NorthWest Biotherapeutics Inc (NWBO)

[Lykiri]

Flipper,

Thank you for the information. It is believed that Topical 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT) can induce anti-tumor immune responses through dangerous signals damage-associated molecular patterns (DAMPs).
I agree that the use of DCvax-L in combination with ALA-PDT seems promising.

I believe the European surgeons mainly used 5-ALA induced FIGR.
FIGR = Fluorescence image guided surgical resection.
IMO not many patients (DCvax-L trial) had Photoferin repetitive photodynamic therapy (rPDT) in addition to 5-ALA-FIGR,

Article:
5-ALA Fluorescence Image Guided Resection of Glioblastoma Multiforme: A Meta-Analysis of the Literature.
https://www.mdpi.com/1422-0067/16/5/10443/htm

Article:
5-ALA in the management of malignant glioma.

The Concept of 5-ALA Based Photodynamics for Diagnosis and Treatment of Malignant Glioma

Five-aminolevulinic acid (5-ALA) is a precursor of fluorescent and phototoxic protoporphyrin IX (PpIX) in the heme biosynthesis pathway. Due to the optical properties of PpIX and the sensitivity of its synthesis to the intracellular metabolic activity, it has potential as a diagnostic (via fluorescence) as well as therapeutic (via phototoxicity) agent. The concept relies on a selective accumulation of PpIX in malignant glioma cells upon a systemic delivery of 5-ALA. The fluorescence of PpIX can easily be imaged intra-operatively and guides surgery in real-time without any concerns about brainshift. 5-ALA has gained clinical approval for fluorescence guided surgery (FGS) of malignant glioma in many countries, most recently (June 2017) in the USA 16. The corresponding technical implementation in surgical microscopes is intended to be applied for glioma of WHO grades III (mostly anaplastic astrocytoma) and IV (mostly GBM) only. The application in lower grade tumors is not indicated as it leads to a high rate of false negatives, but might identify anaplastic foci as discussed in the clinical application chapter.

The therapeutic effectivity and safety of 5-ALA induced PpIX has also been investigated in clinical trials on Photodynamic Therapy (PDT) of GBM 17. The intriguing concept with 5-ALA-based PDT is that only malignant cells are sensitized to a largely undirected irradiation with visible light. PDT might therefore destroy tumor cells within the infiltration zone without harming adjacent functional tissue. PDT could be applied to the resection cavity immediately after having completed fluorescence guided surgery or even completely replace surgery by implanting cylindrical diffuser fibers into the tumor by a stereotactic approach. Both concepts are currently investigated in clinical trials and will be described in more detail below.
The technical implementation, however, requires specialized equipment, such as multiport lasers and medical device class III approved light applicators. Therefore, PDT of GBM is still limited to a few neurosurgical centers. However, approval trials are in preparation 18.

The main challenge of any treatment modality for GBM with curative intent is the need of being able to kill the vast majority—if not the entirety—of malignant cells. With mechanical surgical removal it is impossible to reach this aim. Nevertheless, progression free survival (PFS) is clearly prolonged, if all of the tumor tissue is resected that shows uptake of contrast medium (Gd-DTPA) in magnetic resonance imaging (MRI) 19-22. This so called complete resection of enhancing tumor (CRET) has to be performed with great caution, of course, to not jeopardize functional brain. Therefore, tumor cells will inevitably remain, which have invaded normal brain or reside elsewhere in stem cell niches as tumor initiating cells. Given the heterogenic genetic profile and the high resistance capacity of GBM-cells 23, 24, fighting against any single target (e.g., overexpressed protein) is extremely unlikely to solve the problem. In this context, PDT offers some advantageous properties:

1. PDT causes cell death by very different mechanisms, involving multiple intracellular targets.
2. PDT induced cell death is very immunogenic.
3. PDT induces very low DNA damage, is therefore not negatively influenced by high DNA repair capacity of stem like cells.
4. PDT—depending on the photosensitizer used—provides significant tumor selectivity on a cellular level.
5. 5-ALA based PDT offers additional advantages: no phototoxicity during drug distribution, mitochondrial targeting, photobleaching, fast pharmacokinetics.
https://onlinelibrary.wiley.com/doi/full/10.1002/lsm.22933