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

B细胞性非霍奇金淋巴瘤(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。我们正在研究一种用于惰性淋巴瘤患者的生物联合疗法，该疗法结合了抗CD20单抗、利妥昔单抗和白介素12。利妥昔单抗是一种基因工程的鼠/人嵌合单抗，能与B前和成熟B淋巴细胞上的CD20特异性结合。Fab结构域的结合可能诱导细胞凋亡，而Fc结构域则招募免疫效应器功能来介导B细胞的溶解。白介素12(IL-12)可促进细胞溶解T细胞反应，促进Th1型辅助T细胞的发育，增强NK细胞的杀伤活性，并诱导T细胞和NK细胞分泌干扰素-γ。因此，我们推测联合IL-12和利妥昔单抗可增强利妥昔单抗诱导的免疫介导的细胞裂解。我们在最近完成的这一组合的I期试验中表明，IL-12与标准剂量的利妥昔单抗配合使用的最佳免疫学剂量为300 ng/kg。血清下游分子如干扰素-γ和诱导蛋白-10(IP-10)的水平显著增加，以回应这一剂量的IL-12。我们还观察到这种疗法的应答率为69%，其中许多反应见于经过大量预治疗的患者。在这项应用中，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，并确定其中一种方案是否有足够的前景在III期环境中进一步探索。我们计划进行一项随机的第二阶段研究，以评估同时给予IL-12和利妥昔单抗的疗效，就像在第一阶段研究中一样，还评估仅当对利妥昔单抗或疾病进展的反应不佳时，单独给予利妥昔单抗和IL-12的疗效。如I期试验所示，IL-12可诱导细胞因子如γ-干扰素和趋化因子如IP-10的表达。这些分子已被证明可以上调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联合利妥昔单抗是否可以改变恶性B细胞的基因表达，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预后。

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.