Project 2: CAR-T cell therapy for T cell lymphoma

项目总结/摘要 在这个项目中，我们将改善结果和过继细胞治疗的可及性与工程化的CD5- 特异性嵌合抗原受体（CAR）T细胞在难治性或复发性T细胞淋巴瘤（r/r TCL）患者中的应用。 这些研究建立在上一届SPORE资助的I期临床试验取得的令人鼓舞的结果的基础上， 其中自体CD5 CAR T细胞在44%的复发性TCL患者中产生了稳健的临床应答， 使9名患者中的3名能够进行异基因造血干细胞移植（HSCT）。 这些反应是通过富集最低分化T细胞亚群的CAR T细胞产物实现的。我们 现在将克服我们以前研究中确定的成功和可及性的其余障碍，即 由紧张性CAR信号传导诱导的离体扩增的CD5 CAR T细胞的效力的快速丧失，低频率 患者来源的T细胞的适应性差，以及由于长期制造T细胞而导致的快速疾病进展。 自体细胞产品。我们将使用几种互补的策略来提高CD5的临床效力。 CAR T细胞产品，并使患者能够快速接受这些产品作为库存（现成）细胞。在 在目的1的临床研究中，我们使用药理学抑制剂可逆地抑制紧张性CAR信号传导， cGMP生产过程中产生的CD5 CAR T细胞终末分化，并评估CD5 CAR T细胞 从HSCT（即正常）供体产生的细胞用于其疾病在同种异体HSCT后复发的患者。我们 预测这些改善将保留有益的未分化T细胞亚群，从而改善 CD5 CAR T细胞产物的扩增和抗淋巴瘤活性;这一假设得到了我们早期研究的支持。 临床数据。为了进一步最大化CD5 CAR T细胞的临床效力，并加快治疗患有 为了快速进展的疾病，在目标2中，我们将开发库存的CD5 CAR T细胞用于现成的治疗。 利用我们最新的临床前研究结果，我们将设计这些CD5 CAR T细胞以消除同种异体反应性。 （使用TCR基因编辑）并通过用一种新的同种免疫防御来抵抗宿主免疫排斥， 受体，ADR。这些修饰应确保同种异体CD5 CAR的安全性和功能持久性。 患者体内的T细胞我们将生产和储存高效的ADR武装TCR编辑的CD5 CAR T细胞， 目的3并在耐药TCL患者中启动I期临床试验。总的来说，这些研究应该 为几乎没有其他选择的r/r T细胞淋巴瘤患者提供安全有效的细胞治疗。

PROJECT SUMMARY/ABSTRACT In this project we will improve the outcome and the accessibility of adoptive cell therapy with engineered CD5- specific chimeric antigen receptor (CAR) T-cells in patients with refractory or relapsed T-cell lymphoma (r/r TCL). These studies build on the promising results obtained in the Phase I clinical trial funded in the previous SPORE, where autologous CD5 CAR T-cells produced robust clinical responses in 44% of patients with recalcitrant TCL, enabling three out of nine patients to proceed with allogeneic hematopoietic stem cell transplantation (HSCT). These responses were achieved by CAR T-cell products enriched for minimally differentiated T-cell subsets. We will now overcome the remaining barriers to success and accessibility identified from our previous study, namely the rapid loss of potency of ex vivo expanded CD5 CAR T-cells induced by tonic CAR signaling, low frequency and poor fitness of patient-derived T-cells, and rapid disease progression due to lengthy manufacturing of autologous cell products. We will use several complementary strategies to improve the clinical potency of CD5 CAR T-cell products and to enable patients to rapidly receive these products as banked (off the shelf) cells. In clinical studies in Aim 1, we use pharmacologic inhibitors to reversibly inhibit tonic CAR signaling and the resultant terminal differentiation of CD5 CAR T-cells during cGMP manufacturing, and evaluate CD5 CAR T- cells generated from HSCT (i.e. normal) donors for patients whose disease relapsed after allogeneic HSCT. We predict these improvements will preserve the beneficial undifferentiated T-cell subsets and thus improve expansion and anti-lymphoma activity of CD5 CAR T-cell products; this hypothesis is supported by our early clinical data. To further maximize clinical potency of CD5 CAR T-cells and expedite treatment of patients with rapidly progressing disease, in Aim 2 we will develop banked CD5 CAR T-cells for off-the-shelf therapy. Leveraging our latest preclinical findings, we will engineer these CD5 CAR T-cells to eliminate alloreactivity (using TCR gene editing) and resist host immune rejection, by arming them with a novel alloimmune defense receptor, ADR. These modifications should ensure the safety and functional persistence of allogeneic CD5 CAR T-cells in patients. We will manufacture and bank highly potent, ADR-armed TCR-edited CD5 CAR T-cells in Aim 3 and initiate a Phase I clinical trial in patients with treatment-resistant TCL. Overall, these studies should provide a safe and effective cell therapy for patients with r/r T-cell lymphoma who have few alternative options.