Journal for ImmunoTherapy of Cancer (Jul 2019)

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

  • 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

DOI
https://doi.org/10.1186/s40425-019-0677-y
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 11

Abstract

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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.

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