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Page 2 of 11 Hirschberg et al. Neuroimmunol Neuroinflammation 2018;5:27 I http://dx.doi.org/10.20517/2347-8659.2018.31

classification of the tumor and reducing tumor load, allowing maximum effect of postoperative therapy.
Despite employing modern imaging and surgical techniques, that increase the incidence of gross tumor
[1,2]
resection, the tumor invariably recurs, usually in the vicinity of the surgical resection cavity . The
therapeutic goal following gross surgical resection of brain tumors therefore is to prevent recurrence by
eliminating the infiltrating tumor cells both remaining in the margins of the resection cavity as well as
remote from the tumor site. With this goal in mind anti-cancer immunotherapy is being actively researched
as an important therapeutic modality for the treatment of HGG. Of the several methods to induce effective
anti-tumor immune response, photodynamic therapy (PDT) has some potentially unique properties. PDT
can induce combinations of apoptosis, autophagy and necrosis and immunogenic cell death, depending on a
number of factors including type of photosensitizer, light dose and dose rate. It is the purpose of this review
to focus mainly on the studies related to PDT-generated anti-tumor immunity and vaccines for gliomas.

Photodynamic therapy
PDT of tumors requires the topical, systemic or oral administration of a photosensitizing compound,
[3-8]
illumination of the tumor area by light of a specific wavelength and the presence of oxygen . The photon
energy activates the photosensitizer and initiates a complex photochemical reaction that generates cytotoxic
reactive oxygen species (ROS) as shown in Figure 1. The light activated photosensitizer (PS) transfers
energy to molecular oxygen creating singlet oxygen, a highly reactive and toxic species that rapidly reacts
with cellular components causing oxidative damage, ultimately leading to cell death. Singlet oxygen causes
mainly membrane damage by oxidizing amino acids, unsaturated fatty acids and cholesterol. Both the
cell membrane as well as intracellular membranes such as mitochondria, endo-lysosome and endoplasmic
[8]
reticulum damage is induced by PDT is largly dependent on the type of photosensitizer used .
Different photosensitizers react with specific intracellular organelles, resulting in cell death via several varied
mechanisms [Table 1].

Unlike ionizing radiation and many chemotherapeutic agents, PDT does not exert its effects via DNA
[7]
damage . Additionally, PDT is a highly site-specific form of treatment, since its effect is restricted to the
immediate vicinity of the region of illumination.

PDT TREATMENT INDUCED ANTI-TUMOR IMMUNITY
Tumor destruction caused by PDT is not only a result of direct tumor cell toxicity via the generation of
ROS but it is well established that there is also a significant immunological component involved. The great
majorities of experimental studies have been done on extra-cranial tumors, and are reviewed in several
extensive recent publications [9-14] .

The first evidence for induction of a tumor-specific immune response came by the demonstration that
[15]
normal mice cured by PDT were able to resist a re-challenge with tumor cells in a tumor-specific manner
while immunosuppressed counterparts were not able to resist the re-challenge. Induction of systemic and
memory immunity following PDT treatment has been verified in numerous studies. Systemic immunity
following PDT treatment has been demonstrated by the ability of a locally induced immune response to
affect distant non-treated areas [16-19] . Treatment of subcutaneous (s.c) primary tumors that led to 90%-100% of
tumor ablation after PDT treatment showed a significant reduction of metastasized lung tumors compared
to non-treated controls. In particular, a study using s.c colon carcinoma treated with hypericin-PDT yielded
[20]
100% of tumor cures, and i.v. re challenge with viable tumor cells showed no development of new tumors .
[21]
PDT has been shown to induce apoptosis, necrosis, autophagy and immunogenic cell death (ICD) . ICD is
a cell death mode where the dead and dying cancer cells expose and/or release damage associated molecular