Publications by authors named "Keitaro Fukuda"

16 Publications

  • Page 1 of 1

AIM2 regulates anti-tumor immunity and is a viable therapeutic target for melanoma.

J Exp Med 2021 Sep 29;218(9). Epub 2021 Jul 29.

Department of Dermatology, University of Massachusetts Medical School, Worcester, MA.

The STING and absent in melanoma 2 (AIM2) pathways are activated by the presence of cytosolic DNA, and STING agonists enhance immunotherapeutic responses. Here, we show that dendritic cell (DC) expression of AIM2 within human melanoma correlates with poor prognosis and, in contrast to STING, AIM2 exerts an immunosuppressive effect within the melanoma microenvironment. Vaccination with AIM2-deficient DCs improves the efficacy of both adoptive T cell therapy and anti-PD-1 immunotherapy for "cold tumors," which exhibit poor therapeutic responses. This effect did not depend on prolonged survival of vaccinated DCs, but on tumor-derived DNA that activates STING-dependent type I IFN secretion and subsequent production of CXCL10 to recruit CD8+ T cells. Additionally, loss of AIM2-dependent IL-1β and IL-18 processing enhanced the treatment response further by limiting the recruitment of regulatory T cells. Finally, AIM2 siRNA-treated mouse DCs in vivo and human DCs in vitro enhanced similar anti-tumor immune responses. Thus, targeting AIM2 in tumor-infiltrating DCs is a promising new treatment strategy for melanoma.
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http://dx.doi.org/10.1084/jem.20200962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329870PMC
September 2021

Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors.

Cancer Sci 2021 Aug 30;112(8):3163-3172. Epub 2021 Jun 30.

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

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).
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http://dx.doi.org/10.1111/cas.15009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353905PMC
August 2021

Anti-PD-1 antibody therapy for epithelial skin malignancies: An investigator-initiated, open-label, single-arm, multicenter, phase II clinical trial (NMSC-PD1 Study).

Medicine (Baltimore) 2020 Oct;99(44):e22913

Department of Dermatology, Keio University School of Medicine, Tokyo.

Introduction: Malignant cutaneous epithelial tumors comprise various skin malignancies originating from the cutaneous epithelium, including cutaneous squamous cell carcinoma, basal cell carcinoma, and malignant cutaneous adnexal tumors. Treatment options are limited, as the rarity of these tumors, especially among Asians, renders well-controlled clinical trials extremely challenging to conduct. Thus, we designed a clinical trial to evaluate the efficacy and safety of the anti-programmed cell death-1 (PD-1) monoclonal antibody nivolumab in patients with metastatic cutaneous squamous cell carcinomas and other rare metastatic cutaneous epithelial tumors.

Methods And Analysis: This is an open-label, single-arm, multicenter, phase 2 clinical trial involving patients with metastatic malignant cutaneous epithelial tumors. Nivolumab (480 mg) will be administered intravenously every 4 weeks for a maximum of 26 doses. The primary outcome of the study will be the response rate based on response evaluation criteria in solid tumors, version 1.1. Assuming a null hypothesis of a response rate ≤5% and an alternative hypothesis of a 25% response rate, a minimum of 26 patients are required to achieve a 5% two-sided type I error and 80% power based on the exact binomial distribution. Finally, a target cohort size of 30 patients was determined as some patient dropout will be expected.

Discussion: This is the first phase 2 clinical trial evaluating the efficacy and safety of the PD-1 inhibitor nivolumab in Asian patients with metastatic malignant cutaneous epithelial tumors. The findings of the study will contribute to the development of novel treatment approaches for patients with rare cutaneous malignancies, which remains an unmet clinical need.

Trial Registration: Registry number: jRCT 2031190048.
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http://dx.doi.org/10.1097/MD.0000000000022913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598805PMC
October 2020

Type I interferon signaling limits viral vector priming of CD8 T cells during initiation of vitiligo and melanoma immunotherapy.

Pigment Cell Melanoma Res 2021 07 26;34(4):683-695. Epub 2020 Oct 26.

Department of Dermatology, University of Massachusetts Medical School, Worcester, MA, USA.

Vitiligo is an autoimmune skin disease in which epidermal melanocytes are targeted for destruction by CD8 T cells specific for melanocyte/melanoma-shared antigens. IFNγ is the central cytokine driving disease, but the role of type I IFN in vitiligo remains unclear. We investigated the functional role of type I IFN during vitiligo progression using two different mouse models: one induced with a vaccinia virus (VV) vaccine and one induced with dendritic cells to prime autoimmune T cells. Induction of vitiligo by VV in IFNaR-deficient mice led to the development of severe vitiligo compared with wild-type (WT) mice and was characterized by a significantly enhanced effector CD8 T-cell response. Severe vitiligo in this model was a result of VV persistence, because exacerbation of disease in IFNaR-deficient mice was not observed when antigen-pulsed dendritic cells were used to induce vitiligo instead of virus. Treatment of B16F10 melanoma-inoculated mice with VV vaccine therapy also induced a significantly enhanced anti-tumor response in IFNaR-deficient mice compared with WT. These results not only help define the pathways responsible for vitiligo progression but also suggest that blockade of type I IFNs following administration of a VV vaccine may provide increased immunogenicity and efficacy for melanoma immunotherapy.
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http://dx.doi.org/10.1111/pcmr.12935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035367PMC
July 2021

Outcomes in patients with extramammary Paget disease with brain metastasis: A retrospective analysis.

J Am Acad Dermatol 2020 Dec 23;83(6):1832-1834. Epub 2020 May 23.

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

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http://dx.doi.org/10.1016/j.jaad.2020.05.094DOI Listing
December 2020

Metastatic Cutaneous Squamous Cell Carcinoma in Liver Successfully Treated With Partial Hepatectomy and Adjuvant Irinotecan Chemotherapy.

In Vivo 2020 Mar-Apr;34(2):825-828

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

Background: The management of distant metastatic cutaneous squamous cell carcinoma (cSCC) relies mainly on chemotherapies and radiotherapy. Management of patients with cSCC with surgically resectable distant metastatic lesions is not clear.

Case Report: A 59-year-old male had 4×10 cm-sized cSCC on the perianal skin with inguinal lymph node metastasis. Surgical resection was performed followed by radiation and adjuvant carboplatin and farmorubicin combination therapy. Six months later, 25 mm-sized solitary metastatic nodule arose on the liver. Base on his favorable overall condition fulfilling the criteria of tumor resectability for the treatment of tumors in liver and having good performance status, laparoscopic partial hepatectomy and six courses of adjuvant irinotecan therapy were performed. The surgical margin was negative and the patient has maintained complete remission for over 3 years.

Conclusion: The clinical course of the present case suggests that surgical approaches should also be considered as candidate additional therapy for resectable distant metastatic cSCC.
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http://dx.doi.org/10.21873/invivo.11844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157877PMC
December 2020

Weekly docetaxel monotherapy for metastatic extramammary Paget's disease: Retrospective single-institute analysis.

J Dermatol 2020 Apr 5;47(4):418-422. Epub 2020 Feb 5.

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

Monthly docetaxel (DTX) monotherapy is the first-line regimen that is preferably used for metastatic extramammary Paget's disease (EMPD). However, the high-dose DTX regimen frequently causes severe hematological adverse events (AE). To overcome such safety concerns, a weekly low-dose DTX monotherapy has been proposed for use in the treatment of various cancer types. In this study, we aimed to evaluate the feasibility and efficacy of weekly DTX (25 mg/m ) monotherapy for metastatic EMPD by retrospectively analyzing the clinical courses of 14 patients treated with this regimen. Weekly DTX monotherapy was well tolerated and all patients completed the treatment schedule without treatment withdrawal, dose reduction or treatment-related death. While five cases (35.7%) experienced hematological AE, their severity was mild. The response rate was 35.7% (5/14 cases), which included five partial responses. The mean progression-free survival (PFS) and overall survival were 7.1 (95% confidence interval [CI], 5.1-9.1) and 26.4 months (95% CI, 16.7-36.1), respectively. Furthermore, the median PFS was 7.3 months (95% CI, 4.5-10.0) in patients aged 65 years and younger and 7.1 months (95% CI, 4.4-9.9) in patients older than 65 years. These results suggest that weekly DTX monotherapy may be a useful regimen that has a high treatment continuation rate with low levels of hematological toxicity, regardless of the patient's age for metastatic EMPD.
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http://dx.doi.org/10.1111/1346-8138.15255DOI Listing
April 2020

Corrigendum: Metastatic Extramammary Paget's Disease: Pathogenesis and Novel Therapeutic Approach.

Front Oncol 2018 12;8:47. Epub 2018 Mar 12.

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

[This corrects the article on p. 38 in vol. 8, PMID: 29503810.].
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http://dx.doi.org/10.3389/fonc.2018.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857541PMC
March 2018

Metastatic Extramammary Paget's Disease: Pathogenesis and Novel Therapeutic Approach.

Front Oncol 2018 16;8:38. Epub 2018 Feb 16.

Department of Dermatology, University of Massachusetts Medical School, Worcester, MA, United States.

Extramammary Paget's disease (EMPD) is a rare, slow-growing, cutaneous adenocarcinoma that usually originates in the anogenital area and axillae outside the mammary glands. EMPD mostly progresses slowly and is often diagnosed as carcinoma ; however, upon becoming invasive, it promptly and frequently metastasizes to regional lymph nodes, leading to subsequent distant metastasis. To date, several chemotherapy regimens have been used to treat metastatic EMPD; however, they present limited effect and patients with distant metastasis exhibit a poor prognosis. Recently, basic and translational investigative research has elucidated factors and molecular mechanisms underlying the promotion of metastasis, which can lead to targeted therapy-based emerging treatment strategies. Here, we aim to discuss current therapies and their limitations; advancements in illustrating mechanisms promoting invasion, migration, and proliferation of EMPD tumor cells; and future therapeutic approaches for metastatic EMPD that may enhance clinical outcomes.
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http://dx.doi.org/10.3389/fonc.2018.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820294PMC
February 2018

Periostin antisense oligonucleotide suppresses bleomycin-induced formation of a lung premetastatic niche for melanoma.

Cancer Sci 2018 May 31;109(5):1447-1454. Epub 2018 Mar 31.

Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Metastasis is the leading cause of cancer death. A tumor-supportive microenvironment, or premetastatic niche, at potential secondary tumor sites plays an important role in metastasis, especially in tumor cell colonization. Although a fibrotic milieu is known to promote tumorigenesis and metastasis, the underlying molecular contributors to this effect have remained unclear. Here we show that periostin, a component of the extracellular matrix that functions in tissue remodeling, has a key role in formation of a fibrotic environment that promotes tumor metastatic colonization. We found that periostin was widely expressed in fibrotic lesions of mice with bleomycin-induced lung fibrosis, and that up-regulation of periostin expression coincided with activation of myofibroblasts positive for α-smooth muscle actin. We established a lung metastasis model for B16 murine melanoma cells and showed that metastatic colonization of the lung by these cells was markedly promoted by bleomycin-induced lung fibrosis. Inhibition of periostin expression by giving an intratracheal antisense oligonucleotide targeting periostin mRNA was found to suppress bleomycin-induced lung fibrosis and thereby to attenuate metastatic colonization of the lung by melanoma cells. Our results indicate that periostin is a key player in the development of bleomycin-induced fibrosis and consequent enhancement of tumor cell colonization in the lung. Our results therefore implicate periostin as a potential target for prevention or treatment of lung metastasis.
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http://dx.doi.org/10.1111/cas.13554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980369PMC
May 2018

Vitiligo-like depigmentation in patients receiving programmed cell death-1 inhibitor reflects active vitiligo.

J Am Acad Dermatol 2018 01;78(1):e15-e16

Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2017.07.058DOI Listing
January 2018

Peptide-pulsed dendritic cell vaccine in combination with carboplatin and paclitaxel chemotherapy for stage IV melanoma.

Melanoma Res 2017 08;27(4):326-334

aDepartment of Dermatology bDivision of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine cTokyo Midtown Clinic, Tokyo, Japan.

In this study, we aimed to evaluate the feasibility and efficacy of peptide-pulsed dendritic cell (DC) vaccine in combination with carboplatin and paclitaxel chemotherapy (DCCP) for patients with stage IV melanoma previously treated with dacarbazine-containing regimen. Six HLA-A24 and 3 HLA-A02 patients were treated with carboplatin (area under the curve 5) and paclitaxel (175 mg/m) on day 1 and DCs (2×10 cells) pulsed with Wilms tumor gene 1 (WT1), gp100, tyrosinase, and either MAGE-A3 (for HLA-A24) or MAGE-A2 (for HLA-A02) peptides on days 8 and 22 in 28-day cycle for up to three cycles. DCCP was well tolerated, and median progression-free survival and median overall survival were 2.3 and 12.0 months, respectively. In four of nine patients, a WT1-specific immune response (WT1-IR) was detected using the interferon-γ enzyme-linked ImmunoSpot assay and WT1/HLA tetramer assay. DCCP was more likely to elicit a WT1-IR in patients who received DCs pulsed with the HLA-A24-restricted peptide (75%) compared with patients who received DCs pulsed with the HLA-A02-restricted peptide (0%, P=0.058). Furthermore, three (75%) of four patients with a WT1-IR survived longer than 12 months, whereas only one (20%) of five patients without a WT1-IR who received the BRAF inhibitor after DCCP survived longer than 12 months. These results suggest that DCCP may be beneficial for HLA-A24 melanoma patients with a WT1-IR.
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http://dx.doi.org/10.1097/CMR.0000000000000342DOI Listing
August 2017

Bilateral Necrotizing Fasciitis of the Foot Associated with Group B Streptococcus.

Case Rep Dermatol 2016 Sep-Dec;8(3):243-249. Epub 2016 Sep 12.

Department of Dermatology, Teikyo University Chiba Medical Center, Ichihara, Japan.

Necrotizing fasciitis (NF) is a severe bacterial infection involving fascia and subcutaneous tissue. It generally affects upper or lower extremities unilaterally, and there are few reports of bilateral-extremity NF. Here, we report a case of a 43-year-old male with type 1 diabetes who had NF on the left foot and subsequently developed NF on the other foot 1 week later. The patient survived with antimicrobial therapy and bilateral below-knee amputation. As group B streptococcus (GBS) was isolated by blood culture and culture of excised tissues of both feet, bilateral GBS NF of the foot was diagnosed. GBS is a rare causative pathogen in NF; however, there have been two case reports of bilateral GBS NF of an extremity in which NF appeared on the opposite extremity 1 week after the primary site infection, as in our case. GBS was isolated from cultures of blood and excised tissues of both extremities in both cases. Together, these observations suggest that GBS has a potential to cause secondary NF at remote sites by hematogenous dissemination with approximately 1 week delay and thereby lead to bilateral NF.
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http://dx.doi.org/10.1159/000448163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073656PMC
September 2016

Periostin Is a Key Niche Component for Wound Metastasis of Melanoma.

PLoS One 2015 17;10(6):e0129704. Epub 2015 Jun 17.

Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Tissue injury promotes metastasis of several human cancers, although factors associated with wound healing that attract circulating tumor cells have remained unknown. Here, we examined the primary and metastatic lesions that appeared 1 month after trauma in a patient with acral lentiginous melanoma. The levels of mRNA for periostin (POSTN), type 1 collagen, and fibronectin were significantly increased in the metastatic lesion relative to the primary lesion. The increase of these extracellular matrix proteins at the wound site was reproduced in a mouse model of wound healing, with the upregulation of Postn mRNA persisting the longest. POSTN was expressed in the region surrounding melanoma cell nests in metastatic lesions of both wounded mice and the patient. POSTN attenuated the cell adhesion and promoted the migration of melanoma cells without affecting their proliferation in vitro. In the mouse model, the wound site as well as subcutaneously injected osteoblasts that secrete large amounts of POSTN invited the metastasis of remotely-transplanted melanoma cells on the sites. Osteoblasts with suppression of POSTN by shRNA showed a greatly reduced ability to promote such metastasis. Our results suggest that POSTN is a key factor in promoting melanoma cell metastasis to wound sites by providing a premetastatic niche.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129704PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471156PMC
March 2016

Metastatic eccrine porocarcinoma successfully treated with carboplatin and epirubicin chemotherapy.

J Dermatol 2015 Sep 13;42(9):928-30. Epub 2015 Jun 13.

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

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http://dx.doi.org/10.1111/1346-8138.12977DOI Listing
September 2015
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