Cancer Vaccines for Lymphomas

我的实验室致力于假设B细胞肿瘤衍生的IG独特型（Id）可以作为治疗性疫苗开发的肿瘤特异性抗原。我们的基本科学假设是，持续、有效的T细胞介导的应答，特别是CD 8 + T细胞应答，将是实现证明临床疗效的最终目标所必需的。我们的主要目标是获得一般癌症疫苗概念的确凿证据;即，简单地说，可以诱导针对自身蛋白质的免疫应答，而自身蛋白质本身是免疫原性差的。 我们最近完成的Id-KLH+GM-CSF疫苗接种在既往未经治疗的滤泡性淋巴瘤（FL）患者中的单臂II期临床试验已经实现了这第一个目标。这种精心设计的治疗方案产生了一组同质的患者，所有患者在统一化疗后均处于最小残留疾病状态[首次完全临床缓解（CR）]，并接受疫苗治疗。选择GM-CSF作为免疫佐剂是我们在小动物模型中的实验室研究的直接延伸，表明GM-CSF可以通过几乎完全增强免疫应答的细胞臂来增强原型Id-KLH疫苗的效力。 这项II期研究证明了CD 4+和CD 8 + T细胞应答能够在大多数情况下溶解自体肿瘤，并基于分子缓解的实现提供了抗肿瘤作用的系统性证据，这两项研究都是淋巴瘤疫苗的第一次。 这些令人信服的结果（发表在Nature Medicine，5：1171- 1177，1999）为建立未来的临床研究目标提供了基础。特别是，一项多中心、随机、对照的III期临床试验，旨在为是否可以证明临床获益的问题提供明确的答案，作为NCI IMPACT项目独立建立。这项III期试验于2000年1月在一个校外中心联盟开始，包括莫菲特癌症中心、西北大学、杜克综合癌症中心和宾夕法尼亚大学。 此外，当临床应用于其他选择性疾病适应症时，该制剂可能用作阳性对照。具体地，FL被选择为第一疾病靶标，这在很大程度上是因为恶性细胞来源于成熟的生发中心B细胞，其在表面上具有相对高密度的完整IG。未来计划在CLL（表达相对较少的完整表面IG作为靶点）中进行的试验和已经在多发性骨髓瘤（肿瘤细胞表面缺乏完整表面IG）中进行的工作代表了一种合理的逐步方法，可以检验T细胞应答对临床疗效至关重要的潜在假设。此外，最近启动的一项在套细胞淋巴瘤患者中使用Id-KLH+GM-CSF疫苗制剂的试点临床方案将为该潜在假设提供最严格的检验。MCL占美国所有淋巴瘤的约4%，然而，它代表了一个主要的治疗挑战，因为它的临床行为是侵袭性的，并且用目前可用的疗法无法治愈，中位生存期为3-4年。Id疫苗接种代表了一种新的治疗方式，尚未在侵袭性淋巴瘤中进行评估。本研究设计的主要优势在于，在II期滤泡性低度淋巴瘤研究中引发CD 8 + T细胞免疫的Id-KLH+GM-CSF疫苗制剂可作为阳性对照。MCL中的初步研究也使用与II期滤泡性淋巴瘤研究相同的其他原则进行了合理设计。例如，患者将首先接受4-6个周期的均匀诱导化疗（EPOCH-Rituxan），其设计用于产生同质患者群体，在施用Id疫苗接种时全部处于最小残留疾病状态。在疫苗接种前后将监测患者的肿瘤特异性T细胞应答。

My laboratory is focused on the hypothesis that B-cell tumor-derived Ig idiotype(Id) can serve as a tumor-specific antigen for therapeutic vaccine development. Our underlying scientific hypothesis is that sustained, potent, T-cell-mediated responses, especially CD8+ T cell responses, will be required for achieving the eventual goal of demonstrating clinical efficacy. Our principal objective has been to obtain conclusive proof for the general cancer vaccine concept; i.e., simply that it is possible to induce an immune response against a self protein, which is inherently poorly immunogenic. Our recently completed single-arm Phase II clinical trial of Id-KLH+GM-CSF vaccination in previously untreated patients with FOLLICULAR LYMPHOMAS (FL) has accomplished this first goal. This carefully designed treatment protocol produced a homogeneous group of patients, all in a minimal residual disease state [first complete clinical remission (CR)] following uniform chemotherapy, who were given vaccine treatment. The selection of GM-CSF as the immunological adjuvant; was a direct extension of our laboratory studies in small animal models demonstrating that GM-CSF can enhance the potency of the prototype Id-KLH vaccine by augmenting almost exclusively the cellular arm of the immune response. This Phase II study demonstrated CD4+ and CD8+ T cell responses which were capable of lysing autologous tumor in the majority of cases and provided systematic evidence for anti-tumor effects, based on the achievement of molecular remissions, both firsts for a lymphoma vaccine. These compelling results (published in Nature Medicine, 5:1171-1177,1999)have provided a basis on which to build future clinical research aims. In particular, a multicenter, randomized, controlled Phase III clinical trial, designed to provide the definitive answer to the question of whether clinical benefit can be demonstrated, was established independently as an NCI IMPACT project. This Phase III trial opened in January 2000 at a consortium of extramural centers, including Moffitt Cancer Center, Northwestern University, Duke Comprehensive Cancer Center and University of Pennsylvania. In addition, this formulation can potentially serve as a positive control; when applied clinically to other, selective disease indications. Specifically, FL was selected as the first disease target, in large part because the malignant cells are derived from mature germinal center B cells which have a relatively high density of intact Ig on the surface. Future trials planned in CLL (which express relatively less intact surface Ig as a target) and efforts already underway in MULTIPLE MYELOMA (absence of intact surface Ig on the tumor cell surface), represent a rational, stepwise approach testing the underlying hypothesis that T cell responses are principally important for clinical efficacy. Furthermore, a recently initiated pilot clinical protocol employing the Id-KLH+GM-CSF vaccine formulation in MANTLE CELL LYMPHOMA patients will provide the most rigorous test of this underlying hypothesis. MCL comprises approximately 4% of all lymphomas in the U.S. However, it represents a major therapeutic challenge, because its clinical behavior is aggressive, and it is incurable with current available therapies, with a median survival of 3-4 years. Id vaccination represents a novel treatment modality which has not been evaluated in aggressive lymphomas. A major strength of this study design is that the Id-KLH+GM-CSF vaccine formulation, which elicited CD8+ T cell immunity in the Phase II follicular, low-grade lymphoma study, can serve as a positive control. The pilot study in MCL has also been rationally designed using other principles in common with the Phase II follicular lymphoma study. For example, patients will first receive 4-6 cycles of uniform induction chemotherapy (EPOCH-Rituxan), designed to produce a homogeneous patient population, all in a minimal residual disease state at the time Id vaccination is administered. Patients will be monitored before and after vaccination for tumor-specific T-cell responses.