Biologic therapy for Beta-cell non-Hodgkin's lymphoma

b细胞非霍奇金淋巴瘤（NHL）是美国癌症相关死亡的第六大常见原因，而且这种疾病的发病率正在增加。虽然侵袭性淋巴瘤可以用细胞毒疗法治愈，但大多数惰性淋巴瘤用目前的疗法是无法治愈的。因此，需要新的有效疗法来治疗这些患者。我们正在研究一种结合抗cd20单克隆抗体、利妥昔单抗和白细胞介素-12的惰性淋巴瘤患者的生物联合疗法。利妥昔单抗是一种基因工程嵌合鼠/人单克隆抗体，可特异性结合B前淋巴细胞和成熟B淋巴细胞上的CD20。Fab结构域的结合可诱导细胞凋亡，而Fc结构域可招募免疫效应功能介导b细胞的裂解。白细胞介素-12 （IL-12）已被证明可促进细胞溶解性t细胞反应；促进th1型辅助性t细胞的发育；增强NK细胞的裂解活性；诱导T细胞和NK细胞分泌干扰素- γ。因此，我们假设IL-12联合利妥昔单抗可以增强利妥昔单抗诱导的免疫介导的细胞裂解。我们在最近完成的一项联合I期试验中表明，IL-12与标准剂量的利妥昔单抗的最佳免疫剂量为300ng/kg。血清下游分子如干扰素- γ和诱导蛋白-10 （IP-10）水平在此剂量的IL-12反应中显著增加。我们还观察到对这种疗法有69%的反应率，其中许多反应出现在大量预处理的患者中。在这项申请中，我们建议通过两种不同的治疗方案进一步评估IL-12和利妥昔单抗联合治疗惰性b细胞非霍奇金淋巴瘤患者的疗效和毒性，并确定其中任何一种治疗方案是否有足够的希望在III期环境中进一步探索。我们计划进行一项随机II期研究，以评估IL-12和利妥昔单抗同时给予的疗效，就像在I期研究中一样，并评估仅在利妥昔单抗的次优反应或疾病进展时单独给予IL-12的疗效。如I期试验所示，IL-12诱导细胞因子如γ -干扰素和趋化因子如IP-10的表达。这些分子已被证明可上调t细胞功能并抑制血管生成。因此，该研究的进一步目标是在相关研究中评估IL-12与利妥昔单抗联合使用是否可以改变恶性b细胞中的基因表达，恢复潜在缺陷的t细胞库并抑制血管生成，从而改善惰性淋巴瘤患者的临床结果。

B-cell non-Hodgkin's lymphoma (NHL) is the sixth most common cause of cancer-related deaths in the United States and the incidence of this disease is increasing. While aggressive lymphomas may be cured with cytotoxic therapy, most indolent lymphomas are incurable with current therapy. Novel effective therapies are therefore needed to treat these patients. We are investigating a biological combination therapy for patients with indolent lymphoma that incorporates an anti-CD20 monoclonal antibody, Rituximab, and Interleukin-12. Rituximab is a genetically engineered chimeric murine/human monoclonal antibody that binds specifically to CD20 on pre-B and mature B- lymphocytes. While binding of the Fab domain may induce apoptosis, the Fc domain recruits immune effector functions to mediate lysis of the B-cell. Interleukin-12 (IL-12) has been shown to facilitate cytolytic T-cell responses; promote the development of Th1-type helper T-cells; enhance the lytic activity of NK cells; and induce the secretion of interferon- gamma by both T and NK cells. Therefore, we hypothesized that combining IL-12 with Rituximab would augment the immune mediated cell lysis induced by Rituximab. We have shown in a recently completed Phase I trial of this combination that the optimal immunological dose of IL-12 to give with standard doses of Rituximab is 300ng/kg. A substantial increase in the serum levels of downstream molecules such as interferon-gamma and Inducible Protein-10 (IP-10) was seen in response to this dose of IL-12. We also observed a 69 percent response rate to this therapy, with many of the responses seen in heavily pretreated patients. In this application, we are proposing to further evaluate the efficacy and toxicity of the combination of IL-12 and Rituximab through two different treatment regimens in patients with indolent B-cell non-Hodgkin's lymphoma and to determine if either one is promising enough to explore further in a phase III setting. We plan to do a randomized Phase II study to evaluate the efficacy of IL-12 and Rituximab given concurrently, as in the Phase I study, and to also evaluate the efficacy of Rituximab alone with IL-12 given only if there is a suboptimal response to Rituximab or disease progression. As shown in the Phase I trial, IL-12 induces the expression of cytokines such as gamma-interferon and chemokines such as IP-10. These molecules have been shown to upregulate T-cell function and inhibit angiogenesis. A further goal of the study is therefore to evaluate, in correlative studies, whether the combination of IL-12 plus Rituximab can alter gene expression in the malignant B-cells, restore the potentially deficient T-cell repertoire and inhibit angiogenesis leading to an improve clinical outcome for patients with indolent lymphoma.