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Pearce et al. Neuroimmunol Neuroinflammation 2018;5:47 I http://dx.doi.org/10.20517/2347-8659.2018.46 Page 11 of 16

the DCs and the context in which the DC presents the antigen. To elicit the appropriate lymphocyte and
immune response, DCs must present tumor-specific or tumor-associated antigens, upregulate expression
of MHC-I and II in conjunction with adhesion and co-stimulatory molecules, and induce secretion of
[83]
stimulatory and anti-tumor cytokines including IL-12, IL-15, IL-18, and IFN-γ .
Certain lymphocytes possess inherent capabilities to fight cancer. However, cancers may lack a sufficient
supply of tumor antigens to stimulate this immune response. DC vaccines address the lack of tumor antigen
by supplying antigen and stimulation to DCs ex vivo. Patients can then be vaccinated with these tumor-
specific DCs. By manipulating DCs, both in terms of the antigens they present and the context by which
they do so, activation of lymphocytes can be manipulated in order to yield an anti-tumor response.

Clinical trials using DC vaccines have employed a variety of antigen loading strategies which include pulsing
[84]
maturing DCs with autologous-tumor lysate . In this technique, DCs must be enriched and matured from
monocytes obtained from individual patient’s peripheral blood mononuclear cells [84-87] . The monocytes are
[88]
then expanded and differentiated into immature DCs through exposure to GM-CSF and IL-4 . Immature
DCs are loaded with antigens and matured before being administered to patients as a vaccine.

Pulsing maturing DCs with autologous-tumor lysate has made the most progress in GBM therapeutic
outcomes. Northwest Biotherapeutics’ DCVax®-L has recently shown positive results in a phase III clinical
trial [Table 5]. Patients selected were between 18 and 70 years of age, and had just been newly diagnosed with
GBM. Following surgical resection (the source of autologous tumor-lysate) and chemoradiotherapy, patients
were given a series of DCVax®-L injections in addition to monthly administration of TMZ. Median OS was
23.1 months, with 25.4% of patients surviving for more than three years post-surgery. This therapy was also
well tolerated, with only 2.1% of patients demonstrating grade 3 or 4 adverse events which may have been
[89]
related to surgery and chemoradiotherapy .
Smaller trials using autologous-tumor lysate pulsed vaccines have demonstrated similar safety and efficacy.
In the University of Navarra phase II trial, autologous DC vaccines were administered to 31 patients who had
[90]
a median OS of 23.4 months . The high grade glioma-2006 phase I and II trials administered autologous
[91]
DC vaccines to 77 patients in total with a median OS of 19.4 months , and the phase II DENDR1 trial
[92]
administered autologous tumor lysate vaccines to 24 patients demonstrated a median OS of 20.1 months .
Compared to the 14 months OS following GBM diagnosis and standard of care, DC vaccines pulsed with
autologous tumor lysate have demonstrated a substantial and consistent increase in OS, with little to no
adverse events.

More recent endeavors have sought to tailor protein-specific DC vaccines through lysates composed of
[87]
select tumor-associated antigens or by transfecting DCs with nucleic acids for tumor-specific or tumor-
[93]
[94]
associated antigen , or with cytomegalovirus RNA . A phase I study pulsed DC with lysate containing
tumor-associated antigens including human epidermal growth factor receptor 2 (HER2), tyrosinase related
protein-2, gp100, melanoma-associated antigen 1 (MAGE-1), IL13Rα2, and absent in melanoma 2 (AIM-2),
proteins which are enriched in GBM cancer stem cells (GCSC). The multi-epitope-pulsed DC vaccine was
used to vaccinate 16 patients with newly diagnosed GBM. Median OS was 38.4 months and improved OS
correlated with expression of AIM-2 and MAGE-1 in the tumor. Notably, a decrease was seen in GCSC
marker CD133, suggesting that the multi-epitope-pulsed DC vaccine had successfully reduced the population
[87]
of cancer stem cells , potentially accounting for the significant increase in median OS, nearly three times
that seen with the standard of care.

Transfection of DC to induce expression of tumor-specific or tumor-associated proteins has also
demonstrated success in treating GBM. In a phase I clinical trial GCSC mRNA was isolated from brain