First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors
Abstract Background Transient CD4+ T cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0677-y |
| _version_ | 1819151180063834112 |
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| author | Kohei Shitara Satoshi Ueha Shigeyuki Shichino Hiroyasu Aoki Haru Ogiwara Tetsuya Nakatsura Toshihiro Suzuki Manami Shimomura Toshiaki Yoshikawa Kayoko Shoda Shigehisa Kitano Makiko Yamashita Takayuki Nakayama Akihiro Sato Sakiko Kuroda Masashi Wakabayashi Shogo Nomura Shoji Yokochi Satoru Ito Kouji Matsushima Toshihiko Doi |
| author_facet | Kohei Shitara Satoshi Ueha Shigeyuki Shichino Hiroyasu Aoki Haru Ogiwara Tetsuya Nakatsura Toshihiro Suzuki Manami Shimomura Toshiaki Yoshikawa Kayoko Shoda Shigehisa Kitano Makiko Yamashita Takayuki Nakayama Akihiro Sato Sakiko Kuroda Masashi Wakabayashi Shogo Nomura Shoji Yokochi Satoru Ito Kouji Matsushima Toshihiko Doi |
| author_sort | Kohei Shitara |
| collection | DOAJ |
| description | Abstract Background Transient CD4+ T cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity. Methods Patients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0 mg/kg. The first patient in each cohort received a single administration, and the other patients received two administrations of IT1208 on days 1 and 8. Results Eleven patients were enrolled in the 0.1 mg/kg (n = 4) and 1.0 mg/kg cohorts (n = 7). Grade 1 or 2 infusion-related reactions was observed in all patients. Decreased CD4+ T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0 mg/kg. CD8+ T cells increased on day 29 compared with baseline in most patients, resulting in remarkably decreased CD4/8 ratios. One microsatellite-stable colon cancer patient achieved durable partial response showing increased infiltration of both CD4+ and CD8+ T cells into tumors after IT1208 administration. Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration. Two additional patients with gastric or esophageal cancer achieved stable disease lasting at least 3 months. Conclusions IT1208 monotherapy successfully depleted CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors. |
| first_indexed | 2024-12-22T14:29:18Z |
| format | Article |
| id | doaj.art-f3fa5960399a4030b38ca80859495c2b |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-22T14:29:18Z |
| publishDate | 2019-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-f3fa5960399a4030b38ca80859495c2b2022-12-21T18:22:48ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-07-017111110.1186/s40425-019-0677-yFirst-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumorsKohei Shitara0Satoshi Ueha1Shigeyuki Shichino2Hiroyasu Aoki3Haru Ogiwara4Tetsuya Nakatsura5Toshihiro Suzuki6Manami Shimomura7Toshiaki Yoshikawa8Kayoko Shoda9Shigehisa Kitano10Makiko Yamashita11Takayuki Nakayama12Akihiro Sato13Sakiko Kuroda14Masashi Wakabayashi15Shogo Nomura16Shoji Yokochi17Satoru Ito18Kouji Matsushima19Toshihiko Doi20Department of Gastrointestinal Oncology, National Cancer Center Hospital EastDivision of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of ScienceDivision of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of ScienceDivision of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of ScienceDivision of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of ScienceDivision of Cancer Immunetherapy, National Cancer Center, Exploratory Oncology Research and Clinical Trial Center (EPOC)Division of Cancer Immunetherapy, National Cancer Center, Exploratory Oncology Research and Clinical Trial Center (EPOC)Division of Cancer Immunetherapy, National Cancer Center, Exploratory Oncology Research and Clinical Trial Center (EPOC)Division of Cancer Immunetherapy, National Cancer Center, Exploratory Oncology Research and Clinical Trial Center (EPOC)Division of Cancer Immunetherapy, National Cancer Center, Exploratory Oncology Research and Clinical Trial Center (EPOC)Department of Experimental Therapeutics, National Cancer Center HospitalDepartment of Experimental Therapeutics, National Cancer Center HospitalDepartment of Experimental Therapeutics, National Cancer Center HospitalClinical Research Support Office, National Cancer Center Hospital EastClinical Research Support Office, National Cancer Center Hospital EastClinical Research Support Office, National Cancer Center Hospital EastClinical Research Support Office, National Cancer Center Hospital EastDivision of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of ScienceDivision of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of ScienceDivision of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of ScienceDepartment of Experimental Therapeutics, National Cancer Center Hospital EastAbstract Background Transient CD4+ T cell depletion led to the proliferation of tumor-specific CD8+ T cells in the draining lymph node and increased infiltration of PD-1+CD8+ T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity. Methods Patients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0 mg/kg. The first patient in each cohort received a single administration, and the other patients received two administrations of IT1208 on days 1 and 8. Results Eleven patients were enrolled in the 0.1 mg/kg (n = 4) and 1.0 mg/kg cohorts (n = 7). Grade 1 or 2 infusion-related reactions was observed in all patients. Decreased CD4+ T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0 mg/kg. CD8+ T cells increased on day 29 compared with baseline in most patients, resulting in remarkably decreased CD4/8 ratios. One microsatellite-stable colon cancer patient achieved durable partial response showing increased infiltration of both CD4+ and CD8+ T cells into tumors after IT1208 administration. Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration. Two additional patients with gastric or esophageal cancer achieved stable disease lasting at least 3 months. Conclusions IT1208 monotherapy successfully depleted CD4+ T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors.http://link.springer.com/article/10.1186/s40425-019-0677-yAnti-CD4 antibodyCD4+ T cellsCD8+ T cellsImmunotherapy |
| spellingShingle | Kohei Shitara Satoshi Ueha Shigeyuki Shichino Hiroyasu Aoki Haru Ogiwara Tetsuya Nakatsura Toshihiro Suzuki Manami Shimomura Toshiaki Yoshikawa Kayoko Shoda Shigehisa Kitano Makiko Yamashita Takayuki Nakayama Akihiro Sato Sakiko Kuroda Masashi Wakabayashi Shogo Nomura Shoji Yokochi Satoru Ito Kouji Matsushima Toshihiko Doi First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors Journal for ImmunoTherapy of Cancer Anti-CD4 antibody CD4+ T cells CD8+ T cells Immunotherapy |
| title | First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors |
| title_full | First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors |
| title_fullStr | First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors |
| title_full_unstemmed | First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors |
| title_short | First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors |
| title_sort | first in human phase 1 study of it1208 a defucosylated humanized anti cd4 depleting antibody in patients with advanced solid tumors |
| topic | Anti-CD4 antibody CD4+ T cells CD8+ T cells Immunotherapy |
| url | http://link.springer.com/article/10.1186/s40425-019-0677-y |
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