Enhancing CAR T Cell Homing Through Glycoengineering

通过糖工程增强 CAR T 细胞归巢

基本信息

批准号：
10577107
负责人：
Gheath Al-Atrash
金额：
$ 22.72万
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：
2023-03-09 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577107
关键词：
Acute Myelocytic Leukemia Adoptive Cell Transfers Adoptive Transfer Affinity Allogenic Antigen Targeting Antigens Applications Grants Bone Marrow Bone neoplasms Cell Line Cell Therapy Cell physiology Cells Cellular immunotherapy Clinical Clinical Data Clinical Trials Cytotoxic T-Lymphocytes Data Development Disease Dose Effectiveness Effector Cell Endothelial Cells Engineering Engraftment Foundations Fucose Fucosyltransferase Future Glycoengineering Goals Hematologic Neoplasms Hematopoietic stem cells Home Homing Human Immune Immunotherapeutic agent Immunotherapy In Vitro Infusion procedures Knowledge Leukemic Cell Leukocyte Elastase Ligands Malignant - descriptor Malignant Neoplasms Malignant lymphoid neoplasm Marrow Mediating Membrane Membrane Glycoproteins Methods Myeloid Leukemia Normal tissue morphology Parents Patient Care Patients Phase I Clinical Trials Predisposition Process Proteinase 3 Proteins Publishing Refractory Regulatory T-Lymphocyte Relapse Research Role Safety Selectins Site Solid Neoplasm Stem cell transplant Surface T cell therapy T-Cell Homing Receptors T-Lymphocyte Testing Therapeutic Tissues Toxic effect Tumor Antigens Tumor Tissue Umbilical Cord Blood Umbilical Cord Blood Transplantation Work Xenograft procedure acute myeloid leukemia cell antitumor effect blood product cancer cell cancer immunotherapy cancer therapy cell killing chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy clinical trial enrollment cytotoxic end of life care graft vs host disease improved in vivo innovation leukemia mouse model neoplastic cell novel novel therapeutic intervention participant enrollment patient prognosis pre-clinical response standard of care stem cells success sugar treatment strategy tumor vector

项目摘要

The importance of T cell homing to the tumor site is a critical aspect of the anti-tumor immune cellular response. Most of the recent advances in cancer immunotherapy have focused on generating potent tumor specific T cells and overcoming tumor-induced T cell inhibition and tolerance. However, a rate-limiting step to establishing efficacious cellular therapy for the treatment of malignancies is the lack of T cell homing to the tumor site. To circumvent this obstacle, we investigated fucosylation as a mechanism to enhance cytotoxic T lymphocyte (CTL) homing. Fucosylation, a process mediated by fucosyltransferases, adds fucose sugar groups to cell surface glycoproteins, increasing their affinity to selectins on tumor cells, endothelial cells, and within inflamed tissues. Our preclinical work using ex vivo fucosylation of tumor-specific polyclonally-expanded CTL and regulatory T cells (Treg) showed enhanced CTL homing to bone marrow and tumor sites, and Treg homing to graft-versus-host disease involved tissues, respectively. Furthermore, fucosylation of cord blood (CB) products enhanced the homing and engraftment of CB stem cells to marrow in patients with hematologic malignancies undergoing CB transplants. What remains unknown is whether fucosylation of CAR T cells will enhance their homing into tumor tissue. Without this knowledge, the effectiveness of CAR T cells as an immunotherapeutic strategy for the treatment of cancer will likely remain limited. Our long-term objective is to develop effective cellular immunotherapy for cancer. In this proposal, we will investigate the role of fucosylation in the setting of acute myeloid leukemia (AML), using a fucosylated CAR T cell approach (i.e. fucosylated 8F4-CAR T cells) which targets an antigen that our group discovered, PR1. We hypothesize that immunotherapy using fucosylated 8F4-CAR T cells will inhibit AML in vivo, with minimal off-target toxicity. In our first aim, we will study the effects of ex vivo fucosylation on 8F4-CAR T cell efficacy and safety, and in the second aim, we will determine whether engineering 8F4-CAR T cells to endogenously express fucosyltransferase VII will enhance their anti-tumor activities. We will employ an AML xenograft mouse model in both aims, and will elucidate the mechanisms by which fucosylation augments T cell activity. Our proposed research is significant, in that fucosylation is expected to enhance not only T cell homing and entry into tumor sites, but also their cytolytic machinery, thereby improving their efficacy. Furthermore, since the engineering of an adequate dose of tumor-specific effector cells is at times a limiting step to adoptive cellular therapy, fucosylation will allow for the engineering and infusion of fewer tumor-targeting T cells, as more fucosylated T cells are expected to home favorably to the malignant milieu. Underscored by the fact that stem cell fucosylation has already demonstrated safety and efficacy clinically, we believe our innovative approach may greatly facilitate the effectiveness of T cell therapy in AML as well as other malignant diseases, and could transform our current approach to cellular immunotherapy.

T细胞归巢到肿瘤部位的重要性是抗肿瘤免疫细胞的一个关键方面回复。癌症免疫疗法的大部分最新进展都集中在产生有效的肿瘤上特异性 T 细胞并克服肿瘤诱导的 T 细胞抑制和耐受。然而，速率限制步骤建立有效的治疗恶性肿瘤的细胞疗法的关键在于缺乏T细胞归巢肿瘤部位。为了克服这一障碍，我们研究了岩藻糖基化作为增强细胞毒性 T 的机制。淋巴细胞（CTL）归巢。岩藻糖基化是岩藻糖基转移酶介导的过程，会添加岩藻糖基团与细胞表面糖蛋白结合，增加其与肿瘤细胞、内皮细胞和细胞上选择素的亲和力在发炎的组织内。我们的临床前工作使用肿瘤特异性多克隆扩增的离体岩藻糖基化 CTL 和调节性 T 细胞 (Treg) 显示增强的 CTL 归巢至骨髓和肿瘤部位，并且 Treg 分别归巢到涉及组织的移植物抗宿主病。此外，脐带血岩藻糖基化 (CB) 产品增强了血液病患者的 CB 干细胞归巢和植入骨髓接受 CB 移植的恶性肿瘤。目前尚不清楚的是 CAR T 细胞的岩藻糖基化是否会增强它们进入肿瘤组织的能力。如果没有这些知识，CAR T 细胞作为一种药物的有效性治疗癌症的免疫治疗策略可能仍然有限。我们的长期目标是开发有效的癌症细胞免疫疗法。在这个提案中，我们将使用岩藻糖基化 CAR 研究岩藻糖基化在急性髓系白血病 (AML) 中的作用 T 细胞方法（即岩藻糖基化 8F4-CAR T 细胞）针对我们小组发现的抗原 PR1。我们假设使用岩藻糖基化 8F4-CAR T 细胞的免疫疗法将在体内抑制 AML，且作用最小脱靶毒性。我们的第一个目标是研究离体岩藻糖基化对 8F4-CAR T 细胞功效的影响和安全性，第二个目标，我们将确定是否将8F4-CAR T细胞工程化为内源性表达岩藻糖基转移酶VII将增强其抗肿瘤活性。我们将采用 AML 异种移植物小鼠模型的两个目标都是，并将阐明岩藻糖基化增强 T 细胞活性的机制。我们提出的研究意义重大，因为岩藻糖基化预计不仅会增强 T 细胞归巢，进入肿瘤部位，而且还有其细胞溶解机制，从而提高其疗效。此外，由于设计足够剂量的肿瘤特异性效应细胞有时是过继的限制步骤在细胞疗法中，岩藻糖基化将允许工程化和输注更少的肿瘤靶向 T 细胞，因为更多岩藻糖基化 T 细胞有望顺利回归恶性环境。事实强调的是干细胞岩藻糖基化已经在临床上证明了安全性和有效性，我们相信我们的创新该方法可能会极大地提高 T 细胞治疗 AML 以及其他恶性疾病的有效性，并可能改变我们目前的细胞免疫治疗方法。