Ramaswami Ramya, Kask Angela Shaulov, D'Amico Leonard, Menon Manoj P, Lurain Kathryn, Yarchoan Robert, Ekwede Irene, Couey Paul, Burnham Eli, Angeldekao Allysson, Ha Lee Byung, Kaiser Judith C, Cheever Martin, Uldrick Thomas S, Kwok Li-Lian, Wright Anna, Fling Steven P, Wang Chia-Ching Jackie
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
Cancer Immunotherapy Trials Network (CITN), Fred Hutchinson Cancer Center, Seattle, Washington, USA.
J Immunother Cancer. 2025 Feb 6;13(2):e010291. doi: 10.1136/jitc-2024-010291.
CD4 T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS can contribute to increasing CD4 T cell lymphocytopenia. IL-7 is a cytokine that is essential in T-cell development, proliferation and homeostasis. In PWH, IL-7 administration leads to increased numbers of circulating central memory and naïve T-cell phenotypes.
In this multicenter phase I study with a 3+3 dose escalation design, participants with KS with or without HIV received up to four intramuscular injections of IL-7 (NT-I7) every 9 weeks. The primary endpoint of the study was to evaluate safety over three escalating dose levels (DL) of NT-I7 (DL1:480 µg/kg, DL2: 960 µg/kg and DL3: 1200 µg/kg) and identify a maximum tolerated dose. Secondary endpoints included evaluation of antitumor activity per the modified AIDS Clinical Trials Group Criteria and assessment of the effect of NT-I7 on the kinetics of CD4 and CD8 T-cells.
Eight cisgender male participants (five with HIV infection) were enrolled. Six participants were treated at DL1, and two were treated at DL2. The study was closed to accrual after enrolment of the second participant on DL2 due to termination of study funding. Four of the eight participants (three in DL1 and one in DL2) completed all four doses of the NT-I7. With regard to treatment-emergent adverse events (AEs), all participants had <grade 2 AEs, which included injection site reaction and alanine aminotransferase increase. Injection site reaction was a dose-limiting toxicity in one participant at DL1. The overall KS objective response rate to NT-I7 was 42.9% (95% CI 9.9%, 81.6%) and all three responders were PWH. Absolute lymphocyte counts, CD4 and CD8 T-cell counts increased among all participants following administration of NT-I7. Participants who experienced a response had HIV and lower CD4/CD8 ratio at baseline and throughout the study as compared with those who did not have KS response to NT-I7.
Preliminary data demonstrate safety and activity of IL-7 in patients with KS and activity specifically among individuals HIV-associated KS.
NCT04893018.
CD4 T细胞淋巴细胞减少和免疫功能障碍是导致有或无HIV的人群中卡波西肉瘤（KS）发病和持续存在的因素。KS的标准化疗药物会导致CD4 T细胞淋巴细胞减少加剧。白细胞介素-7（IL-7）是一种在T细胞发育、增殖和稳态中必不可少的细胞因子。在有HIV的人群中，给予IL-7会导致循环中的中枢记忆T细胞和初始T细胞表型数量增加。
在这项采用3+3剂量递增设计的多中心I期研究中，患有或未患有HIV的KS患者每9周接受多达4次IL-7（NT-I7）肌肉注射。该研究的主要终点是评估NT-I7三个递增剂量水平（DL）（DL1：480µg/kg，DL2：960µg/kg和DL3：1200µg/kg）的安全性，并确定最大耐受剂量。次要终点包括根据改良的艾滋病临床试验组标准评估抗肿瘤活性，以及评估NT-I7对CD4和CD8 T细胞动力学的影响。
招募了8名顺性别男性参与者（5名感染HIV）。6名参与者在DL1接受治疗，2名在DL2接受治疗。由于研究资金终止，在DL2的第二名参与者入组后，该研究停止招募。8名参与者中的4名（DL1中的3名和DL2中的1名）完成了所有4剂NT-I7。关于治疗中出现的不良事件（AE），所有参与者的AE均<2级，包括注射部位反应和丙氨酸转氨酶升高。注射部位反应是DL1中一名参与者的剂量限制性毒性。NT-I7对KS的总体客观缓解率为42.9%（95%CI 9.9%，81.6%），所有三名缓解者均为有HIV的人群。在给予NT-I7后，所有参与者的绝对淋巴细胞计数、CD4和CD8 T细胞计数均增加。与对NT-I7无KS反应的参与者相比，有反应的参与者在基线和整个研究过程中均感染HIV且CD4/CD8比值较低。
初步数据证明了IL-7在KS患者中的安全性和活性，特别是在与HIV相关的KS个体中具有活性。
NCT04893018。
