Therapeutic cell engineering using surface-conjugated synthetic nanoparticles

描述（由申请人提供）：细胞治疗（如同种异体骨髓移植或过继性T细胞治疗癌症）的一个主要局限性是移植细胞的活力和功能迅速下降。在细胞转移之后，治疗性细胞通常依赖于辅助药物的共递送，其被设计为使供体细胞功效和体内持久性最大化。实例包括在过继性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）移植后的免疫重建。然而，这些药物通常需要高的和持续的全身剂量以实现期望的治疗效果，由于这些药物的通常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辅助药物递送的策略，该策略基于在输注到患者体内之前将亚微米尺寸的载药合成颗粒直接化学缀合到供体细胞的质膜上，以允许转移细胞在体内的连续假自分泌刺激。我们假设，用佐剂药物负载颗粒“武装”的治疗性HSC或T细胞在使用小剂量的佐剂药物时表现出极大增强的功能性，所述佐剂药物在全身给予时没有实质性作用。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。 公共卫生相关性：我们将设计一个简单和可推广的策略，以增强现有细胞疗法的治疗潜力，如骨髓移植或肿瘤反应性T淋巴细胞的输注。如果成功的话，大量的免疫刺激剂，当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。

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.