Enhancing CAR T Cell Homing Through Glycoengineering

通过糖工程增强 CAR T 细胞归巢

• 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
• 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

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细胞归巢至肿瘤部位的重要性是抗肿瘤免疫细胞治疗的关键方面。 反应大多数癌症免疫治疗的最新进展都集中在产生有效的肿瘤免疫抑制剂。 特异性T细胞和克服肿瘤诱导的T细胞抑制和耐受。然而，速率限制步骤， 建立用于治疗恶性肿瘤的有效细胞疗法的关键是缺乏T细胞归巢到肿瘤细胞的能力。 肿瘤部位。为了规避这一障碍，我们研究了岩藻糖基化作为增强细胞毒性T细胞的机制， 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， 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 在发炎的组织中。我们的临床前工作使用肿瘤特异性多克隆扩增的 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 归巢到移植物抗宿主病分别涉及组织。此外，脐带血的岩藻糖化 (CB)产品增强了血液病患者CB干细胞向骨髓的归巢和植入 进行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 增强它们在肿瘤组织中的归巢。如果没有这些知识，CAR T细胞作为免疫调节剂的有效性将受到影响。 用于治疗癌症的免疫策略可能仍然有限。 我们的长期目标是开发有效的癌症细胞免疫疗法。在本提案中，我们 将使用岩藻糖基化CAR研究岩藻糖基化在急性髓性白血病（AML）中的作用。 T细胞方法（即岩藻糖基化8 F4-CAR T细胞），其靶向我们小组发现的抗原PR 1。 我们假设使用岩藻糖基化8 F4-CAR T细胞的免疫疗法将在体内抑制AML， 脱靶毒性在我们的第一个目标中，我们将研究离体岩藻糖基化对8 F4-CAR T细胞功效的影响。 在第二个目标中，我们将确定是否将8 F4-CAR T细胞内源性地 表达岩藻糖基转移酶VII将增强其抗肿瘤活性。我们将使用AML异种移植 小鼠模型，并将阐明岩藻糖基化增强T细胞活性的机制。 我们提出的研究是重要的，因为岩藻糖基化预计不仅能增强T细胞归巢， 进入肿瘤部位，而且它们的细胞溶解机制，从而提高它们的功效。此外，由于 足够剂量的肿瘤特异性效应细胞的工程化有时是过继性免疫的限制性步骤 细胞疗法，岩藻糖基化将允许工程化和输注更少的肿瘤靶向T细胞， 预期更多的岩藻糖基化T细胞有利地归巢至恶性环境。尤其是 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 这种方法可以极大地促进T细胞疗法在AML以及其他恶性疾病中的有效性， 并可能改变我们目前的细胞免疫疗法。