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 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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0677-y) contains supplementary material, which is available to authorized users.

Identification of TYROBP and C1QB as Two Novel Key Genes With Prognostic Value in Gastric Cancer by Network Analysis

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“…For some patients with distant metastases, palliative local treatments are chosen to control and delay disease progression [15]. With the enhanced study of the immune system, immunotherapy has emerged as very promising method to treat sarcomas after surgery and chemotherapy [16].…”

“…For some patients with distant metastases, palliative local treatments are chosen to control and delay disease progression [ 15 ]. With the enhanced study of the immune system, immunotherapy has emerged as very promising method to treat sarcomas after surgery and chemotherapy [ 16 ]. Researchers have adopted various immunotherapy strategies for different types of immune deficiency, but the main treatment obstacles are identifying the specific target antigen and dealing with the severe adverse effects of the selected treatment [ 17 ].…”

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“…For some patients with distant metastases, palliative local treatments are chosen to control and delay disease progression [15]. With the enhanced study of the immune system, immunotherapy has emerged as very promising method to treat sarcomas after surgery and chemotherapy [16]. Researchers have adopted various immunotherapy strategies for different types of immune de ciency, but the main treatment obstacles are identifying the speci c target antigen and dealing with the severe adverse effects of the selected treatment [17].…”