肿瘤细胞治疗研究
英文原题：Case report of non-gene editing CD7 CAR T cell therapy in CD7(+) Sézary syndrome: preclinical validation and first-in-human use.
我们的 CD7-RTX CAR T 疗法在 1 例 CD7⁺ r/r SS 患者中展现出卓越的安全性和疗效。
引言：Sézary 综合征（SS）是皮肤 T 细胞淋巴瘤（CTCL）的白血病型，与蕈样肉芽肿不同，其特征是血液中存在恶性淋巴细胞，且预后通常很差。SS 治疗以姑息为主，因此亟需新疗法。CD7 表面抗原在 T 细胞表面高度表达并局限于 T 细胞，若肿瘤表达 CD7，该抗原便是有前景的免疫治疗靶点。方法：本文介绍一种不进行基因编辑的 CD7 靶向 CAR-T 疗法，用于治疗复发/难治性（r/r）、表达 CD7 的 SS，并报告其临床前验证和临床应用。CD7 CAR 构建体带有“安全开关”（RTX），可在给予 rituximab 后快速清除治疗用 CAR-T。临床前评估显示，在效应细胞与靶细胞比为 1:1 和 2:1 的共培养体系及小鼠模型中，CD7-RTX CAR-T 清除靶细胞的比例均超过 99%。小鼠模型中的安全开关测试表明，输注 rituximab 可快速清除 CAR-T。该 CD7 疗法中的 RTX 尚未经过临床验证。结果：一名 53 岁、诊断为表达 CD7 的 r/r SS 男性患者以同情用药方式接受 2 × 10⁶ 个 CD7-RTX CAR-T 细胞/kg。CAR-T 治疗后 28 天内，患者达到无需药物且无症状的完全缓解（CR），18 个月随访时仍保持 CR。治疗耐受性良好，未发生严重不良事件（SAE）。讨论：CD7-RTX CAR-T 在一例 CD7⁺ r/r SS 患者中显示出突出的安全性和疗效，这是有记录以来首次将 CD7 靶向 CAR-T 用于治疗 SS。SS 典型情况下为 CD7⁻，因此尽管该患者疗效良好，这种方法可能不适用于大多数 SS 患者。不过，本研究支持充分表征肿瘤的重要性，也显示 CD7-RTX CAR-T 可能用于治疗多种 CD7 表达型恶性肿瘤。未来临床试验需进一步明确其安全性和疗效。
INTRODUCTION: S zary 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. METHODS: 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. RESULTS: A 53-year-old male diagnosed with r/r SS, expressing CD7, was treated with 2 10 6 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). DISCUSSION: 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.
MEMBER ACCOUNT
登录成功会直接打开下一页。
