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

Splenic lymphocytes, isolated from PDT-treated mice, were able to induce anti-tumor immunity in nude
mice. These workers could also demonstrate that PDT induced anti-glioma immunity was significantly
reduced in tumor bearing complement C3 knockout as well as in nude mice.

Although PDT/PCI has clearly demonstrated the induction of a significant anti-tumor immune response,
light based therapies are limited by the rapid absorption of light in tissue. For this reason the therapeutic
efficacy of PDT, using presently available PSs, has been clinically confined mainly to superficial relatively
flat tumors limited to skin and head and neck surfaces as well as bladder and esophagus. Effective PDT has
[45]
been shown to extend only up to a depth of approximately 4 mm in cerebral tissue . It would therefore not
affect the glioma cells in more distant infiltration zones in the resection cavity wall, which can be measured
in cm. In addition, the tumor cells infiltrating normal brain that lead to tumor recurrence are protected by
[46]
the blood brain barrier, so uptake of PS can be inadequate . To overcome the difficulties of in situ light
delivery and dosimetry in postoperative brain tumor resection cavities, PDT produced anti glioma vaccines
are a related approach that takes advantage of the immune stimulatory effects of ex vivo PDT of tumor cell
cultures.

PDT-PRODUCED CANCER VACCINES FOR GLIOMA
Ex vivo produced vaccines
[47]
In earlier studies, using extra cranial tumor models, Gollnick et al. demonstrated that lysates from PDT-
treated tumor cells were more effective as preventative vaccines than tumor cells treated with UV, ionizing
irradiation or cells subjected to freeze-thaw (F/T) cycles. Other groups have extended these results in several
extra cranial models and could demonstrate that PDT-treated tumor cells could act as therapeutic anti-
cancer vaccines [48,49] .

PDT generated vaccines against glioma cells have taken the form of CD activation by the use of crude tumor
lysates, acid eluted crude lysates, and in vitro co-culture of PDT treated glioma cells and DC or macrophages
(Ma) acting as APCs. Figure 2 illustrates the basic concept for an experimental PDT-APC co-culture vaccine.

The generation of vaccines in experimental models using PDT has been explored by a number of groups. For
example, in an in vitro study, employing human glioma spheroids and dendritic cells from human donors,
[50]
Etminan et al. (2011) showed that ALA-PDT of glioma spheroids in vitro promoted DC attraction, uptake
of tumor antigens and maturation of DCs, three important initial steps of the afferent phase of adaptive
immunity. Co-cultured DCs with ALA-PDT-treated spheroids promoted the induction of CD83 (a marker
for mature DCs) and upregulation of the co-stimulatory molecules CD40, CD80 and CD86. Additionally
HSP-70 was upregulated on the spheroids after ALA-PDT treatment.

[51]
Shixiang et al. generated DC vaccines using Photofrine-PDT-treated C6 glioma cell to produce antigenic
peptides to activate DCs ex vivo. Immune response parameters between DC vaccines from PDT acid-
eluted induced supernatants, DC vaccines from PDT-induced C6 supernatants or DCs exposed to antigens
generated by direct acid elution only or freeze-thawing. Effects of these adaptively transfer DCs on host
immunity were evaluated by measuring cytokine induction, as well as assessing DC-induced cytotoxic T
lymphocyte (CTL)-mediated lysis of C6 target. Their results demonstrated that PDT-acid elution resulted in
more effective DC differentiation associated with a high expression of CD80 and MHC-II compared with the
other vaccine treatment groups. In addition the induction of the highest rat serum levels of IL-12 and TNFα
and the lowest IL-10 levels were observed in the PDT acid eluted peptide group. Spleen cells isolated from
these animals effectively mediated lysis of C6 target cells. They concluded that PDT of C6 cells significantly
enhanced tumor cell immunogenicity compared to freeze-thawed C6 cells.