Abstract
BackgroundTransient 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.MethodsPatients 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.ResultsEleven 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.ConclusionsIT1208 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.
Highlights
Immune checkpoint inhibitors such as anti-cytotoxic Tlymphocyte-associated antigen-4 and anti-programmed cell death-1 (PD-1) monoclonal antibody agents or their combinations have improved outcomes of various cancers [1,2,3,4,5,6,7]
One of the possible reasons for treatment failure with PD-1 blockade is the presence of immune suppression through immune checkpoints other than the PD-1/programmed cell death ligand-1 (PD-L1) axis regulating lymphocyte activation and expansion or through immune suppressive cells including forkhead box P3 (Foxp3)+ CD25+ regulatory T cells (Tregs), T helper 2 (Th2) cells, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and plasmacytoid dendritic cells [8,9,10,11,12,13]
We showed that administration of the anti-CD4 monoclonal antibody (mAb) had strong antitumor effects superior to those elicited by CD25+ Regulatory T cells (Tregs) depletion or other immune checkpoint mAbs in B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, which were completely reversed by CD8+ cell depletion [17]
Summary
Immune checkpoint inhibitors such as anti-cytotoxic Tlymphocyte-associated antigen-4 and anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb) agents or their combinations have improved outcomes of various cancers [1,2,3,4,5,6,7]. Several reports suggested that depletion of CD4+ cells, including Tregs, Th2 cells, and a subpopulation of MDSCs and pDCs, results in strong antitumor effects in mouse models due to the enhancement of cytotoxic Tlymphocyte responses [14,15,16]. 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
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