BLys inhibition using TACI-Fc in patients with B-bell non-Hodgkins' Lymphoma

B细胞恶性肿瘤是美国癌症相关死亡的第六大常见原因。虽然有些人 侵袭性淋巴瘤可以用细胞毒疗法治愈，但大多数患者用目前的疗法是无法治愈的。小说 因此，需要有效的治疗方法来治疗这些患者。 B淋巴细胞刺激物(BLyS)是一种促进B细胞存活的肿瘤坏死因子家族分子，是一种关键的调节因子 外周B细胞群。它与BCMA、TACI和BAFF-R三种受体结合。我们已经证明了恶性的B- 细胞可以产生BLyS，B细胞恶性肿瘤患者的细胞通常表达TACI和BAFF-R。我们 已发现BLyS可保护恶性B细胞免于凋亡，且淋巴瘤患者血清BLyS水平 与治疗反应和总存活率相关。我们还发现，有B细胞家族史的患者 恶性肿瘤患者血清BLyS水平升高的发生率较高，这与该基因的多态性有关 BLyS启动子区域。因此，预计抑制BLyS效应的分子将提供一种新的 B细胞恶性肿瘤患者的治疗策略。 TACI-Fc是一种含有TACI受体胞外BLyS结合部分和TACI-Fc的重组融合蛋白 修饰的人lgG1的Fc部分。TACI-Fc通过作为诱饵受体与BLyS结合而起到拮抗剂的作用 BLyS因此潜在地降低了B细胞恶性肿瘤中促进生存的信号。与ZymoGenetics合作 和Serono，我们设计了一项I期临床试验和随后的扩展研究，以评估最佳剂量 和TACI-Fc的潜在活性。在这项提议中，我们计划确定BLyS抑制对 恶性B细胞在非霍奇金淋巴瘤和慢性淋巴细胞白血病患者中的表达 这将改善B细胞恶性肿瘤患者的临床结果。

B-cell malignancies are the sixth most common cause of cancer-related deaths in the United States. While some aggressive lymphomas may be cured with cytotoxic therapy, most patients are incurable with current therapy. Novel effective therapies are therefore needed to treat these patients. B-lymphocyte stimulator (BLyS) is a TNF-family molecule that promotes B-cell survival and is a key regulator of peripheral B-cell populations. It binds to three receptors - BCMA, TACI and BAFF-R. We have shown that malignant B- cells can produce BLyS and that cells from patients with B-cell malignancies commonly express TACI and BAFF-R. We have found that BLyS protects malignant B-cells from apoptosis and that serum BLyS levels in lymphoma patients correlate with response to therapy and overall survival. We have also found that patients with a family history of B-cell malignancies have a higher incidence of elevated serum BLyS levels and this is associated with a polymorphism in the BLyS promoter region. It is therefore anticipated that molecules that inhibit the effects of BLyS will provide a novel strategy to treat patients with B-cell malignancies. TACI-Fc is a recombinant fusion protein containing the extracellular, BLyS-binding portion of the receptor TACI and the modified Fc portion of human lgG1. TACI-Fc acts as an antagonist to BLyS by working as a decoy receptor that binds BLyS thereby potentially decreasing the pro-survival signal in B-cell malignancies. In collaboration with ZymoGenetics and Serono, we have designed a phase I clinical trial and a subsequent extension study to evaluate the optimal dose and potential activity of TACI-Fc. In this proposal, we plan to determine the biological effects of BLyS inhibition on malignant B-cells in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia and to evaluate whether this will lead to an improved clinical outcome for patients with B-cell malignancies.