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Next generation of minimally invasive therapies for glioma

Non-surgical dissection therapy uses interstitial photodynamic treatment with a laser beam and narrow optic fiber for the effective treatment of gliomas.

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Glioma refers to a group of primary malignant brain tumors, with glioblastoma multiforme (GBM) being among the most aggressive forms of cancer. Despite the most advanced surgical, chemotherapy, and radiotherapy treatments, the median overall survival (m-OS) for glioblastoma patients remains just 15 months. While new chemotherapy drugs have been developed for various other cancers, no effective new treatments have emerged for GBM in the past decade. Hence, the search for novel therapies is critically urgent.

Figure 1. (a) Traditional photodynamic therapy; (b) laser beam irradiation from a microscope; (c) laser generator; and (d,e) microscope
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Interstitial PDT as a minimally invasive approach as a photodynamic therapy for malignant brain tumor

Photodynamic therapy (PDT) is a treatment for malignant tumors where tumor cells are destroyed by toxic free radicals generated from a photosensitizer when exposed to laser light. The singlet oxygen produced during this process specifically targets and kills tumor cells, with the advantage that the photosensitizer does not accumulate in normal cells, making the treatment highly selective. PDT was first used in Japan for early-stage lung cancer in 1996, and in 2014, PDT using talaporfin sodium (TPS) as a photosensitizer was applied to treat malignant brain tumors.

After removing all visible tumors, a laser beam was directed onto the resected cavity, improving the median overall survival (m-OS) time of patients to 27.4 months. Although PDT has proven effective for malignant brain tumors, it faces clinical challenges, particularly the limited penetration depth of the laser light, which restricts its use to patients whose tumors can be sufficiently resected. Tumors located in critical brain areas, such as the basal ganglia or brain stem, often require only a biopsy for diagnosis due to the risks of severe postoperative complications. Consequently, PDT is generally reserved for cases where adequate tumor resection is possible.

A recent summary indicated that craniotomy was performed in 78.7% to 79.3% of patients with glioblastoma, while biopsies were conducted in 14.3% to 15% of cases (4). These limitations necessitate urgent improvements in PDT techniques. In response, interstitial PDT (i-PDT) was introduced as a non-dissection alternative, using a fiber probe that can be inserted directly into the tumor to emit laser light. This method offers hope for patients whose tumors cannot be surgically removed due to their location in critical brain areas. i-PDT is being actively researched as a potential breakthrough in minimally invasive therapy, with clinical trials underway in Germany using 5-aminolevulinic acid (5-ALA) as the photosensitizer for malignant gliomas (5).

Figure 2. Tumor histology after i-PDT for various irradiation conditions. (A–E) Various irradiation conditions, and Controls (F,G). (Table 1). Asterisk: location of light source, Arrow: direction of fiber insertion. The area of tumor killing effect by i-PDT was significantly larger at 100 J/cm2 (B,D) than 50 J/cm2 (A,C). At the same energy density of 100 J/cm2, the i-PDT effect was larger, (B) when the power density was lower (150 mW/ cm2) and the irradiation time was longer (1025 s) than (D), when power density was 768.65 mW/cm2 and the irradiation time was 200 s.
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Talaporfin sodium as an effective photosensitizer in interstitial PDT

The photosensitizer plays a crucial role in photodynamic therapy (PDT). In the 1980s, the first-generation photosensitizer, porfimer sodium, was developed and used for treating esophageal, gastric, and cervical cancers in Japan since 1994. Despite its groundbreaking nature, porfimer sodium had limitations: it required a large, costly excimer dye laser. It left patients photosensitive, necessitating a month-long stay in a semi-dark room post-treatment (6). The second-generation photosensitizer, talaporfin sodium (TPS), was introduced in Japan in the early 2000s to address these drawbacks. Since 2004, TPS has been used for early-stage lung cancer patients, reducing photosensitivity to just two weeks and minimizing other side effects. With a 664 nm excitation wavelength, TPS uses a smaller, more cost-effective diode laser generator.

However, 5-aminolevulinic acid (5-ALA), with a 405 nm excitation wavelength, is more commonly used in Europe and the US. Since longer wavelengths penetrate deeper, and 5-ALA’s excitation is hindered by hemoglobin, TPS is considered more effective for deeper tissue penetration. This led to the exploration of interstitial PDT (i-PDT) using TPS. In the initial human trials, i-PDT with TPS was tested on glioma cells in mice. After the tumors grew to about 15 mm, i-PDT was performed using a small plastic optical fiber at varying irradiation energy densities. The results were promising: lower power density with longer irradiation time affected a larger tissue area at the same energy density.

Figure 3. Tumor tissue injury area (A) and residual area (B) for each irradiation condition. The group with an asterisk shows a significant difference (p < 0.01) in necrotic area and morphologically viable area compared to group B, which showed the best PDT effect. Of particular note is that there was no significant difference between Group E, which were irradiated at very high power and energy densities.
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We hypothesized that acute vascular disorders would occur in the high-irradiation group, and indeed, vascular endothelium damage and thrombosis were observed in the PDT-affected areas, indicating ischemic changes in the tumor. A successful reaction requires an oxygen-rich environment since PDT relies on oxygen to produce toxic singlet oxygen. Another study suggested that vascular spasms caused by PDT could be mitigated by incorporating pause times into the treatment to allow for blood reperfusion and oxygen supply.

We believe that low-power irradiation avoids acute venous vascular dysfunction, maintains blood flow, and enables the PDT to affect a larger area. Therefore, when performing i-PDT, it is crucial to consider light propagation within the tumor tissue and set irradiation conditions to achieve an optimal balance between cytotoxic and vascular effects.

Figure 4. Details of HE staining (100 J/cm2 1025 sec).The  near area to a light source shows Ghost cell with nucleus dropout Apoptotic body by nuclear decay (A).  The intermediate area shows nuclear condensation by chromatin condensation and decreasing cell density (B). The Far aria from a light source shows survival tumor cell and N/C ratio is high and dense.
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We successfully demonstrated the tumor-killing effect of i-PDT for transplanted glioma tissues using TPS. The current experimental result is the first of its kind and provides a starting point for clinical trials to treat gliomas. 

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Journal reference

Nagai, K., Akimoto, J., Fukami, S., Saito, Y., Ogawa, E., Takanashi, M., … & Kohno, M. (2024). Efficacy of interstitial photodynamic therapy using talaporfin sodium and a semiconductor laser for a mouse allograft glioma model. Scientific reports, 14(1), 9137. https://doi.org/10.1038/s41598-024-59955-y

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Kenta Nagai is an assistant professor at Tokyo Medical University, department of neurosurgery, Tokyo Japan. He has performed photodynamic therapy for malignant glioma patients since 2014, and researched basic research of photodynamic therapy for malignant brain tumors. From 2020 to 2022, he worked in Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan, as a researcher, and he found out efficacy of interstitial photodynamic therapy using talaporfin sodium and a semiconductor laser for a mouse allograft glioma model [Nagai K. et al. Sci Rep. 2024 Apr 21;14(1):9137.]. In parallel, he also researched pathological diagnosis using Artificial Intelligence (AI).

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