Xu Haichan, Sun Lihua, Wu Zehua, DeStefano Vincent M, Wada Masayuki, Chow Jennifer E, Yi Hui, Wang Guoling, Dai Jing, Zheng Wei, Wang Ting, Zhang Wenli, Song Chengxing, Luo Jing, Ma Yu, Waner Benjamin, Dong Mengjie, Chen Haibo, Qin Baozhen, Zhang Hongyu, Chang Jamie Hsing-Ming, Ma Yupo, Feng Jia
Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, China.
Research & Development Division, iCell Gene Therapeutics Inc., Long Island High Technology Incubator, Stony Brook, NY, United States.
Front Immunol. 2025 Aug 1;16:1604490. doi: 10.3389/fimmu.2025.1604490. eCollection 2025.
Sézary syndrome (SS) is a leukemic form of cutaneous T cell lymphoma (CTCL), distinguished from mycosis fungoides by the presence of cancerous lymphocytes in the blood and often bears very poor prognoses. SS treatment is palliative, and thus novel therapies are needed. The CD7 surface antigen is highly expressed and confined to the surface of T cells, therefore when present, serves as a promising target for immunotherapy.
Herein we describe the preclinical validation and clinical application of our non-gene editing CD7 targeted chimeric antigen receptor (CAR) T therapy to treat relapsed/refractory (r/r) CD7 expressing SS. The CD7 CAR construct possesses a "safety switch" (RTX) to enable rapid depletion of the CAR T treatment with administration of rituximab. Preclinical evaluation of the CD7-RTX CAR T cells demonstrated >99% depletion of target cells in both co-cultures, at 1:1 and 2:1 effector: target (E:T) ratios, and mouse models. In a mouse model, "safety switch" testing resulted in rapid elimination of CAR T cells with rituximab infusion. RTX, in our CD7 therapy, has not yet been clinically validated.
A 53-year-old male diagnosed with r/r SS, expressing CD7, was treated with 2×10 CD7-RTX CAR T cells/kg of body weight, as compassionate use. The patient achieved medication and symptom free complete remission (CR) within 28 days post-CAR. The patient remained in CR at 18-month follow-up. The treatment was well tolerated and without severe adverse events (SAEs).
Our CD7-RTX CAR T therapy demonstrates exceptional safety and efficacy in one patient with CD7 r/r SS. This was the first recorded use of CD7 targeted CAR T therapy to treat SS. SS is prototypically CD7, thus despite its efficacy in this patient, this treatment approach is likely not generalizable to most SS patients. However, this study supports the importance of thorough tumor characterization and the potential use of CD7-RTX CAR T cells to treat a variety of malignancies expressing CD7. Future clinical trials are required to characterize the safety and efficacy of CD7-RTX CAR T cells.
塞扎里综合征（SS）是皮肤T细胞淋巴瘤（CTCL）的白血病形式，其与蕈样肉芽肿的区别在于血液中存在癌细胞淋巴细胞，且通常预后很差。SS的治疗是姑息性的，因此需要新的疗法。CD7表面抗原高度表达且局限于T细胞表面，因此一旦存在，它就是免疫疗法的一个有前景的靶点。
在此我们描述了我们的非基因编辑的靶向CD7的嵌合抗原受体（CAR）T疗法用于治疗复发/难治性（r/r）表达CD7的SS的临床前验证和临床应用。CD7 CAR构建体具有一个“安全开关”（RTX），通过给予利妥昔单抗能够快速清除CAR T治疗。CD7-RTX CAR T细胞的临床前评估表明，在1:1和2:1效应细胞：靶细胞（E:T）比例的共培养以及小鼠模型中，靶细胞的清除率均>99%。在一个小鼠模型中，“安全开关”测试导致利妥昔单抗输注后CAR T细胞迅速清除。在我们的CD7疗法中，RTX尚未经过临床验证。
一名53岁的男性被诊断为r/r SS且表达CD7，作为同情用药接受了2×10个CD7-RTX CAR T细胞/千克体重的治疗。该患者在接受CAR治疗后28天内实现了无药物和症状的完全缓解（CR）。在18个月的随访中，该患者仍处于CR状态。治疗耐受性良好，未出现严重不良事件（SAE）。
我们的CD7-RTX CAR T疗法在一名患有CD7 r/r SS的患者中显示出卓越的安全性和疗效。这是首次记录使用靶向CD7的CAR T疗法治疗SS。SS典型地表达CD7，因此尽管该疗法在这名患者中有效，但这种治疗方法可能不适用于大多数SS患者。然而，这项研究支持了全面肿瘤特征分析的重要性以及使用CD7-RTX CAR T细胞治疗多种表达CD7的恶性肿瘤的潜在用途。未来需要进行临床试验来确定CD7-RTX CAR T细胞的安全性和疗效。
