Therapeutic cell engineering using surface-conjugated synthetic nanoparticles

使用表面共轭合成纳米粒子的治疗性细胞工程

• 批准号: 7998029
• 负责人: Matthias Stephan
• 金额: $ 5.05万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998029
• 关键词: Adjuvant; Adverse effects; Allogeneic Bone Marrow Transplantation; Binding; Bone Marrow Transplantation; Cell Therapy; Cell Transplants; Cell membrane; Cells; Chemicals; Clinical; Dose; Dose-Limiting; Drug Delivery Systems; Drug Design; Engraftment; Exhibits; Hematopoietic stem cells; Immune; Infusion procedures; Interleukin-15; Interleukin-7; Interleukins; Malignant Neoplasms; Modeling; Mus; Nature; Patients; Pharmaceutical Preparations; Stem cell transplant; Surface; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Transplantation; arm; autocrine; cellular engineering; cytokine; in vivo; melanoma; nanoparticle; particle; public health relevance; reconstitution; small molecule; submicron; tumor

DESCRIPTION (provided by applicant): A major limitation of cell therapies, such as allogeneic bone marrow transplantations or adoptive T cell therapy for cancer, is the rapid decline in viability and function of transplanted cells. Following cell transfer, therapeutic cells often rely on the co- delivery of adjuvant drugs, designed to maximize donor cell efficacy and in vivo persistence. Examples include administration of cytokines, including interleukin (IL-) 2, IL-7, IL-21 and IL-15 in adoptive T-cell therapy, or the use of small-molecule drugs to boost immune reconstitution following hematopoietic stem cell (HSC) transplants. However, these agents often require high and sustained systemic doses to achieve the desired therapeutic effect, leading to dose-limiting toxicities due to the generally pleiotropic nature of these drugs, which has restricted their clinical use. We propose a strategy for adjuvant drug delivery in cell therapies, based on chemical conjugation of submicron-sized drug-loaded synthetic particles directly onto the plasma membrane of donor cells prior to infusion into the patient, to permit continuous pseudo-autocrine stimulation of transferred cells in vivo. We hypothesize that that therapeutic HSCs or T cells "armed" with adjuvant drug- loaded particles exhibit greatly enhanced functionality using small doses of adjuvant drugs that have no substantial effect when given systemically. We will test our hypothesis in a mouse melanoma tumor model of adoptive T cell therapy and a murine transplantation model of HSC engraftment and reconstitution. PUBLIC HEALTH RELEVANCE: We will devise a facile and generalizable strategy to robustly augment the therapeutic potential of existing cell therapies, such as bone marrow transplantation or infusion of tumor-reactive T lymphocytes. If successful, a large variety of immune stimulants, which cause serious side effects when infused intravenously, can be safely targeted to therapeutically relevant cells and tissue.

描述（由申请人提供）：细胞疗法（例如同种异体骨髓移植或癌症过继性 T 细胞疗法）的主要局限性是移植细胞的活力和功能迅速下降。细胞转移后，治疗细胞通常依赖于辅助药物的共同递送，旨在最大限度地提高供体细胞的功效和体内持久性。例子包括在过继性 T 细胞疗法中施用细胞因子，包括白细胞介素 (IL-) 2、IL-7、IL-21 和 IL-15，或使用小分子药物来促进造血干细胞 (HSC) 后的免疫重建。 ）移植。然而，这些药物通常需要高且持续的全身剂量才能达到所需的治疗效果，由于这些药物通常具有多效性，导致剂量限制性毒性，这限制了它们的临床使用。我们提出了一种细胞疗法中的辅助药物递送策略，该策略基于在输注到患者体内之前将亚微米大小的载药合成颗粒直接化学缀合到供体细胞的质膜上，以允许对转移细胞进行连续的伪自分泌刺激体内。我们假设，用载药佐剂颗粒“武装”的治疗性 HSC 或 T 细胞使用小剂量的佐剂药物表现出极大增强的功能，而全身给药时没有实质性作用。我们将在过继性 T 细胞治疗的小鼠黑色素瘤肿瘤模型和 HSC 植入和重建的小鼠移植模型中检验我们的假设。 公共健康相关性：我们将设计一种简便且可推广的策略，以大力增强现有细胞疗法的治疗潜力，例如骨髓移植或输注肿瘤反应性 T 淋巴细胞。如果成功的话，多种免疫刺激剂（静脉注射时会引起严重的副作用）可以安全地靶向治疗相关的细胞和组织。