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

描述（由申请人提供）：b细胞恶性肿瘤是美国癌症相关死亡的第六大常见原因。虽然一些侵袭性淋巴瘤可以用细胞毒治疗治愈，但大多数患者用目前的治疗是无法治愈的。因此，需要新的有效疗法来治疗这些患者。b淋巴细胞刺激因子（BLyS）是一种促进b细胞存活的tnf家族分子，是外周b细胞群的关键调节因子。它结合三种受体- BCMA， TACI和BAFF-R。我们已经证明恶性B细胞可以产生BLyS，并且来自B细胞恶性肿瘤患者的细胞通常表达TACI和BAFF-R。我们发现BLyS保护恶性b细胞免于凋亡，淋巴瘤患者血清BLyS水平与治疗反应和总生存率相关。我们还发现，有b细胞恶性肿瘤家族史的患者血清BLyS水平升高的发生率更高，这与BLyS启动子区域的多态性有关。因此，预计抑制BLyS作用的分子将为治疗b细胞恶性肿瘤患者提供一种新的策略。TACI-Fc是一种重组融合蛋白，含有受体TACI的胞外blys结合部分和人lgG1的修饰Fc部分。TACI-Fc作为BLyS的拮抗剂，作为一个诱饵受体结合BLyS，从而潜在地降低b细胞恶性肿瘤的促生存信号。我们与ZymoGenetics和Serono合作，设计了一项I期临床试验和随后的扩展研究，以评估TACI-Fc的最佳剂量和潜在活性。在本提案中，我们计划确定BLyS抑制非霍奇金淋巴瘤和慢性淋巴细胞白血病患者恶性b细胞的生物学效应，并评估这是否会改善b细胞恶性肿瘤患者的临床结果。

DESCRIPTION (provided by applicant): 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.