Tailoring CAR T cell therapy for Hodgkin Lymphoma

项目摘要 尽管开发了基于抗CD 30抗体的疗法并使用了检查点抑制剂，但CD 30 + 恶性肿瘤仍然难以根除，在相当大比例的患者中复发。的 T细胞中嵌合抗原受体（汽车）的工程化已经推动了肿瘤特异性抗体的快速产生， 细胞，增加过继转移细胞疗法的临床适用性。我们已经对 基于T细胞的疗法，用CAR重定向以靶向CD 30抗原，并在I/II期 试验表明，在复发/难治性（r/r）霍奇金淋巴瘤（HL）患者中进行过继转移是安全的， 产生抗肿瘤活性，包括完全反应。 我们现在建议进一步提高患者完全缓解的缓解率和长期持久性 通过克服基于CD30.CAR T细胞的方法的主要障碍来治疗CD 30+恶性肿瘤。 我们将在r/r CD 30+恶性肿瘤（包括HL和皮肤T细胞）患者中进行I期临床试验 淋巴瘤（CTCL），T细胞工程化共表达CD30.CAR和特异性趋化因子受体 CCR 4，以证明增强的向肿瘤的迁移和运输进一步提高抗肿瘤活性。 然后，我们将监测（全身和局部，在肿瘤微环境中）免疫功能， 在接受CAR T细胞的CD 30+恶性肿瘤患者中， 提出合理联合治疗的方法。 最后，我们计划研究这些患者的髓系细胞特征，以及它如何有助于形成亲核细胞。 在CAR-T细胞疗法的背景下，肿瘤发生的景观。 在完成我们的研究后，我们将知道CAR-T的定向归巢对体内功能的临床影响， 对免疫功能的影响和贡献以及与这些相关的促肿瘤发生景观 治疗执行研究的所有组成部分都已到位，我们有足够的个人和机构 确保研究按计划完成和分析的经验

PROJECT ABSTRACT Despite the development of anti-CD30 antibody-based therapies and use of checkpoint inhibitors, CD30+ malignancies remain difficult to eradicate, with relapses occurring in a significant proportion of patients. The engineering of chimeric antigen receptors (CARs) in T cells has propelled the rapid generation of tumor specific cells, increasing the clinical applicability of adoptively-transferred-cell therapies. We have developed immune based therapies based on T cells redirected with a CAR to target the CD30 antigen, and shown in a phase I/II trial that their adoptive transfer in patients with relapsed/refractory (r/r) Hodgkin's Lymphoma (HL) is safe and produces antitumor activity, including complete responses. We now propose to further increase the response rate and long-term durability of complete responses in patients with CD30+ malignancies by overcoming a major barrier of CD30.CAR T cell based approaches. We will conduct a phase I clinical trial in patients with r/r CD30+ malignancies including HL and cutaneous T cells lymphomas (CTCL), with T cells engineered to coexpress the CD30.CAR and the specific chemokine receptor CCR4, to demonstrate that enhanced migration and trafficking to the tumor further improves antitumor activity. We will then monitor (both systemically and locally, in the tumor microenvironment) immune functions and repertoire in patients with CD30+ malignancies receiving CAR T cells, to identify strengths and limits of our approach for proposing rationale combination therapies. Finally, we plan to study the myeloid cells signatures in these patients and how it contributes in shaping the pro- tumorigenic landscape in the context of CAR-T cell therapies. On completion of our study we will know the clinical impact of directed homing of CAR-Ts on in vivo functionality, the effects and contribution on immune functions and on the pro-tumorigenic landscape associated with these therapies. All components to execute the study are in place and we have sufficient individual and institutional experience to ensure the study will be completed and analyzed as planned