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，并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性疗法治愈，但大多数惰性淋巴瘤用目前的疗法无法治愈。 因此，需要新的有效疗法来治疗这些患者。我们正在研究一种生物联合治疗惰性淋巴瘤患者，包括抗CD 20单克隆抗体，利妥昔单抗，白细胞介素-12。 利妥昔单抗是一种基因工程嵌合鼠/人单克隆抗体，可特异性结合前B和成熟B淋巴细胞上的CD 20。 虽然Fab结构域的结合可以诱导细胞凋亡，但Fc结构域募集免疫效应子功能以介导B细胞的裂解。 白细胞介素-12（IL-12）已显示促进细胞溶解性T细胞应答;促进Th 1型辅助性T细胞的发育;增强NK细胞的溶解活性;并诱导T细胞和NK细胞分泌干扰素-γ。 因此，我们假设将IL-12与利妥昔单抗组合将增强由利妥昔单抗诱导的免疫介导的细胞溶解。我们已经在最近完成的这种组合的I期试验中表明，与标准剂量的利妥昔单抗一起给予的IL-12的最佳免疫剂量是300 ng/kg。 响应于该剂量的IL-12，观察到下游分子如干扰素-γ和诱导蛋白-10（IP-10）的血清水平显著增加。 我们还观察到对这种疗法的反应率为69%，其中许多反应见于重度预治疗患者。 在本申请中，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药的疗效，如在I期研究中一样，并评估利妥昔单抗单独与IL-12给药的疗效，只有当对利妥昔单抗的反应不佳或疾病进展时。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。这些分子已显示上调T细胞功能并抑制血管生成。 因此，本研究的另一个目的是在相关研究中评估IL-12加利妥昔单抗的组合是否可以改变恶性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.