Inside-the-body light delivery system using endovascular therapy-based light illumination technology.

BACKGROUND: Light-based therapies are promising for treating diseases including cancer, hereditary conditions, and protein-related disorders. However, systems, methods, and devices that deliver light deep inside the body are limited. This study aimed to develop an endovascular therapy-based light illumination technology (ET-BLIT), capable of providing deep light irradiation within the body. METHODS: The ET-BLIT system consists of a catheter with a single lumen as a guidewire and diffuser, with a transparent section at the distal end for thermocouple head attachment. The optical light diffuser alters the emission direction laterally, according to the optical fibre's nose-shape angle. If necessary, after delivering the catheter to the target position in the vessel, the diffuser is inserted into the catheter and placed in the transparent section in the direction of the target lesion. FINDINGS: ET-BLIT was tested in an animal model. The 690-nm near-infrared (NIR) light penetrated the walls of blood vessels to reach the liver and kidneys without causing temperature increase, vessel damage, or blood component alterations. NIR light transmittance from the diffuser to the detector within the organ or vessel was approximately 30% and 65% for the renal and hepatic arteries, respectively. INTERPRETATION: ET-BLIT can be potentially used in clinical photo-based medicine, as a far-out technology. ET-BLIT uses a familiar method that can access the whole body, as the basic procedure is comparable to that of endovascular therapy in terms of sequence and technique. Therefore, the use of the ET-BLIT system is promising for many light-based therapies that are currently in the research phase. FUNDING: Supported by Programme for Developing Next-generation Researchers (Japan Science and Technology Agency); JSPS KAKENHI (18K15923, 21K07217); JST-CREST (JPMJCR19H2); JST-FOREST-Souhatsu (JPMJFR2017); The Uehara Memorial Foundation; Yasuda Memorial Medical Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; The Japan Health Foundation; Takahashi Industrial and Economic Research Foundation; AICHI Health Promotion Foundation; and Princess Takamatsu Cancer Research Fund.

HER2 targeting near-infrared photoimmunotherapy for a CDDP-resistant small-cell lung cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is tyrosine kinase receptor that belongs to the ErbB family and is overexpressed on the membrane surface of various cancer cells, including small cell lung cancer (SCLC); however, no HER2 targeted therapy for SCLC have yet been established. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy based on photo-absorber, IRDye-700DX (IR700), -antibody conjugates, and near-infrared (NIR) light. METHODS: We used HER2-positive SCLC parental cell lines (SBC-3) and its chemoresistant cell lines, and examined therapeutic efficacy of HER2 targeting NIR-PIT using anti HER2 antibody trastuzumab. RESULTS: We found that HER2 expression was upregulated on chemoresistant cell lines, especially cisplatin-resistance (SBC-3/CDDP). In vitro, the rate of cell death increased with the amount of NIR-light irradiation, and it was significantly higher in SBC-3/CDDP than in SBC-3. In vivo, tumor growth was more suppressed in SBC-3/CDDP group than in SBC-3 group, and survival period tended to be prolonged. CONCLUSION: In this study, we demonstrated that HER2 targeting NIR-PIT using trastuzumab is promising therapy for HER2-positive SCLC, and is more effective when HER2 expression is upregulated due to CDDP resistance, suggesting that the HER2 expression level positively corelated with the efficacy of NIR-PIT.

Near-infrared photoimmunotherapy targeting GPR87: Development of a humanised anti-GPR87 mAb and therapeutic efficacy on a lung cancer mouse model.

BACKGROUND: GPR87 is a G-protein receptor that is specifically expressed in tumour cells, such as lung cancer, and rarely expressed in normal cells. GPR87 is a promising target for cancer therapy, but its ligand is controversial. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy in which a photosensitiser, IRDye700DX (IR700), binds to antibodies and specifically destroys target cells by irradiating them with near-infrared-light. Here, we aimed to develop a NIR-PIT targeting GPR87. METHODS: We evaluated the expression of GPR87 in resected specimens of lung cancer and malignant pleural mesothelioma (MPM) resected at Nagoya University Hospital using immunostaining. Humanised anti-GPR87 antibody (huGPR87) was generated by introducing CDRs from mouse anti-GPR87 antibody generated by standard hybridoma method. HuGPR87 was conjugated with IR700 and the therapeutic effect of NIR-PIT was evaluated in vitro and in vivo using lung cancer or MPM cell lines. FINDINGS: Among the surgical specimens, 54% of lung cancer and 100% of MPM showed high expression of GPR87. It showed therapeutic effects on lung cancer and MPM cell lines in vitro, and showed therapeutic effects in multiple models in vivo. INTERPRETATION: These results suggest that NIR-PIT targeting GPR87 is a promising therapeutic approach for the treatment of thoracic cancer. FUNDING: This research was supported by the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217, JSPS), FOREST-Souhatsu, CREST (JST).

Positive outcome of first-line therapy for a SMARCA4-deficient thoracic sarcomatoid tumor.

SMARCA4-deficient thoracic sarcomatoid tumor is a rare malignancy indicating some characteristics of a smoking-related disease. The purpose of this report is to describe a case of aggressive thoracic tumor with loss of immunochemical SMARCA4 expression and detail the results of our treatment regimen. The patient was a 58-year-old male and clinicopathologically diagnosed with a SMARCA4-deficient thoracic sarcomatoid tumor. Pembrolizumab plus carboplatin and pemetrexed resulted in significant response. This combination therapy showed potential for first-line systemic treatment of SMARCA4-deficient thoracic sarcomatoid tumors.

Near Infrared Photoimmunotherapy for Mouse Models of Pleural Dissemination.

The efficacy of photoimmunotherapy can be evaluated more accurately with an orthotopic mouse model than with a subcutaneous one. A pleural dissemination model can be used for the evaluation of treatment methods for intrathoracic diseases such as lung cancer or malignant pleural mesothelioma. Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer treatment strategy that combines the specificity of tumor-targeting antibodies with toxicity caused by a photoabsorber (IR700Dye) after exposure to NIR light. The efficacy of NIR-PIT has been reported using various antibodies; however, only a few reports have shown the therapeutic effect of this strategy in an orthotopic model. In the present study, we demonstrate an example of efficacy evaluation of the pleural disseminated lung cancer model, which was treated using NIR-PIT.

Near infrared photoimmunotherapy targeting DLL3 for small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) has a poor prognosis, and its treatment options are limited. Delta-like protein 3 (DLL3) is expressed specifically in SCLC and is considered a promising therapeutic target for patients with this disease. Rovalpituzumab tesirine (Rova-T) was the first antibody-drug conjugate targeting DLL3. Although Rova-T development was unfortunately terminated, DLL3 remains an ideal target for SCLC. Near infrared photoimmunotherapy (NIR-PIT) is a new form of cancer treatment that employs an antibody-photosensitiser conjugate followed by NIR light exposure and damage target cells specifically. In this study, we demonstrate DLL3-targeted NIR-PIT to develop a novel molecularly targeted treatment for SCLC. METHODS: The anti-DLL3 monoclonal antibody rovalpituzumab was conjugated to an IR700 photosensitiser (termed 'rova-IR700'). SCLC cells overexpressing DLL3 as well as non-DLL3-expressing controls were incubated with rova-IR700 and then exposed to NIR-light. Next, mice with SCLC xenografts were injected with rova-IR700 and irradiated with NIR-light. FINDINGS: DLL3-overexpressing cells underwent immediate destruction upon NIR-light exposure, whereas the control cells remained intact. The xenograft in mice treated with rova-IR700 and NIR-light shrank markedly, whereas neither rova-IR700 injection nor NIR-light irradiation alone affected tumour size. INTERPRETATION: Our data suggest that targeting of DLL3 using NIR-PIT could be a novel and promising treatment for SCLC. FUNDING: Research supported by grants from the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, JSPS), Medical Research Encouragement Prize of The Japan Medical Association, The Nitto Foundation, Kanae Foundation for the Promotion of Medical Science.

Longitudinal changes in pulmonary function and respiratory impedance of rheumatoid arthritis.

The aim of this study was to examine long-term changes in pulmonary function and respiratory impedance (Zrs) as assessed by forced oscillation technique (FOT) of rheumatoid arthritis (RA)-related pulmonary disorders. Data of 42 RA patients who underwent pulmonary function tests and Zrs measurements at least twice at a >900-day interval were retrospectively reviewed. Zrs, respiratory resistance (Rrs) and reactance (Xrs), were measured as a function of oscillatory frequency from 4 to 36 Hz. The Rrs and difference between inspiratory and expiratory phases of Xrs were significantly decreased. Annual changes in Xrs parameters significantly correlated with those of spirometric parameters. Zrs parameters were significantly different between the low (the lower 75 percentile of incidence) and high (the top quartile) frequency of adverse respiratory event groups. The Zrs combined with spirometry may be beneficial to evaluate alterations in respiratory functions of RA.

Responsiveness to bronchodilator procaterol in COPD as assessed by forced oscillation technique.

The aim of this retrospective study was to assess responses to a bronchodilator by forced oscillation technique (FOT) and to relate the results of respiratory impedance (Zrs) to spirometric parameters in patients with chronic obstructive pulmonary disease (COPD). Zrs was measured as a function of frequency from 4 to 36Hz before and after inhalation of procaterol, a short-acting ß2-agonist (n=60). Respiratory resistance (Rrs) and reactance (Xrs) were significantly frequency-dependent, and inspiratory and expiratory phases were different both before and after procaterol inhalation. The Rrs at 4Hz and Xrs at 4-20Hz during a whole breath were significantly improved after procaterol inhalation. The response to procaterol inhalation varied among patients, and changes in Xrs at 4Hz significantly correlated with% change in forced expiratory volume in one second and changes in forced vital capacity. Taken together, Zrs, and specifically Xrs parameters, are sensitive to acute physiological responses to a bronchodilator in COPD.