Improving Function and Persistence of Chimeric T Cells

描述（由申请人提供）：使用T淋巴细胞的连续免疫疗法对于治疗几种恶性和感染性疾病似乎在临床上是有效的，并且使用人工T细胞受体（cTcR）转导T细胞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T细胞的努力未能证明输注的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解决这个问题。首先，我们将cTcR掺入Epstein巴尔病毒特异性细胞毒性T淋巴细胞（CTL）中。这些CTL维持其天然受体的活性，使得EBV感染的B细胞继续传递共刺激信号，从而确保这些CTL在通过cTcR遇到其肿瘤时持续活化和增殖以溶解细胞。第二，我们将共刺激分子的胞内域作为cTcR的一部分并入，使得单独与靶抗原的相遇赋予足够的共刺激以诱导活化和增殖。使用霍奇金病模型和针对由该肿瘤特异性表达的CD 30分子重定向的T细胞，我们在临床前人类模型中比较了重定向的EBV-CTL的抗肿瘤功效、生长和存活与表达与共刺激内域连接的cTcR的丝裂原活化的T细胞的有效性（Aim 1）。将在异种移植小鼠模型（Aim 2）中比较这些策略的体内疗效和安全性。 在本研究结束时，我们应该有明确的证据证明使用针对CD 30抗原的cTcR+ T细胞治疗HD患者的可行性，以及支持或反驳使用修饰的嵌合受体或病毒抗原特异性CTL来增强携带嵌合受体的T细胞的功能性的数据-不仅对HD疾病有价值的信息，但也适用于任何适合过继免疫治疗的疾病，包括病毒相关疾病。该项目产生的数据对于开发具有重定向T细胞的适当临床试验至关重要。

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.