2. Academic Validation
  3. First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors

First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors

  • J Immunother Cancer. 2019 Jul 24;7(1):195. doi: 10.1186/s40425-019-0677-y.
Kohei Shitara 1,  Satoshi Ueha 2 3,  Shigeyuki Shichino 2 3,  Hiroyasu Aoki 2 3,  Haru Ogiwara 2 3,  Tetsuya Nakatsura 4,  Toshihiro Suzuki 4,  Manami Shimomura 4,  Toshiaki Yoshikawa 4,  Kayoko Shoda 4,  Shigehisa Kitano 5,  Makiko Yamashita 5,  Takayuki Nakayama 5,  Akihiro Sato 6,  Sakiko Kuroda 6,  Masashi Wakabayashi 6,  Shogo Nomura 6,  Shoji Yokochi 2 7,  Satoru Ito 2 7,  Kouji Matsushima 8 9,  Toshihiko Doi 10
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
  • 2 Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba, 278-0022, Japan.
  • 3 Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 4 Division of Cancer Immunetherapy, National Cancer Center, Exploratory Oncology Research and Clinical Trial Center (EPOC), Chuo-ku, Tokyo, Japan.
  • 5 Department of Experimental Therapeutics, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
  • 6 Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
  • 7 IDAC Theranostics Inc., Bunkyo-ku, Tokyo, Japan.
  • 8 Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba, 278-0022, Japan. koujim@rs.tus.ac.jp.
  • 9 Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. koujim@rs.tus.ac.jp.
  • 10 Department of Experimental Therapeutics, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.
PMID: 31340866 DOI: 10.1186/s40425-019-0677-y
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.

Keywords

Anti-CD4 antibody; CD4+ T cells; CD8+ T cells; Immunotherapy.

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