Pinthus Jehonathan H, Waks Tova, Malina Victoria, Kaufman-Francis Keren, Harmelin Alon, Aizenberg Itzhak, Kanety Hannah, Ramon Jacob, Eshhar Zelig
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
J Clin Invest. 2004 Dec;114(12):1774-81. doi: 10.1172/JCI22284.
Prostate cancer is currently the most commonly diagnosed noncutaneous malignancy in American men. When metastatic, usually to the bone, the disease is no longer curable and is usually treated palliatively with androgen ablation. However, after conversion to androgen-independent disease, there is no effective therapy currently available. The "T body" approach, which uses genetically reprogrammed lymphocytes derived from the patient and expressing chimeric receptor genes, combines the effector functions of T lymphocytes and NK cells with the ability of antibodies to recognize predefined surface antigens with high specificity and in a non-MHC-restricted manner. We show here the therapeutic efficacy of human lymphocytes bearing erbB2-specific chimeric receptors on human prostate cancer BM lesions in a SCID mouse model after conditioning of the recipient to allow homing and persistent functioning of the adoptively transferred cells. Induction of stromal cell-derived factor-1 production within the BM using low-dose irradiation or cyclophosphamide combined with IL-2 administration enhanced the homing of systemically delivered T bodies, resulting in decreased tumor growth and prostate-specific antigen secretion, prolongation of survival, and even cure of the treated mice. These preclinical studies strongly support the idea that the T body approach has therapeutic potential in disseminated prostate cancer.
前列腺癌是目前美国男性中最常被诊断出的非皮肤恶性肿瘤。发生转移时，通常转移至骨骼，此时该疾病无法治愈，通常采用雄激素去除疗法进行姑息治疗。然而，在转变为雄激素非依赖性疾病后，目前尚无有效的治疗方法。“T 细胞体”方法利用源自患者的经过基因重编程的淋巴细胞并表达嵌合受体基因，将 T 淋巴细胞和自然杀伤细胞的效应功能与抗体以高特异性且非主要组织相容性复合体（MHC）限制的方式识别预定义表面抗原的能力结合起来。我们在此展示了携带 erbB2 特异性嵌合受体的人淋巴细胞在 SCID 小鼠模型中对人前列腺癌骨髓病变的治疗效果，前提是对受体进行预处理以允许过继转移细胞归巢并持续发挥功能。使用低剂量辐射或环磷酰胺联合白细胞介素-2 给药诱导骨髓内基质细胞衍生因子-1 的产生，增强了全身递送的 T 细胞体的归巢，导致肿瘤生长减缓、前列腺特异性抗原分泌减少、生存期延长，甚至治愈了接受治疗的小鼠。这些临床前研究有力地支持了“T 细胞体”方法在播散性前列腺癌中具有治疗潜力这一观点。
