Improving Function and Persistence of Chimeric T Cells

描述（由申请人提供）：使用T淋巴细胞的过继免疫治疗在临床上对几种恶性和感染性疾病的治疗是有效的，并且使用人工T细胞受体（cTcR）的T细胞转导可以通过将细胞免疫应答重定向到几乎任何表面靶抗原来潜在地扩展该方法。然而，最近使用嵌合受体表达的T细胞的研究未能证明注入T细胞的持久性或功能性。这可能是因为肿瘤靶细胞不表达重新激活和维持T细胞所需的共刺激分子。我们设计了两种方法来克服这个问题。首先，我们将cTcR纳入eb病毒特异性细胞毒性T淋巴细胞（CTL）。这些CTL维持其天然受体的活性，因此ebv感染的B细胞继续传递共刺激信号，确保这些CTL在通过cTcR遇到肿瘤时持续激活和增殖。其次，我们将把共刺激分子的内结构域作为cTcR的一部分，这样，与目标抗原的单独接触就会产生足够的共刺激，从而诱导活化和增殖。使用霍奇金病模型和针对该肿瘤特异性表达的CD30分子的重定向T细胞，我们在临床前人类模型中比较了重定向ebv - ctl的抗肿瘤功效、生长和存活，以及表达与共刺激内质相关的cTcR的丝裂原激活T细胞的有效性（Aim 1）。这些策略的体内有效性和安全性将在异种移植小鼠模型（Aim2）中进行比较。

DESCRIPTION (provided by applicant): Adoptive immunotherapy with T lymphocytes appears clinically effective for therapy of several malignant and infectious disorders, and transduction of T cells with artificial T cell receptors (cTcR) can potentially expand the approach by redirecting the cellular immune response to almost any surface target antigen. However, recent efforts using chimeric receptor-expressing T cells have failed to demonstrate persistence or functionality of the infused T cells. This is likely because the tumor target cells do not express the costimulator molecules required to reactivate and sustain T cells. We have devised two means to overcome this problem. First, we will incorporated the cTcR in Epstein Barr Virus-specific cytotoxic T lymphocytes (CTL). These CTL maintain the activity of their native receptors, so that EBV-infected B cells continue to transfer costimulatory signals, ensuring sustained activation and proliferation for these CTL to be cytolytic when they encounter their tumor through the cTcR. Second, we will incorporate the endodomains of costimulatory molecules as part of the cTcR, so that encounter with the target antigen alone imparts sufficient costimulation to induce activation and proliferation. Using the Hodgkin Disease model and T cells redirected against the CD30 molecule that is specifically expressed by this tumor we compare in a pre-clinical human model the anti-tumor efficacy, growth and survival of redirected EBV-CTLs with the effectiveness of mitogen-activated T cells expressing cTcR linked to costimulatory endodomins (Aim 1). The in vivo efficacy and safety of these strategies will be compared in a xenograft mice model (Aim2). At the end of this study we should have clear evidence of the feasibility of using cTcR+ T cells directed against the CD30 antigen for the treatment of patients with HD and data to support or refute the use of modified chimeric receptors or viral antigen-specific CTL to augment the functionality of chimeric receptor bearing T cells - information of value not only for HD disease, but for any disease amenable to adoptive immunotherapy including virus-associated diseases. The data produced by this project will be crucial to develop appropriate clinical trails with redirected T cells.