Publications by authors named "Shigehisa Kitano"

84 Publications

Comparison of Tumor Microenvironments Between Primary Tumors and Brain Metastases in Patients With NSCLC.

JTO Clin Res Rep 2021 Oct 20;2(10):100230. Epub 2021 Sep 20.

Division of Medical Oncology, Department of Internal Medicine, James Thoracic Center, The Ohio State University, Columbus, Ohio.

Introduction: This study investigates the immune profile of the primary lung tumors and the corresponding brain metastasis from patients with NSCLC using multiplex fluorescence immunohistochemistry.

Methods: The study evaluated 34 patients who underwent autopsy or surgical resection for brain metastasis and autopsy, surgical resection, or core biopsy for primary lung cancer. We compared the densities of various immune cells in the primary tumors and the brain metastases by multiplex fluorescence immunohistochemical analysis.

Results: The density of CD4-positive (CD4) T-cells, CD8-positive T-cells, and CD4 Foxp3-positive T-cells were statistically higher in both tumor and stromal areas in primary lung cancer specimens when compared with brain metastases samples ( < 0.0001). Only CD204-positive cells were statistically higher in the tumor areas of the brain metastases ( = 0.0118). Tumor-infiltrating lymphocytes associated with brain metastases positively correlated with overall survival, but primary lung tumor-infiltrating lymphocytes did not. The density of CD4 and CD4 Foxp3-positive T-cells in brain metastases with radiation was statistically higher in the carcinoma and stromal areas compared with those without radiation ( = 0.0343,  = 0.0173).

Conclusions: Our findings that CD204-positive cells were higher in brain metastases may have broader implications for treatment as these macrophages may be immunosuppressive and make the immune environment less reactive. Furthermore, the finding that the density of CD4 T-cells was higher in cancer and stroma areas of brain metastases after radiotherapy supports the addition of immunotherapy to radiation therapy in the treatment of brain metastases in NSCLC.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501504PMC
October 2021

Neurological disorders associated with immune checkpoint inhibitors: an association with autoantibodies.

Cancer Immunol Immunother 2021 Sep 13. Epub 2021 Sep 13.

Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Among diverse neurological immune-related adverse events (irAEs), autoimmune encephalitis, aseptic meningitis, Guillain-Barré syndrome (GBS), myasthenia gravis (MG), and myositis are particularly important. The clinical presentation may be different from that of patients with conditions unrelated to immune checkpoint inhibitors (ICIs). Many of the autoantibodies detected in patients' sera are committed to the pathogenesis, while the clinical significance of such autoantibodies in cases of neurological irAEs is different from the significance in cases of typical neuronal disorders. A broad range of clinical symptoms complicates the diagnosis of autoimmune encephalitis. The clinical features of aseptic meningitis induced by classical drugs are different from those of aseptic meningitis induced by ICIs. Although autoantibodies against synaptic receptors or neuronal cell surface proteins are not detected, anti-Ma2 antibodies, which are onconeural antibodies against intracellular proteins, are detected in patients with autoimmune encephalitis associated with ICIs. GBS induced by ICIs sometimes shows gradual progression and a relapse of symptoms, suggesting chronic inflammatory demyelinating polyneuropathy. Bulbar symptoms and myasthenic crisis are frequently observed in ICI-induced MG. Anti-acetylcholine receptor antibodies are found in only half of patients with MG occurring as an irAE. ICI-induced myositis is accompanied by ocular muscle symptoms, such as ptosis and diplopia, which can suggest MG. Patients receiving ICI treatment present clinical features and laboratory findings that represent a mixture of MG and myositis. Anti-striational antibodies may act as biomarkers in cases in which MG and myositis overlap. A correct understanding of neurological adverse events is required to achieve the best management of patients.
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http://dx.doi.org/10.1007/s00262-021-03053-9DOI Listing
September 2021

Chilblain lupus-like cutaneous reaction associated with systemic lupus erythematosus induced by immune checkpoint inhibitor.

Rheumatology (Oxford) 2021 Aug 31. Epub 2021 Aug 31.

Division of Cancer Immunotherapy Development, Advanced Medical Development Center; The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.1093/rheumatology/keab670DOI Listing
August 2021

Pembrolizumab plus chemotherapy in triple-negative breast cancer.

Lancet 2021 07;398(10294):24

Department of Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.

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http://dx.doi.org/10.1016/S0140-6736(21)00380-9DOI Listing
July 2021

Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study.

Invest New Drugs 2021 Jun 12. Epub 2021 Jun 12.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background osteosarcoma is a rare, primary malignant bone tumour with limited available treatments for advanced or recurrent disease, resulting in a poor prognosis for patients. TAS-115 is a novel tyrosine kinase inhibitor under investigation in a phase I study in patients with solid tumours. We report data of osteosarcoma patients in the expansion cohort of this ongoing study. Patients and methods an analysis of this multicentre, open-label study was performed 6 months after the final patient was enrolled, and included patients aged ≥15 years, with unresectable or recurrent osteosarcoma, and who had refractory to standard therapy or for whom no standard therapy was available. TAS-115 650 mg/day was orally administered in a 5 days on/2 days off schedule. Results a total of 20 patients with osteosarcoma were enrolled. The most common adverse drug reactions (ADRs) were neutrophil count decreased (75%), aspartate aminotransferase increased (50%), and platelet count decreased (50%); 85% of patients had grade ≥ 3 ADRs. Long-term disease control (>1 year) with TAS-115 was achieved in three patients. The best overall response was stable disease (50%); no patient achieved a complete or partial response. Median progression-free survival was 3 months; 4-month and 12-month progression-free rates were 42% and 31%, respectively. Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013).
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http://dx.doi.org/10.1007/s10637-021-01107-4DOI Listing
June 2021

Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study).

Jpn J Clin Oncol 2021 Aug;51(8):1232-1241

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Background: Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma.

Methods: This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours.

Result: Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events.

Conclusion: The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.
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http://dx.doi.org/10.1093/jjco/hyab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326387PMC
August 2021

Case Report: A Case of Trimethoprim/Sulfamethoxazole-Triggered Hypotensive Shock: Cytokine Release Syndrome Related to Immune Checkpoint Inhibitors and Drug-Induced Hypersensitivity Syndrome.

Front Oncol 2021 30;11:681997. Epub 2021 Apr 30.

Department of Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Currently, only a few reports exist on the cytokine release syndrome (CRS) as one of the severe immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs). Notably, it is very rare that grade 4 CRS related to ICI therapy overlaps with the drug-induced hypersensitivity syndrome (DiHS). A 46-year old woman with metastatic kidney cancer had grade 3 interstitial pneumonitis induced by four cycles of combination therapy of anti-programmed death-1 and anti-cytotoxic T lymphocyte-4 antibodies after right cytoreductive nephrectomy. Prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) was started concomitantly with prednisolone therapy to treat the interstitial pneumonitis. She developed hypotensive shock when reducing the dosage of prednisolone, and required intubation and ventilation using vasopressors at the intensive care unit. She subsequently exhibited prominent leukocytosis and an increased level of C-reactive protein, suggesting markedly increased cytokine levels. Interestingly, facial edema and erythema increased in association with pyrexia, leukocytosis, liver dysfunction, and renal failure, suggesting that she developed DiHS. She received hemodialysis three times, a plasma exchange, and anti-interleukin-6 therapy to treat severe renal dysfunction, a thrombotic thrombocytopenic purpura-suspected condition, and possible grade 4 CRS, respectively. Although these therapies did not elicit sufficient effects, high-dose administration of intravenous immunoglobulin was successful. With steroid mini-pulse therapy and the subsequent administration of prednisolone, she recovered successfully. To the best of our knowledge, this is the first report that ICIs and TMP/SMX can induce hypotensive shock accompanied with CRS and DiHS during immunosuppressive therapy for an irAE. Importantly, the prophylactic administration of TMP/SMX should be performed cautiously to avoid severe drug reactions such as CRS or DiHS.
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http://dx.doi.org/10.3389/fonc.2021.681997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121494PMC
April 2021

Phase I study of tamibarotene monotherapy in pediatric and young adult patients with recurrent/refractory solid tumors.

Cancer Chemother Pharmacol 2021 07 7;88(1):99-107. Epub 2021 Apr 7.

Clinical Research Support Office, National Cancer Center Hospital East, Chiba, Japan.

Purpose: Tamibarotene is a synthetic retinoid that inhibits proliferation and induces differentiation of malignant cells by binding to the retinoic acid receptor α/β. Previous in vitro studies have shown that some pediatric solid tumors with retinoic acid receptors differentiate in response to retinoic acid. We conducted a phase I dose-escalation study to determine the recommended dose of tamibarotene for further study in pediatric and young adult patients with recurrent/refractory solid tumors.

Methods: Pediatric and young adult patients with recurrent/refractory solid tumors were administered tamibarotene at 4, 6, 8, 10, and 12 mg/m/day for 14 or 21 days of a 28 day cycle. Safety, efficacy, and pharmacokinetics of tamibarotene were evaluated.

Results: Twenty-two patients (median age 8 years) were enrolled in this study. No dose-limiting toxicity (DLT) was encountered, and tamibarotene was generally well tolerated. Two patients experienced severe adverse events (AEs), leading to discontinuation of the treatment. One grade 4 venous thrombosis and one grade 2 erythema multiforme were observed, which promptly resolved after tamibarotene discontinuance. The grade 4 venous thrombosis was a severe AE but not DLT because it occurred after the evaluation period. Pharmacokinetic analyses showed a dose-dependent increase in the maximum drug concentration (C) and area under the concentration-time curve (AUC). None of the patients achieved a complete response or partial response. Seven patients had stable disease lasting longer than 18 weeks.

Conclusions: The recommended dose for phase II study of tamibarotene in pediatric and young adult patients with refractory solid tumors is 12 mg/m/day for 21 days in a 28 day cycle.
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http://dx.doi.org/10.1007/s00280-021-04271-9DOI Listing
July 2021

Transient Depletion of CD4 Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer.

Cancer Immunol Res 2021 06 5;9(6):624-636. Epub 2021 Mar 5.

Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Antibody-mediated transient depletion of CD4 cells enhances the expansion of tumor-reactive CD8 T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4 cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4 cells promoted replacement of T-cell clones among CD4 and CD8 T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4 T-cell depletion and an increase in CD8 T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood-tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8 overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4 cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4 cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer..
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0989DOI Listing
June 2021

The safety, tolerability and pharmacokinetics of niraparib in Japanese patients with solid tumours: results of a phase I dose-escalation study.

Jpn J Clin Oncol 2021 Apr;51(5):693-699

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Background: Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status.

Methods: This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response.

Results: There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0-24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3-4 h. Two patients, both in cohort 2, had a partial response to treatment.

Conclusions: Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours.
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http://dx.doi.org/10.1093/jjco/hyab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086052PMC
April 2021

First-in-human study of the cancer peptide vaccine TAS0313 in patients with advanced solid tumors.

Cancer Sci 2021 Apr 25;112(4):1514-1523. Epub 2021 Feb 25.

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

TAS0313, a novel cancer vaccine cocktail, was developed to overcome the disadvantages of previously developed short and long peptide vaccines; it comprises several long peptides targeting multiple cancer antigens. We evaluated TAS0313 monotherapy in Japanese patients with advanced solid tumors for which no other therapies were available. In the dose-finding cohort, patients received TAS0313 (9 or 27 mg) on days 1, 8, and 15 of cycles 1 and 2, and then on day 1 of each subsequent 21-day cycle. The primary objective was the evaluation of safety and tolerability. Secondary objectives were evaluation of efficacy, tumor responses, and immune activation (CTL, IgG, and tumor-infiltrating lymphocyte [TIL] levels). The full analysis set contained 10 patients in the 9-mg group and seven in the 27-mg group. No dose-limiting toxicities were reported in cycle 1. All adverse drug reactions (ADRs) were grade 1 or 2; the most common ADRs were injection site-related events. The best response was stable disease in four of 17 patients. The median progression-free survival (PFS) duration was 2.2 (95% confidence interval, 1.0-2.3) months overall; patients with baseline low lymphocyte counts (≤750/μL) had shorter PFS. Compared with baseline, TILs were increased in five patients. Although CTLs, IgG, and TILs were induced, no correlative pattern with clinical outcomes was observed. The safety, tolerability, and induction of immune responses in patients with advanced solid tumors receiving TAS0313 were confirmed. Further evaluation of TAS0313's efficacy as monotherapy or in combination with pembrolizumab is underway. The study is registered at www.clinicaltrials.jp (JapicCTI-183824).
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http://dx.doi.org/10.1111/cas.14765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019195PMC
April 2021

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors.

Invest New Drugs 2021 08 9;39(4):1036-1046. Epub 2021 Feb 9.

Department of Medical Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.

Background This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017.
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http://dx.doi.org/10.1007/s10637-020-01055-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279981PMC
August 2021

Immunological status of peripheral blood is associated with prognosis in patients with bone and soft-tissue sarcoma.

Oncol Lett 2021 Mar 18;21(3):212. Epub 2021 Jan 18.

Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital, Tokyo 104-0045, Japan.

Immune-checkpoint inhibitors have shown promising antitumor effects against certain types of cancer. However, specific immune-checkpoint inhibitors for patients with sarcoma have yet to be identified, whereas the immunological status of peripheral blood in patients with bone sarcoma and soft-tissue sarcoma (STS) remains unknown. In addition, it is unclear whether the immunological status from the peripheral blood could be used as a prognostic indicator. Therefore, the present study aimed to clarify the immunological status of peripheral blood samples derived from patients with bone sarcoma and STS. Immune monitoring was performed using the peripheral blood samples of 61 patients with no metastasis of high-grade sarcoma. A total of 25 patients with metastatic sarcoma were used for comparison. A total of 41 immune cell subsets were analyzed using multicolor-flow cytometry. The patients that did not have metastasis demonstrated higher quantities of monocytic myeloid-derived suppressor cells (M-MDSCs) and T cell immunoglobulin and mucin domain-3 (Tim-3) CD8 T cells, which were significantly associated with poor disease-free survival (DFS) time, while higher quantities of NKG2D CD8 T cells were significantly associated with improved DFS time. Multivariate Cox regression analysis demonstrated that the number of Tim-3 CD8 T cells was associated with lower DFS time. A significant association was also found between the number of M-MDSCs and progression-free survival (PFS) time in patients with metastasis. The results suggested the occurrence of immune surveillance, which indicated that the host immune reaction against cancer existed in patients with bone sarcoma and STS. Notably, a high number of M-MDSCs was associated with both DFS and PFS time, suggesting a strong prognostic value. The data suggested that the immune status of peripheral blood was associated with the prognosis in patients with sarcoma, as previously reported in patients with other cancer types. In summary, the results may assist with the development of novel strategies for sarcoma treatment, based on the use of biomarkers or immunotherapy.
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http://dx.doi.org/10.3892/ol.2021.12473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836390PMC
March 2021

Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment.

Br J Cancer 2021 03 30;124(5):925-932. Epub 2020 Nov 30.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) with large cell neuroendocrine carcinoma (LCNEC) patients remains unclear. Thus, we performed a retrospective study to examine the relationship between the pretreatment NLR and clinical outcome in advanced LCNEC patients and the impact of the immune-related tumour microenvironment (TME).

Methods: This retrospective study included 63 advanced LCNEC patients who had received chemotherapy. We collected clinical data and investigated the TME status (CD4, CD8, CD20 and FOXP3).

Results: The overall survival of the patients with a low NLR (<5) was significantly longer than those with a high NLR (≥5) (14.9 vs. 5.2 months; p < 0.001). A multivariate analysis identified a high NLR as a predictor of a poor prognosis (HR, 3.43; 95% CI, 1.73-6.79; p < 0.001). The NLR was inversely correlated with tumoural and stromal CD8-positive tumour-infiltrating lymphocytes (tumoural: r = -0.648, p = 0.005, stromal: r = -0.490, p = 0.046).

Conclusions: A high NLR was associated with a poor prognosis in advanced LCNEC patients. Our study revealed that the NLR can reflect the TME, at least in part, suggesting that the NLR plays an important role not only as a clinical outcome predictor but also as a tumour immune status indicator.
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http://dx.doi.org/10.1038/s41416-020-01188-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921668PMC
March 2021

Histological characteristics of lung adenocarcinoma with uncommon actionable alterations: special emphasis on MET exon 14 skipping alterations.

Histopathology 2021 Jun 11;78(7):987-999. Epub 2021 Mar 11.

Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Aims: In the evolving era of precision medicine, increasing emphasis is placed on detecting molecular alterations driving the development of specific cancers and targeting them with matched therapies that can yield the best outcomes for patients. Lung adenocarcinomas with uncommon actionable alterations, including MET exon 14 skipping (METex14), ERBB2 and BRAF mutations, are rare and poorly characterised cancers.

Methods And Results: To more clearly understand the histopathological features of lung adenocarcinoma with uncommon actionable alterations, we compared the histological features of 678 cases with mitogenic driver alterations from 996 surgically resected lung adenocarcinomas. Genomic data from our cohort revealed METex14, ERBB2 and BRAF mutations in 13, 16 and 15 cases, respectively. Patients who had lung adenocarcinoma with METex14 were often elderly females. Histological features such as clear cell features (23%), hyaline globules (31%) and nuclear pleomorphism (39%) were the most frequently identified in METex14-positive cases; among those, three cases (23%) had tumour cells with bizarre giant or multilobulated nuclei. Additionally, the micropapillary pattern was the most frequently identified in ERBB2-mutated lung adenocarcinoma (31%). Lung adenocarcinoma with BRAF mutations tended to be less invasive, and the BRAF V600E mutation was identified in only one case with lepidic adenocarcinoma. Immunohistochemically, all METex14, ERBB2 and BRAF-positive tumours, except for invasive mucinous adenocarcinoma, were positive for thyroid transcription factor 1 (TTF-1).

Conclusions: Our data from Japanese patients showed that lung adenocarcinoma with METex14 had unique clinicopathological characteristics: tumour cells with marked nuclear pleomorphism, hyaline globules and expression of TTF-1 in elderly women who never or lightly smoked.
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http://dx.doi.org/10.1111/his.14311DOI Listing
June 2021

Dose exploration results from Phase 1 study of cemiplimab, a human monoclonal programmed death (PD)-1 antibody, in Japanese patients with advanced malignancies.

Cancer Chemother Pharmacol 2021 01 4;87(1):53-64. Epub 2020 Nov 4.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Purpose: Part 1 of this two-part, open-label, Phase 1 study (NCT03233139) assessed the safety, tolerability, pharmacokinetics, immunogenicity, and clinical activity of cemiplimab in Japanese patients with advanced malignancies.

Methods: Patients received cemiplimab 250 mg (n = 6) or 350 mg (n = 7) every 3 weeks intravenously for up to 108 weeks in Part 1. Tumor responses were assessed by investigators every 9 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1.

Results: Of 13 patients enrolled, median age was 62 years (range 33-75) and eight patients were female. Median duration of cemiplimab exposure was 13.1 weeks (range 3.0‒113.6). At the time of data cut-off, 11 patients (84.6%) had discontinued treatment (majority due to disease progression: n = 8, 61.5%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection (each n = 3, 23.1%). Five grade ≥ 3 TEAEs were reported in four patients: autoimmune colitis, dehydration, hyponatremia, hypophosphatemia, and muscular weakness. No dose-limiting toxicities were reported and no TEAEs led to death. Cemiplimab concentrations in serum were consistent with previously reported pharmacokinetic characteristics of cemiplimab. No anti-drug antibodies were detected in serum. Objective response rate [ORR; complete response + partial response (PR)] was 30.8% (four PR) and disease control rate [ORR + stable disease (SD)] was 46.2% (6/13; two SD).

Conclusion: Cemiplimab exhibited antitumor activity in Japanese patients with advanced malignancies. The safety profile was comparable to those previously reported for cemiplimab and other PD-1 inhibitors.

Trial Registration: NCT03233139 at ClinicalTrials.gov.
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http://dx.doi.org/10.1007/s00280-020-04161-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801352PMC
January 2021

Complete Pathological Response to Neoadjuvant Pembrolizumab in a Patient With Chemoresistant Upper Urinary Tract Urothelial Carcinoma: A Case Report.

Front Oncol 2020 24;10:564714. Epub 2020 Sep 24.

Department of Urology, Iwate Medical University School of Medicine, Iwate, Japan.

Treatment options as second-line therapy for advanced ureteral carcinoma are limited, and patients experiencing recurrence after first-line cisplatin-based chemotherapy have a poor prognosis. Recently, the programmed death-1 (PD-1) inhibitor pembrolizumab provided a better survival benefit with a complete response rate (9.2%) for chemoresistatant urothelial carcinoma. However, the dynamic changes of the cancer microenvironment about the cases of complete response are still unknown. We herein report a case of a 57-year-old man who had been diagnosed with localized, non-muscle-invasive bladder cancer (pT1N0M0, high grade), for which he underwent transurethral resection of the bladder cancer twice. Given that gemcitabine plus carboplatin as first-line neoadjuvant chemotherapy was unable to control left vesico-ureteral junction recurrence with muscle invasion (T3N0M0, high grade), the patient received the PD-1 inhibitor pembrolizumab as second-line neoadjuvant therapy in an attempt to stop tumor growth, which promoted dramatic tumor shrinkage without serious adverse effects and allowed subsequent nephroureterectomy and lymphadenectomy. To the best of our knowledge, this has been the first study to report that pembrolizumab administration before surgery for chemotherapy-resistant ureteral carcinoma promoted a pathological complete response, providing a better understanding of the cancer microenvironment after immunotherapy.
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http://dx.doi.org/10.3389/fonc.2020.564714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541700PMC
September 2020

Correlation between the expression of folate receptor alpha (FRα) and clinicopathological features in patients with lung adenocarcinoma.

Lung Cancer 2020 07 11;145:152-157. Epub 2020 May 11.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Objectives: Folate receptor alpha (FRα) is expressed on the cell surface, mediates its intracellular transport via receptor-mediated endocytosis, and is involved in cell division. Whether FRα could be a potential therapeutic target in FRα-expressing cancers remains unknown. Here, we retrospectively investigated the correlations between tumor FRα expression in lung adenocarcinoma (LADC) and clinicopathological features.

Materials And Methods: FRα expression was evaluated using a tissue microarray (TMA) constructed from surgical specimens of LADC and compared with clinicopathological features including the EGFR mutation status and the expressions of PD-L1, PD-L2, PD-1, CD4, CD8, CD204, and αSMA. If the proportion of positively stained tumor cells was greater than or equal to 5%, the tumor was considered to show FRα expression; if the H-score was more than or equal to 60, the tumor was considered to show high FRα expression.

Results: Overall, 466 TMA cores created from 233 LADC patients were evaluated: FRα-positive expression (FRα-pos)/negative (FRα-neg), 222/11; FRα high expression (FRα-HE)/low (FRα-LE), 190/43. AnEGFR mutation was present in 53.2 % of the patients. The median H-score of FRα expression, FRα-pos rate, and FRα-HE rate for EGFR mutation/wild type were 159/104 (p = 0.0002), 97.6/92.7 % (p = 0.0773), and 88.7/73.4 % (p = 0.0026), respectively. The H-scores for FRα had mild correlations with the proportion of tumor cells with positive staining for PD-L1 (r=-0.2557, p < 0.0001), the number of CD8-positive cells per square millimeter (r=-0.1767, p = 0.0069), and the area with positive staining for αSMA (r = 0.2049, p = 0.0017). No correlations were seen between FRα expression and other cancer-immunity markers.

Conclusion: Tumor FRα expression was significantly higher in LADCs withEGFR mutation than in those with wild-type EGFR. This study suggested that FRα expression was related to cancer and microenvironment-immunity markers such as PD-L1 expression, CD8 cells, and αSMA.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.002DOI Listing
July 2020

Microsatellite instability and mismatch repair protein expressions in lymphocyte-predominant breast cancer.

Cancer Sci 2020 Jul 13;111(7):2647-2654. Epub 2020 Jun 13.

Department of Breast Oncology, Juntendo University School of Medicine, Tokyo, Japan.

The frequency of microsatellite instability (MSI) is reportedly extremely low in breast cancer, despite widespread clinical expectations that many patients would be responsive to immune-checkpoint inhibitors (ICI). Considering that some triple-negative breast cancers (TNBC) responded well to ICI in a clinical trial and that a high density of tumor-infiltrating lymphocytes (TILs) is frequently observed in other cancers with high levels of microsatellite instability (MSI-H), we hypothesized that some TNBC with a high density of TILs would be MSI-H. Medullary carcinoma (MedCa) of the breast, a rare histological type, is characterized by a high density of TILs. Considering that MedCa of the colon is often MSI-H, we suspected that MedCa in breast cancer might also include MSI-H tumors. Therefore, we conducted MSI tests on such breast cancers with a high density of TILs. The MSI status of 63 TIL-high TNBC and 38 MedCa tumors, all from Asian women who had undergone curative surgery, were determined retrospectively. DNA mismatch repair (MMR) proteins and PD-L1 expression were also investigated immunohistochemically. All samples were microsatellite stable, being negative for all microsatellite markers. TIL-high TNBC with low MLH1 protein had higher levels of PD-L1 in stromal immune cells (P = .041). MedCa tumors showed significantly higher PD-L1 expression in immune cells than in TIL-high TNBC (<.001). We found that MSI-H tumors were absent in TIL-high breast cancers. Examination of MMR proteins, not a purpose of Lynch syndrome screening, may merit further studies to yield predictive information for identifying patients who are likely to benefit from ICI.
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http://dx.doi.org/10.1111/cas.14500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385389PMC
July 2020

Feasibility study of nivolumab as neoadjuvant chemotherapy for locally esophageal carcinoma: FRONTiER (JCOG1804E).

Future Oncol 2020 Jul 12;16(19):1351-1357. Epub 2020 May 12.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

One of the standard treatments of resectable esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemotherapy followed by surgery. Nivolumab showed efficacy for metastatic ESCC. However, the safety and efficacy of neoadjuvant nivolumab with chemotherapy for ESCC is unknown. Therefore, we will conduct FRONTiER to evaluate the safety and efficacy of nivolumab adding to neoadjuvant chemotherapy. FRONTiER comprises four experimental cohorts: (A) including nivolumab plus 5-FU+CDDP (cisplatin and 5-fluorouracil [CF]); (B) including one prior administration of nivolumab and the cohort A regimen; (C) including nivolumab plus docetaxel+ CF; (D) including one prior administration of nivolumab and the cohort C regimen; an expanded cohort. The primary end point is the incidence of dose-limiting toxicities from the initial dose to the 30th postoperative day. NCT03914443.
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http://dx.doi.org/10.2217/fon-2020-0189DOI Listing
July 2020

CD20 tumor-infiltrating immune cells and CD204 M2 macrophages are associated with prognosis in thymic carcinoma.

Cancer Sci 2020 Jun 8;111(6):1921-1932. Epub 2020 May 8.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Thymic carcinoma is a rare malignant disease with no standard systemic chemotherapy. The purpose of the present study was to investigate tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME), focusing on the impact of TIIC and program death-ligand 1 (PD-L1) expression on clinical outcomes in thymic cancer. Patients with thymic carcinoma resected between 1973 and 2017 were investigated. The tissue specimens were analyzed through immunohistochemical staining to elucidate the prognostic effects of TIIC, their ratios and PD-L1 in a preliminary cohort (n = 10). The density of TIIC as well as PD-L1 expression was evaluated in intraepithelial and tumor-stromal areas on the representative whole section of tumors. The immune factors showing significant association with disease-free survival (DFS) were evaluated in the total cohort (n = 42). TIIC in the preliminary population showed no significant difference between the two groups. However, CD8, CD20, CD204, FOXP3 and CD20/CD204 ratio demonstrated a tendency to act as predictive markers for recurrence. In the total cohort, significant differences were observed for CD8 , CD20 and CD204 cells in tumor islets, and for CD8 , CD20 and FOXP3 cells as well as the CD8/CD204 and CD20/CD204 ratios in the stroma, indicating their prognostic effect. The prognostic effect of the PD-L1 expression in tumor cells could not be established, possibly because of intratumoral heterogeneity. CD8, CD20 and CD204 positive TIIC in stroma were identified as possible better prognostic biomarkers, considering the heterogeneity of other biomarkers. The present study paves the way for exploring strategies of combination immunotherapy targeting B cell immunity in thymic carcinoma.
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http://dx.doi.org/10.1111/cas.14409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293080PMC
June 2020

Infection risk with PI3K-AKT-mTOR pathway inhibitors and immune checkpoint inhibitors in patients with advanced solid tumours in phase I clinical trials.

ESMO Open 2020 04;5(2)

Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Background: Patients undergoing chemotherapy are known to be at risk for infection from myelosuppression by cytotoxic agents (CTAs) or immunosuppressive effects from mTOR inhibitors. The infection risk of newly developed anticancer agents has not been fully evaluated. It remains unknown how T-cell activation induced by immune checkpoint inhibitors (ICIs) relates to infection.

Methods: We retrospectively examined infection risk in patients with cancer treated with investigational agents in a phase I study. The investigational agents were classified into four groups: CTA, phosphatidylinositol 3 kinase/Akt/mammalian target of rapamycin inhibitor (PAM), molecular targeted agent (MTA) and ICI. All infection-related adverse events (AEs) during treatment were recorded. We compared the CTA, PAM and ICI with MTA, because MTA are already considered low risk and were used in the largest number of patients.

Results: A total of 641 patients were enrolled: 35 CTAs (5.5%), 61 PAMs (9.5%), 445 MTAs (69.4%) and 100 ICIs (15.6%). Among all patients, 132 (20.6%) experienced infection-related AEs and 46 (7.2%) developed 50 ≥grade 3 infection-related AEs. In any infection-related AEs, the ORs compared with MTAs were 2.19 (95% CI 1.03 to 4.66) for CTAs, 3.55 (95% CI 2.02 to 6.24) for PAMs and 1.05 (95% CI 0.60 to 1.85) for ICIs, respectively. In time to the first infection-related AE analysis, the risks for any infection-related AE from CTAs and PAMs were higher than those from MTAs (HR 1.84 (95% CI 0.82 to 4.11); p=0.05 and 3.96 (95% CI 2.18 to 7.22); p<0.001). The risk from ICIs was not significantly different from that of MTAs (HR 0.71 (95% CI 0.46 to 1.10); p=0.19).

Conclusion: Our results validate that PAMs and CTAs carry a higher infection risk in patients with advanced solid tumours compared with MTAs. We suggest that the infection risk of ICIs is a similar infection risk to MTAs.
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http://dx.doi.org/10.1136/esmoopen-2019-000653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174012PMC
April 2020

Neutrophil-to-lymphocyte ratio and histological type might predict clinical responses to eriburin-based treatment in patients with metastatic breast cancer.

Breast Cancer 2020 Jul 27;27(4):732-738. Epub 2020 Feb 27.

Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: Metastatic breast cancer (MBC) is generally considered to be incurable. Although many options are available for treating MBC, physicians often encounter difficulties in choosing the most appropriate treatment because the MBCs of individual patients respond differently even to the same treatments. Thus, predictive markers for therapeutic efficacy are urgently needed. Neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR, respectively), have been studied and established as prognostic markers for breast cancer patients but whether either or both of these markers are predictive of treatment responses is still unclear. Herein, we investigated predictive markers for eribulin-based treatment responsiveness in patients with MBC, by examining clinicopathological features, including several markers of immunocompetent cells in peripheral blood.

Methods: Clinicopathological features of the 104 patients with metastatic/Stage IV breast cancer given eribulin-based regimens were investigated in relation to clinical responses to eribulin-based treatments and progression-free-survival (PFS).

Results: Special histological types and high NLR at baseline were independently related to poor clinical responses to the treatments (p = 0.023 and 0.039, respectively). The Cox hazard model revealed that patients with oestrogen receptor (ER)-negative tumours and high NLR, monocyte-to-lymphocyte ratio (MLR) and PLR showed significantly shorter PFS (p = 0.021, 0.005, 0.008 and 0.030, respectively). On multivariate analysis, only ER status and NLR remained independent factors related to PFS (p = 0.011 and 0.003, respectively).

Conclusions: Our data revealed that special histological types and high NLR might be factors related to low responsiveness to eribulin-based regimens in patients with MBC.
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http://dx.doi.org/10.1007/s12282-020-01069-0DOI Listing
July 2020

CD4 T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy.

Cancer Immunol Res 2020 03 23;8(3):334-344. Epub 2019 Dec 23.

Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.

Accumulating evidence indicates that CD8 T cells in the tumor microenvironment and systemic CD4 T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non-small lung cancer and found that responders had significantly ( < 0.0001) higher percentages of effector, CD62L CD4 T cells prior to PD-1 blockade. Conversely, the percentage of CD25FOXP3 CD4 T cells was significantly ( = 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62L CD4 T cells and CD25FOXP3 cells to predict nonresponders. Mass cytometry analysis revealed that the CD62L CD4 T-cell subset expressed T-bet, CD27, FOXP3, and CXCR3, indicative of a Th1 subpopulation. CD62L CD4 T cells significantly correlated with effector CD8 T cells ( = 0.0091) and with PD-1 expression on effector CD8 T cells ( = 0.0015). Gene expression analysis revealed that , and were preferentially expressed in CD62L CD4 T cells derived from responders. Notably, long-term responders, who had >500-day progression-free survival, showed significantly higher numbers of CD62L CD4 T cells prior to PD-1 blockade therapy. Decreased CD62L CD4 T-cell percentages after therapy resulted in acquired resistance, with long-term survivors maintaining high CD62L CD4 T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4 T-cell immune statuses in their peripheral blood.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0574DOI Listing
March 2020

First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.

Cancer Sci 2020 Feb;111(2):571-579

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH) -vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.
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http://dx.doi.org/10.1111/cas.14265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004556PMC
February 2020

Relationship between the immune microenvironment of different locations in a primary tumour and clinical outcomes of oesophageal squamous cell carcinoma.

Br J Cancer 2020 02 25;122(3):413-420. Epub 2019 Nov 25.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.

Background: Tumour microenvironments can differ according to intratumoural locations. We investigated the immune status at different locations in primary tumours and its clinical significance in oesophageal squamous cell carcinoma (ESCC).

Methods: The number of CD8 tumour-infiltrating immune cells (TIICs) and PD-1 TIICs, and PD-L1 expression on tumour cells (PD-L1) were immunohistochemically examined in the surface (Surf), centre (Cent) and invasive front (Inv) of tumours surgically resected from 192 patients with ESCC.

Results: The PD-L1 rate was lower in Inv than in Cent (12.0% vs. 18.2%, P = 0.012), although the numbers of CD8 TIICs and PD-1 TIICs were comparable among intratumoural locations. High numbers of CD8 and PD-1 TIICs and positive PD-L1 were related to better overall survival (OS) only in Surf and Cent (CD8: P = 0.012 in Surf, 0.018 in Cent, and 0.165 in Inv; PD-1: P = 0.028 in Surf, 0.021 in Cent, and 0.208 in Inv; and PD-L1: 0.044 in Surf, 0.026 in Cent, and 0.718 in Inv). Positive PD-L1 in Surf and/or Cent but not in Inv demonstrated a strong tendency toward better OS (P = 0.053).

Conclusions: Immune microenvironments according to the intratumoural location have different effects on the survival of patients with ESCC.
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http://dx.doi.org/10.1038/s41416-019-0622-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000821PMC
February 2020

Improved survival among patients enrolled in oncology phase 1 trials in recent decades.

Cancer Chemother Pharmacol 2020 02 19;85(2):449-459. Epub 2019 Nov 19.

Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: This study aimed to compare the survival of patients enrolled in phase 1 trials in recent decades.

Methods: The medical records of consecutive patients with advanced cancer who participated in single-agent oncology phase 1 trials from 1995 to 2015 at a single institution were retrospectively investigated.

Results: A total of 267 (34.1%) patients participated in 1995-2004 and 516 (65.9%) participated in 2005-2015. The median follow-up period was 25.4 months (range 1.3-166.9). The response rate did not differ significantly between the two periods (3.9% vs. 6.2%, p = 0.17). The median survival times were 9.5 (95% confidence interval 8.4-11.2) months in 1995-2004 and 11.8 (95% confidence interval 10.9-13.3) months in 2005-2015 (p = 0.0009). The enrolment period was an independent prognostic factor of overall survival according to multivariate analysis (hazard ratio: 0.85, 95% confidence interval 0.72-0.99, p = 0.042).

Conclusions: In our single-centre, retrospective analysis, the trends in patients characteristic were consistent with those of Western countries, and the overall survival of cancer patients enrolled in oncology phase 1 trials tended to improve in recent decades, suggesting that patient selection, the population that benefits from investigational agents and treatment after phase 1 trials have improved.
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http://dx.doi.org/10.1007/s00280-019-03992-2DOI Listing
February 2020

Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports.

BMC Cancer 2019 Oct 29;19(1):1019. Epub 2019 Oct 29.

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Background: Nivolumab is an immune checkpoint inhibitor specific to the programmed death 1 (PD-1) receptor. Nivolumab has shown clinical responses in many malignancies. Although immune-related adverse events (irAEs) associated with nivolumab are largely tolerable, severe irAEs have occurred in some patients. However, the mechanisms underlying the development of irAEs are not fully clarified.

Case Presentation: We report 2 patients with metastatic melanoma who developed colitis, an irAEs caused by nivolumab. Both patients experienced colitis after nivolumab administration. Pathological examination of the colon showed robust infiltration of CD8 cells and T-bet expressing CD4 cells in both cases, indicating helper T cells (Th) 1 to be responsible for the dominant response. Additionally, we observed the serum C-reactive protein level (CRP) as well as interleukin-6 (IL-6) reflected the clinical course of irAEs clearly in the two cases.

Conclusion: Our two cases suggested that the development of irAEs due to nivolumab is associated with Th1 dominant response. CRP as well as IL-6 was found to be a potential biomarker for irAEs. Our findings may help to understand the mechanisms underlying irAEs caused by nivolumab and manage irAEs in clinical practice.
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http://dx.doi.org/10.1186/s12885-019-6138-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819390PMC
October 2019

Impact of low-dose anti-thymocyte globulin on immune reconstitution after allogeneic hematopoietic cell transplantation.

Int J Hematol 2020 Jan 22;111(1):120-130. Epub 2019 Oct 22.

Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan.

How low-dose anti-thymocyte globulin (ATG) for prophylaxis of graft-versus-host disease (GVHD) influences immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HCT) remains incompletely understood. We prospectively enrolled 41 consecutive adult patients and conducted cytometry-based immunophenotyping for 12 months after allo-HCT. Rabbit ATG (Thymoglobulin) was administered at a median total dose of 1.75 mg/kg in 16 of the 41 patients. Compared with patients who did not receive ATG, those who did had a significantly smaller number of naïve T cells (especially CD4+ ) within three months after allo-HCT. No significant difference was observed between the two groups in the reconstitution of other T cells (effector, memory, Th1, Th2, Th17, Treg, and Tfh), B cells (transitional, naïve, memory, and plasmablast), NK cells (regulatory and cytolytic), or dendritic cells (myeloid and plasmacytoid). Patients with fewer CD4+ naïve T cells than the median count (7.60 cells/µL) at two months after allo-HCT developed chronic GVHD less frequently than those with CD4+ naïve T cells above the median count (2-year cumulative incidences were 0.31 and 0.53, respectively; p = 0.133). This pilot study suggests low-dose Thymoglobulin suppresses the recovery of naïve T cells after allo-HCT, which may contribute to a lower incidence of chronic GVHD.
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http://dx.doi.org/10.1007/s12185-019-02756-1DOI Listing
January 2020

[Ⅲ.Cross-Organ Developmental Status and Challenges of Immune Checkpoint Inhibitors].

Authors:
Shigehisa Kitano

Gan To Kagaku Ryoho 2019 08;46(8):1249-1257

Dept. of Experimental Therapeutics, National Cancer Center Hospital.

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August 2019
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