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

非霍奇金淋巴瘤(NHL)或慢性淋巴细胞白血病(CLL)患者对嵌合体的反应良好 抗原受体(CAR)重定向编码共刺激分子CD19抗原的T细胞 内域。尽管最近关于治疗效果的报道令人鼓舞，但这种方法并没有 区分正常和恶性B细胞，为B细胞的严重枯竭奠定基础， 低丙种球蛋白血症和其他由于激活的T细胞持续存在而引起的延迟性毒性反应。 为了在不显著降低抗肿瘤效力的情况下绕过这一障碍，我们正在进行一期临床试验。 项目2的试验(目标1)，CAR修饰的T细胞识别恶性B细胞的Ig kappa轻链 中心假设是，这种疗法将根除kappa阳性的NHL和CLL细胞，同时保留 表达非靶向轻链的正常B细胞，从而在关键时间保持B细胞的功能 病人的临床病程。为了减少由于不同水平或 完全失去肿瘤抗原的表达，我们选择了CD23-它是由 CLL细胞-作为第二个靶抗原。这种修饰可以增强T细胞对肿瘤细胞的杀伤作用 识别kappa轻链，我们打算在临床前模型中测试这一预测(目标2)。在一个 附加模型我们计划在T细胞方案中添加选定的免疫调节药物，以颠覆 免疫抑制肿瘤微环境，克服肿瘤相关新生血管，Treg细胞 募集和抑制性免疫.细胞因子(目标3)，所有这些都继续阻碍 有效的T细胞免疫疗法。更好地控制肿瘤细胞逃逸策略有望得到加强 抗肿瘤作用超过了通常单独使用CAR修饰的T细胞的效果。这些信息 从目标1中的临床评估以及目标2和3中的临床前研究中获得的结果应 通知设计人员

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