Chimeric T Cell for Therpay of Hodgkin Disease

描述(申请人提供)：针对EB病毒(EBV)抗原的细胞毒性T淋巴细胞(CTL)疗法已经在EBV相关霍奇金病(HD)患者中产生了完全的肿瘤反应，且没有毒性。然而，许多HD肿瘤是EBV抗原阴性的。为了将免疫治疗扩展到这种EBV阴性HD的患者，我们建议针对CD30分子，在EBV阳性和EBV阴性HD中所有的恶性细胞都表达CD30分子。我们假设，我们可以通过将EBV CTL重定向到CD30分子，通过强迫表达针对该分子的嵌合抗原受体(CAR)来开发和扩展EBV CTL的已证明的有效性。我们还假设，我们将能够进一步设计CAR+CTL，以克服保护HD细胞免受免疫攻击的分子和细胞屏障。这些假设将在三个具体目标上得到检验。在目标1中，我们建议通过过度表达趋化因子TARC的受体(CCR4)来改善CAR+CTL对HD肿瘤细胞的归巢，TARC是HD肿瘤结构性产生的，其受体在CTL上是缺失的。在目标2中，我们将评估如果进一步修饰CCR4+和CD30CAR+CTL以产生它们自己的生长细胞因子(IL-15)，是否会增强这些CTL的扩张性和持久性，这是维持其功能所必需的。最后，在目标3中，我们将分析调节性T细胞和我们的CAR+CTL之间的相互作用。我们将发现我们所做的修改是否允许CAR+CTL抵抗支配HD肿瘤部位的调节性T细胞的抑制作用，或者是否需要替代策略。我们建议的修改将在临床前、体外和体内进行测试，并将形成我们继续T细胞治疗癌症的临床研究的基础。公共卫生相关性：我们已经成功地治疗了复发霍奇金病(HD)患者，方法是使用他们自己的免疫细胞针对通常位于肿瘤细胞上的病毒蛋白。现在，我们希望通过靶向所有HD细胞上的其他蛋白质，并通过使免疫细胞更有效来扩大这种有希望的治疗方法的应用。

DESCRIPTION (provided by applicant): Cytotoxic T-lymphocyte (CTL) therapy directed to Epstein-Barr virus (EBV) antigens has produced complete tumor responses in patients with EBV associated Hodgkin disease (HD) without toxicity. Many HD tumors, however, are EBV antigen negative. To extend immunotherapy to patients with such EBV negative HD, we propose to target the CD30 molecule, which is expressed by all malignant cells in both EBV positive and EBV negative HD. We hypothesize that we can exploit and extend the demonstrated effectiveness of EBV CTLs by redirecting them to the CD30 molecule, by forcing expression of a chimeric antigen receptor (CAR) targeting this molecule. We also hypothesize that we will be able to further engineer the CAR+ CTLs to overcome the molecular and cellular barriers that protect HD cells from immune attack. These hypotheses will be tested in three specific aims. In Aim 1, we propose to improve the homing of CAR+ CTLs to HD tumor cells by overexpressing the receptor (CCR4) for the chemokine TARC, which is constitutively produced by HD tumors, and whose receptor is lacking on CTLs. In Aim 2 we will evaluate whether expansion and persistence of our CCR4+ and CD30CAR+ CTLs is enhanced if these CTLs are further modified to produce their own growth cytokine (IL-15), which is essential to sustain their function. Finally, in Aim 3 we will analyze the interactions between regulatory T cells and our CAR+ CTLs. We will discover whether the modifications we have made allow the CAR+ CTLs to resist the inhibitory effects of the regulatory T cells that dominate sites of HD tumor, or whether alternative strategies will be required. The modifications we propose will be tested pre-clinically in vitro and in vivo and will form the basis of our continued clinical investigation of T- cell therapy for cancer. PUBLIC HEALTH RELEVANCE: We have had success in treating patients with relapsed Hodgkin disease (HD) by using their own immune cells directed to viral proteins that are often on the tumor cells. We now want to extend the application of this promising treatment by targeting other proteins that are on all HD cells, and by making the immune cells more potent.