Abstract
Cergutuzumab amunaleukin (CEA-IL2v) is an immunocytokine directed against carcinoembryonic antigen (CEA) containing an IL2v-moiety with abolished IL-2 receptor (IL-2R) α binding. We describe the biodistribution and tumor accumulation of 89Zr-labeled CEA-IL2v. Twenty-four patients with advanced solid CEA positive (CEA+) or negative (CEA−) tumors received CEA-IL2v 6 mg (4 CEA+; 3 CEA−), 20 mg (9 CEA+), or 30 mg (4 CEA+; 4 CEA−) biweekly. In cycle 1, 2 mg of the total dose comprised 89Zr-CEA-IL2v (50 MBq) and serial 89Zr-PET imaging was conducted. Four CEA+ patients with visually confirmed 89Zr-CEA-IL2v tumor accumulation at 20 mg had repeated 89Zr-PET imaging during cycle 4. 89Zr-CEA-IL2v immuno-PET demonstrated preferential drug accumulation in CEA+ tumors (%ID/mLpeak CEA− 3.6 × 10−3 vs. CEA+ 6.7 ×∙10−3). There was a non-significant trend towards dose-dependent tumor uptake, with higher uptake at doses ≥20 mg. Biodistribution was dose- and CEA-independent with major accumulation in lymphoid tissue compatible with IL-2R binding. Reduced exposure and reduced tumor accumulation (%ID/mLpeak 57% lower) on cycle 4 vs. cycle 1 was consistent with peripheral expansion of immune cells. The findings of this immune PET imaging study with 89Zr-CEA-IL2v support the therapeutic concept of CEA-IL2v, confirming selective and targeted tumor accumulation with this novel immunocytokine.
Highlights
Local immune suppression has been recognized as an emerging hallmark of many types of cancer
Out of 21 patients evaluable for response, the best response was stable disease in three patients (14%) and progressive disease in 18 patients (86%). In this small www.oncotarget.com study, no relation between drug tumor accumulation and response was identified. In this exploratory clinical immuno-positron emission tomography (PET) study, we showed that carcinoembryonic antigen (CEA)-IL-2 variant (IL2v) targets CEA+ tumors preferentially with a non-significant trend towards dosedependent CEA-mediated tumor accumulation
89Zr-immuno PET revealed differences in drug PK in tumor tissue compared with blood PK, which will be relevant to the selection of appropriate drug schedules for subsequent clinical trials
Summary
Local immune suppression has been recognized as an emerging hallmark of many types of cancer. Stimulation of the immune system has proven to induce significant anti-tumor immune responses in several types of cancer including non-small cell lung, head and neck, renal cell, colorectal cancer and melanoma [1, 2]. IL-2 activates regulatory T cells (Tregs), which has an immunosuppressive effect Both activation of Tregs and (pulmonary) vascular leakage are considered to be mediated by binding of IL-2 to IL-2-receptor alpha (IL-2Rα/CD25) [5]. This high-affinity receptor subunit is preferentially expressed on Tregs and endothelial cells, but it is not required for effector T-cell activation and expansion, which occurs primarily through the IL-2Rβ and IL-2Rγ subunits [6]
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