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

• Published in: Journal for immunotherapy of cancer 2019-07, Vol.7 (1), p.195-195, Article 195
• Main Authors: Shitara, Kohei, Ueha, Satoshi, Shichino, Shigeyuki, Aoki, Hiroyasu, Ogiwara, Haru, Nakatsura, Tetsuya, Suzuki, Toshihiro, Shimomura, Manami, Yoshikawa, Toshiaki, Shoda, Kayoko, Kitano, Shigehisa, Yamashita, Makiko, Nakayama, Takayuki, Sato, Akihiro, Kuroda, Sakiko, Wakabayashi, Masashi, Nomura, Shogo, Yokochi, Shoji, Ito, Satoru, Matsushima, Kouji, Doi, Toshihiko
• Format: Article
• Language: English
• Subjects: Anti-CD4 antibody; Antibodies; Antigens; Apoptosis; Biological response modifiers; Biopsy; Cancer; Cancer metastasis; Cancer therapies; CD4+ T cells; CD8+ T cells; Chemotherapy; Colon cancer; Colorectal cancer; Criminal investigation; Cytotoxicity; Disease; Drug dosages; Esophageal cancer; Genes; Hepatitis; Immunologic factors; Immunotherapy; Interferon; Liver; Liver cancer; Lymphocytes; Monoclonal antibodies; Neutropenia; Patients; Pharmacokinetics; T cells; Thrombocytopenia; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1186/s40425-019-0677-y

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. 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. 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. 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.