Vascular targeted photodynamic therapy with TOOKAD-from local ablation to systemic cancer treatment
Background:
Local therapies that allow for safe ablation of primary lesions and trigger anti-tumor immunity with minimal side effects, may be particularly effective in management of early-stage cancer. Vascular-targeted photodynamic therapy (VTP) with TOOKAD®, recently granted EMA approval as a first-line treatment for localized prostate cancer, has been shown by us to also trigger anti-tumor immunity. Our recent preclinical and current clinical studies aim to test the hypothesis that synchronizing TOOKAD®VTP with immune-modulation that attenuates the pro-tumor immunity, will result in systemic micrometastases annihilation and a high cure rate.
Methods:
4T1-Luc, adenosquamous JA and Met-Lu cells were orthotopically grafted in the mammary pad, esophagus and prostate of immune-competent mice and rats, respectively. Seven days postgrafting, tumors were treated with TOOKAD®VTP, with or without immune-modulators. Immune profiles were examined by 10-X genomics, FACS analysis and immunohistochemistry. Animal survival and lung and lower abdomen metastases counts were followed up for 3 months. Clinical protocols were composed based on the preclinical data and utilized in the clinical studies that will be described in other lectures of this session.
Results:
TOOKAD®VTP triggered anti-tumor immunity sufficient to achieve 60-90% cure in various cancer models. However, primary lesion annihilation did not prevent disease progression in the more aggressive cancers such as 4T1-Luc breast cancer. TOOKAD®VTP synchronized with metronomic administration of immune-modulators was associated with a 60-90% disease-free animals and resistance to re-challenge. The rate of success was highly pending on the exact synchronization of the immune modulating agents with the VTP timing. The required modulators match the deciphered immune profiles. This combined immuno-VTP therapy concept has been translated to clinical trials currently ongoing at Memorial Sloan Kettering Cancer Center.
Conclusion:
Application of TOOKAD®VTP to localized tumors combined with immune modulation appears to provide novel means to treat early disseminated cancers.
Laser speckle imaging is a technique that has been developed to non-invasively monitor in vivo blood flow dynamics and
vascular structure, at high spatial and temporal resolution. It can record the full-field spatio-temporal characteristics of
microcirculation and has therefore, often been used to study the blood flow in tumors after photodynamic therapy (PDT).
Yet, there is a paucity of reports on real-time laser speckle imaging (RTLSI) during PDT. Vascular-targeted
photodynamic therapy (VTP) with WST11, a water-soluble bacteriochlorophyll derivative, achieves tumor ablation
through rapid occlusion of the tumor vasculature followed by a cascade of events that actively kill the tumor cells.
WST11-VTP has been already approved for treatment of early/intermediate prostate cancer at a certain drug dose, time
and intensity of illumination. Application to other cancers may require different light dosage. However, incomplete
vascular occlusion at lower light dose may result in cancer cell survival and tumor relapse while excessive light dose
may lead to toxicity of nearby healthy tissues. Here we provide evidence for the feasibility of concomitant RTLSI of the
blood flow dynamics in the tumor and surrounding normal tissues during and after WST11-VTP. Fast decrease in the
blood flow is followed by partial mild reperfusion and a complete flow arrest within the tumor by the end of
illumination. While the primary occlusion of the tumor feeding arteries and draining veins agrees with previous data
published by our group, the late effects underscore the significance of light dose control to minimize normal tissue
impairment. In conclusion- RTSLI application should allow to optimize VTP efficacy vs toxicity in both the preclinical
and clinical arenas.
The article is devoted to in vivo investigations of absorption in biological tissue sensitized by preparations used for diagnostics and therapy of tumors. Efficiency of method of difhse reflectance spectroscopy for in vivo evaluation of accumulation of sensitizers is demonstrated.
Study is devoted to investigation of fluorescent and photodynamic properties of near-infrared photosensitizer bacteriochloriphyllide-serine. The peculiarities of its fluorescence excited by different lasers, dynamics and selectivity of accumulation were investigated. Photodynamic therapy of mice and investigation of tissue de-oxygenation during tumor irradiation were performed. It was shown that bacteriochloriphyllide-serine is an effective photosensitizer for PDT and fluorescent diagnostics of tumors.
The study is devoted to investigation of fluorescent and photodynamic properties of near-infrared photosensitizer bacteriochlorophyllide-serine. The peculiarities of its fluorescence under different laser excitation conditions, dynamics of concentration and selectivity of accumulation were investigated. Photodynamic therapy of mice and investigation of tissue deoxygenation during tumor irradiation were performed. It was shown that bacteriochlorophyllide-serine is an effective photosensitizer for PDT and fluorescent diagnostics of tumors.
Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. Invivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the i.v. infused photosensitizer drug. The effects of two-session PDT were evaluated. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week, post second-session PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. Two-session PDT or one single session PDT induced a similar extent of damage. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Maximum lesion size of over 3 cm in dimension could be achieved with a single 1-cm interstitial treatment, suggesting the therapy is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat prostate cancer.
In this study, photodynamic therapy (PDT) mediated with a novel, second generation photosensitizer Tookad (palladium-bacteriopheophorbide, WST09, STEBA Biotech, France), is investigated as an alternative modality in the treatment of prostate cancer. In vivo normal canine prostate and spontaneous advanced prostate cancer are used as the animal model. PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the i.v. infused photosensitizer. The effects of drug concentration, drug-light interval, and light fluence rate on the PDT efficacy were studied. The prostates and adjacent tissues (bladder and underlying colon) were harvested and subjected to histopathological examination. During the one-week to 3-month period post PDT treatment, the dogs recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. Light irradiation delivered during drug infusion or within 15 min post drug infusion induced the similar extend of damages. PDT induced prostate lesions in both normal and cancerous prostate were characterized by marked hemorrhagic necrosis and atrophy. Maximum lesion size of over 3 cm in dimension could be achieved with a single 1-cm interstitial treatment, suggesting the therapy is very effective in ablating cancerous prostatic tissue. In conclusion, the second generation photosensitizer Tookad mediated PDT may provide an effective alternative to treat prostate cancer.
Photodynamic therapy (PDT) utilizes optical energy to activate a pre-administered photosensitizer drug to achieve a localized tumor control. In the presented study, PDT mediated with a second-generation photosensitizer, WST09 (TOOKAD, Steba Biotech, The Netherlands), is investigated as an alternative therapy in the treatment of prostate cancer. In vivo canine prostate is used as the animal model. PDT was performed by irradiating the surgically exposed prostates both superficially and interstitially with a diode laser (763 nm) to activate the intra-operatively i.v. infused photosensitizer. During light irradiation, tissue optical properties, and temperature were monitored. During the one-week to 3-month period post PDT treatment, the dogs recovered well with little or no complications. The prostates were harvested and subjected to histopathological evaluations. Maximum lesion size of over 3 cm in dimension could be achieved with a single treatment, suggesting the therapy is extremely effective in destroying prostatic tissue. Although we found there was loss of epithelial lining in prostatic urethra, there was no evidence it had caused urinary tract side effects as reported in those studies utilizing transurethral irradiation. In conclusion, we found second generation photosensitizer WST09 mediated PDT may provide an excellent alternative to treat prostate cancer.
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