Liao John B, Jejurikar Nikita S, Hitchcock-Bernhardt Katie M, Gwin William R, Reichow Jessica L, Dang Yushe, Childs Jennifer S, Coveler Andrew L, Swensen Ron E, Goff Barbara A, Disis Mary L, Salazar Lupe G
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States of America; UW Medicine Cancer Vaccine Institute, University of Washington, 850 Republican St, Seattle, WA 98195, United States of America.
Gynecol Oncol. 2024 Dec;191:74-79. doi: 10.1016/j.ygyno.2024.09.019. Epub 2024 Oct 2.
Denileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood.
A phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 μg/kg, 15 μg/kg, and 25 μg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex.
The maximum tolerated dose was 15 μg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1-2. One patient treated at the 25 μg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-β, sIL2Ra in ascites or peripheral blood.
Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels.
ClinicalTrials.gov # NCT00357448.
地尼白介素-妥昔单抗（ONTAK）是一种白喉毒素/白细胞介素-2受体融合蛋白，能够耗竭外周血中的调节性T细胞。局部免疫微环境中的调节性T细胞已被证明与卵巢癌的不良预后相关。本研究探讨了地尼白介素-妥昔单抗（ONTAK）能否安全地腹腔内给药于晚期难治性卵巢癌患者，并评估其对腹水和外周血中调节性T细胞及肿瘤相关细胞因子的影响。
一项腹腔内地尼白介素-妥昔单抗（ONTAK）的I期剂量递增研究纳入了10例晚期难治性卵巢癌患者，分为3个剂量组（5μg/kg、15μg/kg和25μg/kg）。连续测定CA-125评估临床反应。使用RT-PCR定量调节性T细胞，通过Luminex测定细胞因子水平。
最大耐受剂量为15μg/kg，在扩展组的6例患者中有1例出现剂量限制性毒性。大多数不良事件为短暂的1-2级。1例接受25μg/kg剂量治疗的患者发生细胞因子风暴，住院时间延长。3例患者治疗后CA-125下降，但均未达到部分缓解标准。地尼白介素-妥昔单抗（ONTAK）治疗使外周血和腹水中的调节性T细胞减少。治疗患者的腹水或外周血中IL-8、TGF-β、sIL2Ra未显示任何显著变化。
地尼白介素-妥昔单抗（ONTAK）可安全地腹腔内给药于复发性难治性卵巢癌患者。腹水中和外周血中的调节性T细胞减少，但细胞因子水平无显著变化。
ClinicalTrials.gov # NCT00357448
