Fish of the day: Published: 10 Jul 2018
Photodynamic therapy mediated immune therapy of brain tumors **** Henry Hirschberg1, Kristian Berg2, Qian Peng3
Photochemical internalization (PCI), a derivative of PDT, has been shown to increase the efficacy of drugs, gene transfection as well as a variety of other anti-cancer agents that are taken up into cells by endocytosis[29-33]. PCI is based on the use of specially designed photosensitizers, such as AlPcS2a, TPPS2a, TPcS2a that localize preferentially in the membranes of endocytic and lysosomal intracellular vesicles. 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.
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 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 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 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 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"
Although the experience with PDT/PCI produced anti HGG vaccines is limited and no clinical trials have been done, PDT/PCI appears to be an inducer of immunogenic cancer cell death, an important step in the afferent phase of the immune anti-tumor response. Light activated induced immunotherapy therefore holds the potential to become a complementary therapeutic option for for patients with HGG. Taking into account the penetration limitations of light activated therapies in the brain the further development of ex vivo PDT/PCI generated APC or peptide vaccines seems the most attractive approach. A deeper and detailed understanding of the induction of the antitumor immunity induced by light activated therapies would allow in the defining of protocols which would focus and enhance the immune system to recognize and prevent the inevitable post-operative recurrence of the tumor. Combining PDT induced anti-tumor vaccines with other therapeutic modalities including check-point inhibitors, is an exciting field to explore. Although not discussed in this review both PDT and PCI have an effect on the vasculature and have been show to temporarily open the blood brain barrier in a limited site specific region[66-68]. What additional role this would play in the development of an effective and safe anti-HGG patient therapy, remains to be established.