PHASE I STUDY--ADOPTIVE CELLULAR THERAPY WITH BRYOSTATIN

发展成功的过继细胞疗法的主要障碍 对于人类癌症的治疗一直无法扩大特效性 相关时间内肿瘤免疫细胞对治疗量的反应性 框架。淋巴因子激活的杀伤细胞可以从外周血中产生 血液中的单个核细胞在几天内就足够多了，但是 这些细胞对患者的肿瘤并不是特别敏感 尚未被证明能增强大剂量白介素2的活性 它们通常是共同管理的。肿瘤浸润性T淋巴细胞 可以被证明是特异性的肿瘤敏感型，但这些只是 限量供应。先前激活和扩大的努力 肿瘤致敏的T淋巴细胞参与了体外刺激 自体肿瘤或抗原模拟，例如抗CD3 到目前为止，结果并不令人满意。 支持这一应用的假设是T淋巴细胞 先前因滞留在肿瘤引流中而对肿瘤致敏 体外可通过药理学方法激活和扩张淋巴结 激活信号转导通路，该通路通常由 与T细胞受体结合的抗原。在一系列临床前研究中 研究，我们已经证明，这可以通过使用 蛋白激酶C激活剂Bryostatin 1，一种钙离子载体，以及 小剂量白介素2。这些被激活的和被激活的 扩张性引流淋巴结淋巴细胞联合系统性红斑狼疮 白介素2可以治愈已建立的动物肿瘤，并提供持久的， 肿瘤特异性免疫。 我们提出了一项I期研究，以证明该药物的临床可行性、安全性、 以及这种方法的毒性。超越为后续活动搭建舞台 第二阶段调查，这项研究可能会有广泛的 对采用细胞疗法的新兴方法的影响 抗原性定义的T细胞群体有少量可用 作为治疗药物的靶标。

A major obstacle to the development of successful adoptive cellular therapy for the treatment of human cancer has been the inability to expand specific tumor-reactive immune cells to therapeutic numbers within a relevant time frame. Lymphokine activate killer cells can be generated from peripheral blood mononuclear cells in sufficient numbers in a matter of days, but these are not specifically sensitized to a patient's patients's tumor and have not been shown to enhance the activity of high dose interleukin-2 with which they are routinely coadministered. Tumor infiltrating T lymphocytes can be shown to be specifically tumor sensitized, but these are only available in limited number. Previous efforts to activate and expand tumor-sensitized T lymhocytes have involved either in vitro stimulation with autologous tumor or antigen mimicry, for example, with anti-CD3 monoclonal antibodies, and results to date have been unsatisfactory. The hypothesis which underlies this application is that T lymphocytes previously sensitized to tumor by virtue of residence in tumor-draining lymph nodes can be activated an expanded in vitro via pharmacological activation of the signal transduction pathway that is normally triggered by antigen binding to the T cell receptor. In a series of preclinical studies, we have demonstrated that this can be accomplished through the use of the protein kinase C activator, bryostatin 1, a calcium ionophore, and low dose interleukin-2. Adoptive cellular transfer of these activated and expanded draining lymph node lymphocytes in conjunction with systemic interleukin=-2 can cure established animal tumors and confer long-lasting, tumor-specific immunity. We propose a phase I study to demonstrate the clinical feasibility, safety, and toxicity of this approach. Beyond setting the stage for subsequent phase II investigations, this study potentially will have broad implications for emerging approaches to adoptive cellular therapy in which antigenically defined T cell populations available in small numbers are targeted as therapeutic agents.