Next Generation Engineered NK Cells for Lymphoma Patients after CD19 CAR-T Cell Failure.

下一代工程 NK 细胞治疗 CD19 CAR-T 细胞失败后的淋巴瘤患者。

基本信息

批准号：
10649393
负责人：
Rafet Basar
金额：
$ 37.06万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649393
关键词：
Adoptive Transfer Allogenic Antigen Targeting Antigens Autologous B lymphoid malignancy B-Lymphocytes CASP9 gene CD19 gene CD70 antigen CISH gene Cancer Center Cell Therapy Cells Classification Clinic Clinical Clinical Protocols Clinical Research Cryopreservation Data Disease remission Dose Effector Cell Endowment Event Exhibits FDA approved Failure Generations Genes Good Manufacturing Process Human Immune Immune Targeting In Vitro Institutional Review Boards Interleukin-15 Link Lymphoid Cell Lymphoma cell Malignant lymphoid neoplasm Mediating NK cell therapy Natural Killer Cells Patient-Focused Outcomes Patients Pattern Phase I/II Clinical Trial Population Preparation Prognosis Proliferating Protein Deficiency Proteins Proteomics Protocols documentation Publishing Refractory Relapse Research Resistance Retroviral Vector Safety Sampling Signal Transduction Specificity T cell therapy T-Lymphocyte Testing Toxic effect Translations Tumor Antigens Umbilical Cord Blood Viral aerobic glycolysis biobank c-myc Genes cellular transduction checkpoint inhibition chimeric antigen receptor T cells cost cost effective treatment cytokine design engineered NK cell exhaustion first-in-human fitness genetically modified cells graft vs host disease human study immune checkpoint immunoengineering improved outcome in vivo innovation interest knockout gene lymph nodes lymphoid neoplasm manufacture manufacturing process metabolic fitness neoplastic cell new therapeutic target next generation novel novel strategies overexpression patient population peripheral blood pharmacologic point of care pressure prevent receptor safety testing senescence suicide gene transcriptomics tumor vector

项目摘要

Summary: CD19 directed CAR-T cells have transformed the treatment landscape of B-cell lymphoid malignancies. However, despite high initial complete remission rates, relapses occur within the first year of therapy in approximately 50% of patients who receive commercially available autologous CAR19 T-cells. Relapses can be classified into two patterns: CD19-positive relapse related to CAR T-cell exhaustion and senescence, or CD19- negative relapse related to target antigen loss. Patients who relapse after CAR19 T-cell therapy have poor prognosis; hence, there is an urgent need to develop the next-generation of CAR engineered immune effector cells that target tumors with efficacy and with minimal toxicity. There is growing interest in natural killer (NK) cells as a candidate for CAR therapy as they may prevent antigen escape through their innate ability to kill tumor cells and they are safe and well-suited for use in the allogeneic therapy setting. In a first-in-human study, our group showed the safety and promising activity of cord blood (CB) derived CAR-NK cells targeting CD19 in patients with B-lymphoid malignancies (Liu et al NEJM 2020). This proposal aims to build on this platform to develop the next-generation NK cell therapies by enhancing NK cell potency and persistence through optimal costimulatory signaling, cytokine armoring and checkpoint inhibition. We have identified CD70, as a novel therapeutic target in patients with B-NHL after CAR19 T-cell failure and developed a novel strategy to target CD70 by genetically modifying CB-NK cells with a retroviral vector (iC9-CD27-DAP10-CD3ζ-IL-15) that incorporates (i) the gene for a truncated human CD27 (the natural receptor for CD70) to redirect their specificity; (ii) DAP10 as an NK-specific costimulatory domain linked to a CD3ζ signaling endodomain; (iii) IL-15 to support their survival and proliferation, and (iv) inducible caspase-9 (iC9) as a suicide gene. Our preliminary data show the efficacy and safety of this approach in vitro and in vivo and support its translation to the clinic. In addition, we have developed a robust strategy to cryopreserve CAR-NK cells, allowing for the generation of a biobank of off-the-shelf engineered NK cells, thus reducing cost and increasing accessibility. Finally, we have devised a novel strategy to target the immune checkpoint CIS in our CAR-NK cells to modulate their metabolic fitness and potency. We hypothesize that targeting CD70 with iC9/CAR27D10ζ/IL-15 NK cells will greatly improve outcomes in patients with NHL after CAR19 T-cell failure and that by targeting the immune checkpoint CIS we can further enhance the CAR-NK cells’ metabolic fitness and potency. These concepts will be evaluated in three specific aims: In Aim 1 we will conduct a Phase I/II clinical trial to test the safety and efficacy of iC9/CAR27D10ζ/IL-15 NK cells in patients with CD70+ NHL who have failed CAR19 T-cell therapy (FDA approved, IND #27757). In Aim 2 we will apply innovative single-cell proteomic and transcriptomic studies to comprehensively characterize the fate of the CAR-NK cells and to identify key mechanisms of efficacy and resistance. In Aim 3, we will perform mechanistic studies to elucidate how CIS deletion enhances the metabolic fitness of CAR-NK cells and will perform IND enabling studies in preparation for the next-generation clinical studies testing CIS deficient iC9/CAR27D10ζ/IL-15 NK cells.

概括： CD19 定向 CAR-T 细胞改变了 B 细胞淋巴恶性肿瘤的治疗格局。然而，尽管初始完全缓解率很高，但在治疗的第一年内就会出现复发大约 50% 接受市售自体 CAR19 T 细胞的患者可能会出现复发。分为两种模式：与 CAR T 细胞耗竭和衰老相关的 CD19 阳性复发，或 CD19- 与靶抗原丢失相关的阴性复发患者在 CAR19 T 细胞治疗后复发的情况较差。因此，迫切需要开发下一代CAR工程化免疫效应器。人们对自然杀伤（NK）细胞越来越感兴趣。作为 CAR 疗法的候选者，因为它们可以通过其固有的杀死肿瘤细胞的能力来防止抗原逃逸在一项首次人体研究中，它们是安全的并且非常适合用于同种异体治疗。显示了针对患者的 CD19 的脐带血 (CB) 来源的 CAR-NK 细胞的安全性和有前景的活性 B 淋巴恶性肿瘤（Liu et al NEJM 2020）该提案旨在在此平台上开发通过最佳共刺激增强 NK 细胞效力和持久性，下一代 NK 细胞疗法我们已经确定 CD70 作为新的治疗靶点。在 CAR19 T 细胞失败后的 B-NHL 患者中，开发了一种通过基因靶向 CD70 的新策略用逆转录病毒载体 (iC9-CD27-DAP10-CD3z-IL-15) 修饰 CB-NK 细胞，该载体包含 (i) 基因截短的人类 CD27（CD70 的天然受体）以重定向其特异性；(ii) DAP10 作为 NK 特异性；与 CD3ze 信号传导内域相连的共刺激结构域；(iii) IL-15 支持其生存和增殖， (iv) 诱导型 caspase-9 (iC9) 作为自杀基因，我们的初步数据显示了其有效性和安全性。体外和体内方法并支持其转化为临床此外，我们还开发了一种强大的方法。冷冻保存 CAR-NK 细胞的策略，允许生成现成的工程 NK 生物库最后，我们设计了一种新的策略来瞄准。我们的 CAR-NK 细胞中的免疫检查点 CIS 可调节其代谢适应性和效力。使用 iC9/CAR27D10z/IL-15 NK 细胞靶向 CD70 将极大改善 NHL 患者的预后 CAR19 T 细胞失败，通过靶向免疫检查点 CIS，我们可以进一步增强 CAR-NK 细胞的能力这些概念将在三个具体目标中进行评估：在目标 1 中，我们将进行。一项 I/II 期临床试验，测试 iC9/CAR27D10ze/IL-15 NK 细胞在 CD70+ 患者中的安全性和有效性 CAR19 T 细胞疗法失败的 NHL（FDA 批准，IND #27757）在目标 2 中，我们将应用创新技术。单细胞蛋白质组学和转录组学研究，全面表征 CAR-NK 细胞的命运并确定功效和耐药性的关键机制在目标 3 中，我们将进行机制研究阐明 CIS 缺失如何增强 CAR-NK 细胞的代谢适应性，并将开展 IND 支持研究为测试 CIS 缺陷的 iC9/CAR27D10z/IL-15 NK 细胞的下一代临床研究做准备。