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Photodynamic therapy (PDT) has been used to treat malignant pleural mesothelioma. Current practice involves delivering light to a prescribed light fluence with a point source, monitored by eight isotropic detectors inside the pleural cavity. An infrared (IR) navigation system was used to track the location of the point source throughout the treatment. The recorded data were used to reconstruct the pleural cavity and calculate the light fluence to the whole cavity. An automatic algorithm was developed recently to calculate the detector positions based on recorded data within an hour. This algorithm was applied to patient case studies and the calculated results were compared to the measured positions, with an average difference of 2.5 cm. Calculated light fluence at calculated positions were compared to measured values. The differences between the calculated and measured light fluence were within 14% for all cases, with a fixed scattering constant and a dual correction method. Fluence‐surface histogram (FSH) was calculated for photofrin‐mediated PDT to be able to cover 80% of pleural surface area to 50 J cm−2(83.3% of 60 J cm−2). The study demonstrates that it will be possible to eliminate the manual measurement of the detector positions, reducing the patient's time under anesthesia. [ABSTRACT FROM AUTHOR]

Treatment de‐escalation is sought in the management of precursor lesions of early stage breast cancer, driving the appeal of adjuvant modalities to lumpectomy that reduce toxicity and minimally detract from patient quality of life. We investigate photodynamic therapy (PDT), with the photosensitizing prodrug, 5‐aminolevulinic acid (ALA), as adjuvant therapy to complete resection of murine mammary tumor (propagated from TUBO cells). ALA was delivered either systemically (oral, 250 mg kg−1) at 5 h before 632 nm illumination or topically (20% solution) to the resection site at 10 min before light delivery to 135 J cm−2. Treatment with either oral‐ALA‐PDT (oALA‐PDT) or topical‐ALA‐PDT (tALA‐PDT) to the mammary fat pad after TUBO complete resection (CR) produced long‐term tumor control with 90‐day complete response rates of 21% and 32%, respectively, compared to control rates of 0–5% in mice receiving only CR. Thus, CR/tALA‐PDT was equipotent to CR/oALA‐PDT despite ~10‐fold lower levels of ALA‐induced protoporphyrin XI as photosensitizer after topical versus oral‐ALA administration. CR/oALA‐PDT produced more vascular damage, greater proportion of tissue‐resident neutrophils and stronger inflammation when compared to CR/tALA‐PDT. Collectively, these data provide rationale for ongoing investigation of ALA‐PDT as adjuvant therapy after lumpectomy for increased probability of local control in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Immune checkpoints including PD‐1 and CTLA‐4 help to regulate the intensity and timeframe of the immune response. Since they become upregulated in cancer and prevent sufficient antitumor immunity, monoclonal antibodies against these checkpoints have shown clinical promise for a range of cancers. Multimodal treatment plans combining immune checkpoint inhibitors with other therapies, including photodynamic therapy (PDT), may help to expand treatment efficacy and minimize side effects. PDT's cytotoxic effects are spatially limited by the light activation process, constraining PDT direct effects to the treatment field. The production of damage‐associated molecular patterns and tumor‐associated antigens from PDT can encourage accumulation and maturation of antigen‐presenting cells and reprogram the tumor microenvironment to be more susceptible to therapies targeting immune checkpoints. [ABSTRACT FROM AUTHOR]

Peritoneal carcinomatosis (PC) can occur as an advanced consequence of multiple primary malignancies. Surgical resection, radiation or systemic interventions alone have proven inadequate for this aggressive cancer presentation, since PC still has a poor survival profile. Photodynamic therapy (PDT), in which photosensitive drugs are exposed to light to generate cytotoxic reactive oxygen species, may be an ideal treatment for PC because of its ability to deliver treatment to a depth appropriate for peritoneal surface tumors. Additionally, epidermal growth factor receptor (EGFR) signaling plays a variety of roles in cancer progression and survival as well as PDT‐mediated cytotoxicity, so EGFR inhibitors may be valuable in enhancing the therapeutic index of intraperitoneal PDT. This study examines escalating doses of benzoporphyrin derivative (BPD)‐mediated intraperitoneal PDT combined with the EGFR‐inhibitor cetuximab in a canine model. In the presence or absence of small bowel resection (SBR) and cetuximab, we observed a tolerable safety and toxicity profile related to the light dose received. Additionally, our findings that BPD levels are higher in the small bowel compared with other anatomical regions, and that the risk of anastomotic failure decreases at lower light doses will help to inform the design of similar PC treatments in humans. [ABSTRACT FROM AUTHOR]

As part of a preclinical trial for the treatment of peritoneal carcinomatosis (PC) with photodynamic therapy (PDT), we have assessed changes in optical properties, tissue oxygenation and drug concentration as a result of benzoporphyrin derivative (BPD)‐mediated PDT using diffuse reflectance and fluorescence measurements. PDT can effectively treat superficial disease spread, but treatment efficacy is influenced by physical properties of the treated tissue which can change over the treatment time. In this study, healthy canines were given BPD and irradiated with 690 nm light during a partial bowel resection, and spectroscopic and fluorescence measurements were made using an in‐house built spectroscopic probe. Hemoglobin concentration, oxygenation and optical properties were determined to be highly heterogeneous between canines and at different anatomical locations within the same subject, so further development of PDT dosimetry systems will need to address this patient and location‐specific dose optimization. Compared to other photosensitizers, we found no apparent BPD photobleaching after PDT. [ABSTRACT FROM AUTHOR]

The distributions of light and tissue oxygenation (StO2) within the chest cavity were determined for 15 subjects undergoing macroscopic complete resection followed by intraoperative photodynamic therapy (PDT) as part of a clinical trial for the treatment of malignant pleural mesothelioma (MPM). Over the course of light delivery, detectors at each of eight different sites recorded exposure to variable fluence rate. Nevertheless, the treatment‐averaged fluence rate was similar among sites, ranging from a median of 40–61 mW cm−2 during periods of light exposure to a detector. StO2 at each tissue site varied by subject, but posterior mediastinum and posterior sulcus were the most consistently well oxygenated (median StO2 >90%; interquartile ranges ~85–95%). PDT effect on StO2 was characterized as the StO2 ratio (post‐PDT StO2/pre‐PDT StO2). High StO2 pre‐PDT was significantly associated with oxygen depletion (StO2 ratio < 1), although the extent of oxygen depletion was mild (median StO2 ratio of 0.8). Overall, PDT of the thoracic cavity resulted in moderate treatment‐averaged fluence rate that was consistent among treated tissue sites, despite instantaneous exposure to high fluence rate. Mild oxygen depletion after PDT was experienced at tissue sites with high pre‐PDT StO2, which may suggest the presence of a treatment effect. [ABSTRACT FROM AUTHOR]

Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intraoperatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT‐induced changes in tumor oxygen level. Here, we demonstrate ROSED in a clinical setting, Photofrin‐mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood‐flow‐derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5 × 109 μMs cm−2 to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter‐ and intrapatient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J cm−2 was prescribed to all patients. [ABSTRACT FROM AUTHOR]

Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcomes. However, current practice when delivering intrapleural PDT uses a point source to deliver light that is monitored by seven isotropic detectors placed within the pleural cavity to assess its uniformity. We have developed a real‐time infrared (IR) tracking camera to follow the movement of the light point source and the surface contour of the treatment area. The calculated light fluence rates were matched with isotropic detectors using a two‐correction factor method and an empirical model that includes both direct and scattered light components. Our clinical trial demonstrated that we can successfully implement the IR navigation system in 75% (15/20) of the patients. Data were successfully analyzed in 80% (12/15) patients because detector locations were not available for three patients. We conclude that it is feasible to use an IR camera‐based system to track the motion of the light source during PDT and demonstrate its use to quantify the uniformity of light distribution, which deviated by a standard deviation of 18% from the prescribed light dose. The navigation system will fail when insufficient percentage of light source positions is obtained (<30%) during PDT. [ABSTRACT FROM AUTHOR]

We have demonstrated that lung‐sparing surgery with intraoperative photodynamic therapy (PDT) achieves remarkably extended survival for patients with malignant pleural mesothelioma (MPM). Nevertheless, most patients treated using this approach experience local recurrence, so it is essential to identify ways to enhance tumor response. We previously reported that PDT transiently activates EGFR/STAT3 in lung and ovarian cancer cells and inhibiting EGFR via erlotinib can increase PDT sensitivity. Additionally, we have seen higher EGFR expression associating with worse outcomes after Photofrin‐mediated PDT for MPM, and the extensive desmoplastic reaction associated with MPM influences tumor phenotype and therapeutic response. Since extracellular matrix (ECM) proteins accrued during stroma development can alter EGF signaling within tumors, we have characterized novel 3D models of MPM to determine their response to erlotinib combined with Photofrin‐PDT. Our MPM cell lines formed a range of acinar phenotypes when grown on ECM gels, recapitulating the locally invasive phenotype of MPM in pleura and endothoracic fascia. Using these models, we confirmed that EGFR inhibition increases PDT cytotoxicity. Together with emerging evidence that EGFR inhibition may improve survival of lung cancer patients through immunologic and direct cell killing mechanisms, these results suggest erlotinib‐enhanced PDT may significantly improve outcomes for MPM patients. Here, we report the development of a novel 3‐D malignant pleural mesothelioma cell culture model using a patient‐derived cell line and its use to quantify photodynamic therapy (PDT) dose–response (figure). The translational potential of this system in further demonstrated in evaluating efficacy of molecularly targeted therapeutics in combination with PDT. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy (PT) and photodynamic therapy (PDT) and the largest‐ever mesothelioma PT experience (n = 10). PDT photosensitizers included porfimer sodium (2 mg·kg−1; 24 h drug‐light interval) or 2‐[1‐hexyloxyethyl]‐2‐devinyl pyropheophorbide‐a (HPPH) (4 mg·m−2;48 h) with wavelengths of 630 nm to 60J·cm−2 and 665 nm to 15‐45J·cm−2, respectively. With a median age of 69 years, patients were predominantly male (90%) with epithelioid histology (100%) and stage III‐IV disease (100%). PT was delivered to a median of 55.0 CGE/1.8‐2.0 CGE (range 50–75 CGE) adjuvantly (n = 8) or as salvage therapy (n = 2) following extended pleurectomy/decortication (ePD)/PDT. Two‐year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. All patients received chemotherapy, and four received immunotherapy. Surgical complications included atrial fibrillation (n = 3), pneumonia (n = 2), and deep vein thrombosis (n = 2). Median survival from PT completion was 19.5 months (30.3 months from diagnosis), and 1‐ and 2‐year survival rates were 58% and 29%. No patient experienced CTCAEv4 grade ≥2 acute or late toxicity. Our prolonged survival in very advanced‐stage patients compares favorably to survival for PT without PDT and photon therapy with PDT, suggesting possible spatial or systemic cooperativity and immune effect. Malignant pleural mesothelioma (MPM) remains difficult to treat, with high failure rates despite optimal therapy. We present a novel trial combining proton therapy (PT) and photodynamic therapy (PDT) with porfimer sodium or 2‐[1‐hexyloxyethyl]‐2‐devinyl pyropheophorbide‐a in Stage III‐IV MPM. All patients received chemotherapy, and four received immunotherapy. Two‐year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. Median survival from PT completion was 19.5 months, and 1‐ and 2‐year survival rates were 58% and 29%. Our prolonged survival in very advanced‐stage patients compares favorably to survival for PT without PDT and photon therapy with PDT. [ABSTRACT FROM AUTHOR]

Inflammatory cells, most especially neutrophils, can be a necessary component of the antitumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has been suggested to be particularly important in instances when the delivered photodynamic therapy (PDT) dose is insufficient. In these cases, the release of neutrophil granules and engagement of antitumor immunity may play an important role in eliminating residual disease. Herein, we utilize in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin‐PDT. Luminol‐generated chemiluminescence increased transiently 1 h after PDT, followed by a subsequent decrease at 4 h after PDT. The production of luminol signal was not associated with the influx of Ly6G+ cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1 h after PDT were prognostic of a complete response at 90 days after PDT. Taken together, this research supports an important role for early activity by Ly6G+ cells in the generation of long‐term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT. As neutrophils can be necessary for antitumor activity after photodynamic therapy, we utilized in vivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after its administration. In murine mesothelioma, chemiluminescence increased at 1 h after photodynamic therapy (PDT) and subsequently decreased at 4 h after PDT. Luminol signal was not representative of neutrophil influx, but instead with neutrophil function (oxidative burst). Importantly, greater luminol signal 1 h after PDT predicted tumors with no regrowth after 90 days. This supports an important role for early neutrophil activity in optimal PDT response and highlights luminol chemiluminescence as a useful approach for preclinical studies. [ABSTRACT FROM AUTHOR]

This preclinical study examines light fluence, photodynamic therapy ( PDT) dose and 'apparent reacted singlet oxygen,' [1O2]rx, to predict local control rate ( LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma ( RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm−2) and in-air fluence rates (50-150 mW cm−2) at Photofrin dosages of 5 and 15 mg kg−1 and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [1O2]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [1O2]rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [1O2]rx ≥ 1.1 m m or PDT dose ≥1200 μ m J cm−2 but cannot be predicted with fluence alone. LCR increases with increasing [1O2]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [1O2]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR. [ABSTRACT FROM AUTHOR]

We describe progress on a one-step photodynamic therapy ( PDT) technique that is simple: device tip delivery of sensitizer, oxygen and light simultaneously. Control is essential for their delivery to target sites to generate singlet oxygen. One potential problem is the silica device tip may suffer from biomaterial fouling and the pace of sensitizer photorelease is slowed. Here, we have used biomaterial ( e.g. proteins, cells, etc.) from SQ20B head and neck tumors and whole blood for an assessment of fouling of the silica tips by adsorption. It was shown that by exchanging the native silica tip for a fluorinated tip, a better nonstick property led to an increased sensitizer output by ~10%. The fluorinated tip gave a sigmoidal photorelease where singlet oxygen is stabilized to physical quenching, whereas the native silica tip with unprotected SiO-H groups gave a slower (pseudolinear) photorelease. A further benefit from fluorinated silica is that 15% less biomaterial adheres to its surface compared to native silica based on a bicinchoninic acid assay ( BCA) and X-ray photoelectron spectroscopy ( XPS) measurements. We discuss how the fluorination of the device tip increases biofouling resistance and can contribute to a new pointsource PDT tool. [ABSTRACT FROM AUTHOR]

Photodynamic therapy ( PDT) can treat superficial, early-stage disease with minimal damage to underlying tissues and without cumulative dose-limiting toxicity. Treatment efficacy is affected by disease physiologic properties, but these properties are not routinely measured. We assessed diffuse reflectance spectroscopy ( DRS) for the noninvasive, contact measurement of tissue hemoglobin oxygen saturation ( St O2) and total hemoglobin concentration ([ tHb]) in the premalignant or superficial microinvasive oral lesions of patients treated with 5-aminolevulinic acid ( ALA)- PDT. Patients were enrolled on a Phase 1 study of ALA- PDT that evaluated fluences of 50, 100, 150 or 200 J cm−2 delivered at 100 mW cm−2. To test the feasibility of incorporating DRS measurements within the illumination period, studies were performed in patients who received fractionated (two-part) illumination that included a dark interval of 90-180 s. Using DRS, tissue oxygenation at different depths within the lesion could also be assessed. DRS could be performed concurrently with contact measurements of photosensitizer levels by fluorescence spectroscopy, but a separate noncontact fluorescence spectroscopy system provided continuous assessment of photobleaching during illumination to greater tissue depths. Results establish that the integration of DRS into PDT of early-stage oral disease is feasible, and motivates further studies to evaluate its predictive and dosimetric value. [ABSTRACT FROM AUTHOR]

Immune checkpoints including PD‐1 and CTLA‐4 help to regulate the intensity and timeframe of the immune response. Since they become upregulated in cancer and prevent sufficient antitumor immunity, monoclonal antibodies against these checkpoints have shown clinical promise for a range of cancers. Multimodal treatment plans combining immune checkpoint inhibitors with other therapies, including photodynamic therapy (PDT), may help to expand treatment efficacy and minimize side effects. PDT's cytotoxic effects are spatially limited by the light activation process, constraining PDT direct effects to the treatment field. The production of damage‐associated molecular patterns and tumor‐associated antigens from PDT can encourage accumulation and maturation of antigen‐presenting cells and reprogram the tumor microenvironment to be more susceptible to therapies targeting immune checkpoints. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been used to treat malignant pleural mesothelioma. Current practice involves delivering light to a prescribed light fluence with a point source, monitored by eight isotropic detectors inside the pleural cavity. An infrared (IR) navigation system was used to track the location of the point source throughout the treatment. The recorded data were used to reconstruct the pleural cavity and calculate the light fluence to the whole cavity. An automatic algorithm was developed recently to calculate the detector positions based on recorded data within an hour. This algorithm was applied to patient case studies and the calculated results were compared to the measured positions, with an average difference of 2.5 cm. Calculated light fluence at calculated positions were compared to measured values. The differences between the calculated and measured light fluence were within 14% for all cases, with a fixed scattering constant and a dual correction method. Fluence‐surface histogram (FSH) was calculated for photofrin‐mediated PDT to be able to cover 80% of pleural surface area to 50 J cm−2(83.3% of 60 J cm−2). The study demonstrates that it will be possible to eliminate the manual measurement of the detector positions, reducing the patient's time under anesthesia. [ABSTRACT FROM AUTHOR]

Treatment de‐escalation is sought in the management of precursor lesions of early stage breast cancer, driving the appeal of adjuvant modalities to lumpectomy that reduce toxicity and minimally detract from patient quality of life. We investigate photodynamic therapy (PDT), with the photosensitizing prodrug, 5‐aminolevulinic acid (ALA), as adjuvant therapy to complete resection of murine mammary tumor (propagated from TUBO cells). ALA was delivered either systemically (oral, 250 mg kg−1) at 5 h before 632 nm illumination or topically (20% solution) to the resection site at 10 min before light delivery to 135 J cm−2. Treatment with either oral‐ALA‐PDT (oALA‐PDT) or topical‐ALA‐PDT (tALA‐PDT) to the mammary fat pad after TUBO complete resection (CR) produced long‐term tumor control with 90‐day complete response rates of 21% and 32%, respectively, compared to control rates of 0–5% in mice receiving only CR. Thus, CR/tALA‐PDT was equipotent to CR/oALA‐PDT despite ~10‐fold lower levels of ALA‐induced protoporphyrin XI as photosensitizer after topical versus oral‐ALA administration. CR/oALA‐PDT produced more vascular damage, greater proportion of tissue‐resident neutrophils and stronger inflammation when compared to CR/tALA‐PDT. Collectively, these data provide rationale for ongoing investigation of ALA‐PDT as adjuvant therapy after lumpectomy for increased probability of local control in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]