Therapeutic cell engineering using surface-conjugated synthetic nanoparticles

描述（由申请人提供）：细胞疗法的一个主要限制，如异体骨髓移植或过继性T细胞治疗癌症，是移植细胞的活力和功能的迅速下降。在细胞转移后，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t细胞治疗中使用细胞因子，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和持续的全身剂量才能达到预期的治疗效果，由于这些药物的一般多效性，导致剂量限制性毒性，这限制了它们的临床使用。我们提出了一种在细胞治疗中辅助药物递送的策略，该策略基于在输注患者之前将亚微米大小的载药合成颗粒直接偶联到供体细胞的质膜上，从而允许在体内对转移细胞进行持续的伪自分泌刺激。我们假设，治疗性造血干细胞或T细胞“武装”了辅助药物负载颗粒，使用小剂量的辅助药物表现出极大的增强功能，而系统给予时没有实质性效果。我们将在过继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验证我们的假设。

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.