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的一个重要方面 回应。癌症免疫治疗的最新进展大多集中在产生强大的肿瘤上。 特异性T细胞和克服肿瘤诱导的T细胞抑制和耐受。然而，限制速率的步骤是 建立有效的细胞疗法治疗恶性肿瘤是缺乏T细胞归巢到 肿瘤部位。为了绕过这一障碍，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。岩藻糖基化是由岩藻糖基转移酶介导的一个过程，它将岩藻糖加到岩藻糖链上 细胞表面糖蛋白的基团，增加它们对肿瘤细胞、内皮细胞和 在发炎的组织内。我们使用体外岩藻糖基化肿瘤特异性多克隆扩增的临床前工作 CTL和调节性T细胞(Treg)显示出增强的CTL归巢到骨髓和肿瘤部位，Treg 归宿到移植物抗宿主病分别涉及组织。此外，脐带血的岩藻糖基化 (CB)产品促进了血液病患者的脐带血干细胞归巢和植入骨髓 接受CB移植的恶性肿瘤患者。目前尚不清楚的是，CAR T细胞的岩藻糖基化是否会 增强它们对肿瘤组织的定位。如果不知道这一点，CAR T细胞作为一种 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。在这项提案中，我们 将使用岩藻糖化CAR研究岩藻糖化在急性髓系白血病(AML)发病中的作用 T细胞方法(即岩藻糖化的8F4-CAR T细胞)，靶向我们小组发现的抗原PR1。 我们假设，使用岩藻糖基化的8F4-CAR T细胞进行免疫治疗将在体内抑制AML，最低限度 偏离目标的毒性。在我们的第一个目标中，我们将研究体外岩藻糖化对8F4-CAR T细胞效力的影响 和安全性，在第二个目标中，我们将确定工程8F4-CAR T细胞是否内源性 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 在这两个目的的小鼠模型，并将阐明岩藻糖化增强T细胞活性的机制。 我们提出的研究是有意义的，因为岩藻糖化不仅有望增强T细胞归巢和 进入肿瘤部位，还包括它们的细胞溶解机制，从而提高它们的疗效。此外，由于 设计足够剂量的肿瘤特异性效应细胞有时是采用的一个限制步骤 细胞治疗，岩藻糖化将允许更少的肿瘤靶向T细胞的工程和输注，因为 更多的岩藻糖化T细胞有望更好地适应恶性环境。强调这一事实的是 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 这种方法可以极大地促进T细胞治疗在急性髓细胞白血病和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治疗方法。