular form, 5-fluorouracil. If sufficient time is allowed for
pattern (DAMP) molecules with Toll like receptors (TLR). The schematic shows RRV spreading, the administered prodrug converts to
the two signaling pathways that operate in parallel but independent to each
other; both lead to expression of pro-inflammatory cytokines. The presence of a cytotoxic form, killing infected cells and providing
anti-inflammatory (M2) cytokines inhibits the expression of pro-inflammatory tumor cytoreduction. Predicated upon successful and
cytokines of both inflammatory response pathways. NF: Neurofibromatosis;
JNK: Jun‑NH2‑kinase extensive preclinical testing, [104-108] phase I clinical trials

Neuroimmunol Neuroinflammation | Volume 1 | Issue 2 | September 2014 71