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Page 4 of 11 Hirschberg et al. Neuroimmunol Neuroinflammation 2018;5:27 I http://dx.doi.org/10.20517/2347-8659.2018.31

Upon exposure to light of appropriate wave lengths, the photosensitizers induce the formation of short
range singlet molecular oxygen, destroying the intracellular vesicles membranes, thus leading to the release
of the contents of these vesicles into the cell cytosol. The released macromolecules can now exert their full
biological activity instead of being degraded by lysosomal hydrolases.

[34]
Norum et al. (2017) has examined the efficacy of PCI delivery of bleomycin (BLM-PCI) and its impact on
systemic anti-tumor immunity in an extra-cranial mouse model. Their results showed that both PDT and
BLM-PCI were incapable of inducing a curative effect in athymic mice at the light dose tested. In contrast,
50% of the light dose of that used in athymic mice resulted in a curative effect in 90% of the animals after
BLM-PCI and 70% after PDT in normal mice. Inhibition of tumor cell growth was observed when combined
with co-injection of splenic T cells from mice treated and cured with BLM-PCI. The anti-tumor immunity
induced by BLM-PCI was equal to that obtained with PDT treatment, but at a lower light dose. Furthermore,
the induced immune response after BLM-PCI was sufficient to reject tumor re-challenge immediately after
PCI and lasted for at least two months.

An additional and novel method for enhancing the efficacy of peptide vaccines in extra cranial studies has
[35]
been explored by Haug et al. (2018) utilizing PCI to promote the escape of trapped endocytosed peptides
into the cytosol of APCs. Their results showed that PCI caused a 30-fold increase in MHC class I/peptide
complex formation and surface presentation on APCs, and a subsequent 30- to 100-fold more efficient
activation of antigen-specific CTLs compared to using the peptide alone. These in vitro effects of PCI were
translatable in vivo by the successful induction of antigen-specific CTL responses to cancer antigens in
C57BL/6 mice following intradermal peptide vaccination and local light treatment. It is noteworthy that both
macrophages and DC were used as APCs with approximately equal efficacy in these experiments. If these
promising PCI strategies might be translatable to post-operative HGG treatment by the use of indwelling
balloon light applicators, as has been proposed and tried for both radiation and PDT treatment, remains to
be determined [36-39] .

PDT for the treatment of brain tumors
PDT has been investigated as an adjuvant for the treatment of malignant gliomas for approximately
35 years [39-43] . Although numerous clinical trials have been initiated, the vast majority have consisted of
uncontrolled phase I/II studies containing small numbers of patients. For example, in the single center
[39]
phase III trial reported by Eljamel et al. using both flourecent guided resction combined with ALA and
Photofrin repetitive PDT, a mean overall survival (OS) of the treatment group was 52.8 weeks compared to
[41]
24.6 weeks in the control group. In a phase II uncontrolled trial of 22 patients reported by Muragaki et al. ,
using talaporfin sodium as a PS, a median of survival of 99 weeks was observed. This compared favorably to
the 54-64 weeks OS obtained from previous trials employing standard post operative treatment consisting
of radiation and TMZ. Due to differences in methodology and types of malignant brain tumors treated,
it has been very difficult to evaluate PDT efficacy from these limited trials. For a more detailed account of
[42]
[43]
the results of a number of PDT clinical trials for HGG, Bechet et al. and Quirk et al. give an excellent
overview. Additionally, none of these clinical trials have included an evaluation of the effects of PDT on the
immune response to treatment. Overall, the results of PDT trials for malignant gliomas have been relatively
modest, thus providing the rationale for alternative PDT mediated treatment approaches such as PDT
induced immunotherapy.

PDT mediated immunity of brain tumors
There have been few experimental studies exploring the effects of direct PDT of brain tumors. Li et al. [44]
showed that PDT in vivo generated regional and systemic anti-tumor immunity in mice with G422 gliomas
in the brain. The infiltration of immune cells and the release of inflammatory factors, such as TNF-α and
IFN-γ, were increased in animals with G422 gliomas following PDT, compared to non-treated controls.