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）：细胞疗法的主要局限性，例如同种异体骨髓移植或用于癌症的过养T细胞疗法，是移植细胞的生存能力和功能的迅速下降。细胞转移后，治疗细胞通常依赖于辅助药物的共递送，辅助药物旨在最大化供体细胞功效和体内持久性。例如，在产卵T细胞疗法中给予细胞因子，包括白介素（IL-）2，IL-），IL-7，IL-21和IL-15，或使用小分子药物来促进造血干细胞（HSC）移植后促进免疫重构。但是，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作用，从而导致剂量限制性毒性，这是由于这些药物的普遍多效性，这限制了它们的临床使用。我们提出了一种在细胞疗法中辅助药物递送的策略，基于亚微米尺寸的药物载荷的合成颗粒的化学结合，直接在供体细胞的质膜上，然后再输注患者，以允许在体内连续的假拟南芥对转移的细胞进行连续的假性自由分泌刺激。我们假设使用辅助药物载荷颗粒“武装”的治疗性HSC或T细胞使用小剂量的辅助药物显示出大大增强的功能，这些辅助药在系统地给出时没有实质性作用。我们将在收养T细胞疗法的小鼠黑色素瘤肿瘤模型以及HSC植入和重建的鼠移植模型中检验我们的假设。 公共卫生相关性：我们将制定一种易于且可推广的策略，以鲁棒性增强现有细胞疗法的治疗潜力，例如骨髓移植或肿瘤反应性T淋巴细胞的输注。如果成功，则可以将各种免疫兴奋剂静脉注入时会导致严重的副作用，可以安全地靶向治疗相关的细胞和组织。