Yasuhiro Maruoka

Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective cancer treatment that employs an antibody photoabsorber conjugate (APC) composed of a targeting monoclonal antibody (mAb) conjugated with a photoactivatable phthalocyanine-derivative dye. Once injected and allowed to bind to a tumor, the APC is activated by local near-infrared light which kills cancer cells and induces a strong immune response in the tumor microenvironment by unmasking of new tumor antigens emerging from damaged tumor cells. Due to its ability to incite an immune reaction, even in poorly immunogenic tumors, NIR-PIT has the potential to enhance immunogenicity in tumors especially after immune checkpoint inhibition. In this study, we employ a poorly immunogenic MOC2-luc syngeneic tumor model and evaluate the efficacy of cancer-targeting CD44-targeted NIR-PIT. Increased infiltration of CD8+ T cells observed after NIR-PIT suggested an enhanced immune environment. Next, we evaluated tumor progression and survival after the combination of CD44-targeted NIR-PIT and short-term administration of an anti-PD1 immune checkpoint inhibitor (ICI) to further activate CD8+ T cells. Additionally, in mice in which the tumors were eradicated by this combination therapy, a re-challenge with fresh MOC2-luc cells demonstrated failure of tumor implantation implying acquired long-term immunity against the cancer cells. Combination therapy decreased tumor progression and prolonged survival significantly. Therefore, we concluded that NIR-PIT was able to convert a minimally immunogenic tumor unresponsive to anti-PD-1 ICI into a highly immunogenic tumor responsive to anti-PD-1 ICI, and this therapy was capable of inducing long-term immunity against the treated cancer.

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that induces necrotic/immunogenic cell death. It employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is activated by NIR light. Tumor-targeting NIR-PIT is also at least partly mediated by a profound immune response against the tumor. Cytotoxic T-lymphocyte antigen-4 (CTLA4) is widely recognized as a major immune checkpoint protein, which inhibits the immune response against tumors and is therefore, a target for systemic blockade. We investigated the effect of combining tumor-targeted NIR-PIT against the cell-surface antigen, CD44, which is known as a cancer stem cell marker, with a systemic CTLA4 immune checkpoint inhibitor in three syngeneic tumor models (MC38-luc, LL/2, and MOC1). CD44-targeted NIR-PIT combined with CTLA4 blockade showed greater tumor growth inhibition with longer survival compared with CTLA4 blockade alone in all tumor models. NIR-PIT and CTLA4 blockade produced more complete remission in MOC1 tumors (44%) than NIR-PIT and programmed cell death protein 1 (PD-1) blockade (8%), which was reported in our previous paper. However, the combination of NIR-PIT and CTLA4 blockade was less effective in MC38-luc tumors (11%) than the combination of NIR-PIT and PD-1 blockade (70%). Nonetheless, in many cases ineffective results with NIR-PIT and PD-1 blockade were reversed with NIR-PIT and CTLA4 blockade.

Near infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that employs a monoclonal antibody (mAb) conjugated to a photo-absorber dye, IRDye700DX, which is activated by 690 nm light. Cancer cell-targeted NIR-PIT induces rapid necrotic/immunogenic cell death (ICD) that induces antitumor host immunity including re-priming and proliferation of T cells. Interleukin-15 (IL-15) is a cytokine that activates natural killer (NK)-, B- and T-cells while having minimal effect on regulatory T cells (Tregs) that lack the IL-15 receptor. Here, we hypothesized that IL-15 administration with cancer cell-targeted NIR-PIT could further inhibit tumor growth by increasing antitumor host immunity. Three syngeneic mouse tumor models, MC38-luc, LL/2, and MOC1, underwent combined CD44-targeted NIR-PIT and short-term IL-15 administration with appropriate controls. Comparing with the single-agent therapy, the combination therapy of IL-15 after NIR-PIT inhibited tumor growth, prolonged survival, and increased tumor infiltrating CD8+ T cells more efficiently in tumor-bearing mice. IL-15 appears to enhance the therapeutic effect of cancer-targeted NIR-PIT.

Journal of Clinical and Diagnostic Research aims to publish findings of doctors at grass root level and post graduate students, so that all unique medical experiences are recorded in literature.

Balloon pulmonary angioplasty (BPA) is used for inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but its effect cannot be evaluated noninvasively. We devised a noninvasive quantitative index of response to BPA using three-dimensional fractal analysis (3D-FA) of technetium-99m-macroaggregated albumin (99mTc-MAA) single-photon emission computed tomography (SPECT). Forty CTEPH patients who underwent pulmonary perfusion scintigraphy and mean pulmonary arterial pressure (mPAP) measurement by right heart catheterization before and after BPA were studied. The total uptake volume (TUV) in bilateral lungs was determined from maximum intensity projection 99mTc-MAA SPECT images. Fractal dimension was assessed by 3D-FA. Parameters were compared before and after BPA, and between patients with post-BPA mPAP more than 30 mmHg and less than or equal to 30 mmHg. Receiver operating characteristic analysis was carried out. BPA significantly improved TUV (595±204–885±214 ml, P<0.001) and reduced the laterality of uptake (238±147–135±131 ml, P<0.001). Patients with poor therapeutic response (post-BPA mPAP≥30 mmHg, n=16) showed a significantly smaller TUV increase (P=0.044) and a significantly greater post-BPA fractal dimension (P<0.001) than the low-mPAP group. Fractal dimension correlated with mPAP values before and after BPA (P=0.013 and 0.001, respectively). A post-BPA fractal dimension threshold of 2.4 distinguished between BPA success and failure with 75% sensitivity, 79% specificity, 78% accuracy, and area under the curve of 0.85. 3D-FA using 99mTc-MAA SPECT pulmonary perfusion scintigraphy enables a noninvasive evaluation of the response of CTEPH patients to BPA.

Purpose: Lung metastases (LMs) and their radioiodine uptake affect prognosis in patients with differentiated thyroid carcinoma (DTC). We herein investigate the value of metabolic tumor volume (MTV) in LMs on positron emission tomography/computed tomography (PET/CT) using 2-[F-18]-fluoro-2-deoxy-D-glucose (F-18 FDG PET/CT) in predicting short-term progression after initial I-131 therapy in DTC patients. Materials and Methods: We retrospectively evaluated 111 DTC patients with LMs. Diagnostic CT and I-131 scintigraphy were performed within 1 week of I-131 therapy. Maximum standardized uptake value (SUVmax) and total MTV (MTVtotal) were compared between patients with I-131-positive and I-131-negative LMs and between patients with and without short-term progression. Correlation analyses were performed between F-18 FDG PET/CT parameters and thyroglobulin (TG) level, and predictive factors for short-term progression were analyzed by logistic regression and receiver operating characteristic curve analysis.Results: Patients with short-term progression had significantly higher SUVmax and MTVtotal than those without. TG levels were significantly correlated with SUVmax (r = 0.21) and MTVtotal (r = 0.51) after I-131 therapy. MTVtotal showed significant association (χ² = 16.5, odds ratio = 0.02) with short-term progression after initial I-131 therapy and had the highest predictive value of all the putative risk factors. Conclusions: MTVtotal in LMs on F-18 FDG PET/CT is an independent predictive factor with a high predictive value for short-term progression of DTC after initial I-131 therapy. It is recommended that F-18 FDG PET/CT be performed before planning therapy during the evaluation of DTC patients with LM.

Background: The purpose of this study was to retrospectively investigate the association between 2-[F-18]-fluoro-2-deoxy-D-glucose (18F-FDG) accumulation in lung metastasis (LM) before 131I therapy and refractoriness to 131I therapy for differentiated thyroid carcinoma (DTC) patients. Methods and Findings: Sixty-one DTC patients with LM who underwent Positron emission tomography/computed tomography using 18F-FDG (18F-FDG PET/ CT) before an initial 131I therapy were retrospectively evaluated. Maximum of standardized uptake value (SUVmax) in LM with the highest 18F-FDG accumulation was measured in each patient. The SUVmax was compared between patients with and without 131I-positive LM, and between patients with and without an increased level of thyroglobulin (tumor marker) 12 ± 2 months after 131I therapy using the Wilcoxon test. Discussion: Predictability for the patients with an increased thyroglobulin level was also analyzed by receiver-operating-characteristic (ROC) analysis. SUVmax of LM was significantly greater for patients without 131I-positive LM than for those with 131I-positive LM (5.9 ± 6.0 vs. 1.9 ± 2.0, p<0.01) and was significantly greater for patients with an increased level of TG after 131I therapy than for those without (7.0 ± 4.9 vs. 1.2 ± 1.0, p 3.8 showed an increased TG level after 131I therapy. Use of the optimal cutoff threshold for SUVmax of 1.6 differentiated patients with an increased level of TG from those without at a sensitivity of 74.2%, a specificity of 94.4%, an accuracy of 81.6% and an AUC of 0.91. Conclusion: 18F-FDG accumulation in LM from DTC can be one of predictors for refractoriness to 131I therapy.

Acquired perforating dermatosis (APD) is an uncommon cutaneous perforating disorder. We report a patient on hemodialysis who developed skin eruption and jaundice. He underwent FDG PET/CT under suspicion of biliary malignancies. PET/CT showed no significant abnormal uptake except of multiple FDG-avid nodules in the skin. The eruption he had was histopathologically diagnosed as APD by skin biopsy. His case suggests that APD should be considered as a differential diagnosis when multiple cutaneous FDG accumulations are found in a patient on hemodialysis. To the best of our knowledge, this is the first report showing the FDG PET/CT findings of APD.