CHIMERIC T CELL ANTIGENS TARGETING IG KAPPA LIGHT CHAIN IN B CELL LYMPHOMA

患有非霍奇金淋巴瘤（NHL）或慢性淋巴细胞白血病（CLL）的患者对嵌合抗体应答良好。 抗原受体（CAR）-重定向的T细胞，其对CD 19抗原具有特异性并编码共刺激因子 胞内域。尽管最近的治疗效果报告令人鼓舞，但这种方法并不 区分正常和恶性B细胞，为严重的B细胞耗竭奠定基础， 低丙种球蛋白血症以及可能由于活化T细胞的持续存在而引起的其他延迟毒性作用。 为了绕过这一障碍，而又不损失抗肿瘤效力，我们正在进行1期临床试验， 项目2的试验（目标1），识别恶性B细胞的IG κ轻链的CAR修饰的T细胞 中心假设是这种疗法将根除kappa阳性NHL和CLL细胞，同时保留 表达非靶向轻链的正常B细胞，从而在免疫应答中的关键时间保留B细胞功能。 患者的临床表现。为了减少由于不同水平或不同的细胞毒性而导致的次优细胞杀伤的可能性， 完全丧失肿瘤抗原表达，我们选择了CD 23-，它是独立表达的， CLL细胞-作为第二靶抗原。这种修饰可以增强T细胞实现的肿瘤细胞杀伤 识别κ轻链，这是我们打算在临床前模型中测试的预测（目标2）。中 我们计划将选定的免疫调节药物添加到T细胞方案中，以颠覆T细胞方案。 免疫抑制性肿瘤微环境，克服肿瘤相关新生血管生成，Treg细胞 募集和抑制性免疫细胞因子（目的3），所有这些都继续阻碍发展， 有效的T细胞免疫疗法。更好地控制肿瘤细胞逃避策略有望增强 这表明，CAR修饰的T细胞的抗肿瘤作用超出了单独使用CAR修饰的T细胞通常看到的那些抗肿瘤作用。的信息 从目标1中的临床评价以及目标2和3中的临床前研究中获得的信息应 通知设计

Patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) respond well to chimeric antigen receptor (CAR)-redirected T cells specific for the CD19 antigen and encoding costimulatory endodomains. Despite encouraging recent reports of therapeutic efficacy, this approach does not distinguish between normal and malignant B cells, setting the stage for profound B cell depletion, hypogammaglobulinemia and perhaps other delayed toxic effects due to the persistence of activated T cells. To circumvent this obstacle without substantial loss of antitumor potency, we are testing in a phase 1 clinical trial (Aim 1) of Project 2, CAR-modified T cells that recognize the Ig kappa light chain of malignant B cells The central hypothesis is that such therapy will eradicate kappa-positive NHL and CLL cells while sparing normal B cells that express the nontargeted light chain, thus preserving B cell function at a critical time in the patient's clinical course. To reduce the likelihood of suboptimal cell killing due to varying levels or a complete loss of tumor antigen expression, we have chosen CD23 - which is independently expressed by CLL cells - as a second target antigen. This modification could boost the tumor cell kill achieved with T cells that recognize kappa light chain, a prediction we intend to test in a preclinical model (Aim 2). In an additional model we plan to add selected immunomodulatory drugs to the T cell regimen to subvert the immune-inhibitory tumor micro-environment, overcoming tumor-associated neoangiogenesis, Treg cell recruitment and inhibitory immune.cytokines (Aim 3), all of which continue to impede the development of effective T cell immunotherapy. Better control of tumor cell evasion tactics is expected to enhance antitumor effects beyond those typically seen with use of CAR-modified T cells alone. The information gained from the clinical evaluation in Aim 1, together with the preclinical studies in Aims 2 and 3, should inform the design of