Therapeutic cell engineering using surface-conjugated synthetic nanoparticles

描述(申请人提供)：细胞疗法的一个主要局限性，如异基因骨髓移植或癌症的过继T细胞疗法，是移植细胞的活性和功能迅速下降。在细胞转移后，治疗性细胞通常依赖于辅助药物的联合传递，旨在最大化供体细胞的效率和体内持久性。例如，在过继T细胞治疗中应用细胞因子，包括白介素2、白介素7、白介素21和白介素15，或使用小分子药物促进造血干细胞(HSC)移植后的免疫重建。然而，这些药物通常需要高剂量和持续的全身剂量才能达到预期的治疗效果，由于这些药物通常具有多效性，导致剂量限制毒性，这限制了它们的临床应用。我们提出了一种细胞治疗中的辅助药物传递策略，该策略基于亚微米级的载药合成颗粒在注入患者之前直接连接到供体细胞的质膜上，以允许体内转移细胞的连续伪自分泌刺激。我们假设，治疗性HSCs或T细胞“武装”辅助药物载药颗粒，使用小剂量的辅助药物显示出极大的增强功能，而这些药物在全身给药时没有实质性效果。我们将在过继T细胞治疗的小鼠黑色素瘤模型和小鼠移植模型中验证我们的假设。 与公共卫生相关：我们将设计一种简便和可推广的策略，以有力地增强现有细胞疗法的治疗潜力，如骨髓移植或输注肿瘤反应性T淋巴细胞。如果成功，多种免疫刺激剂可以安全地靶向治疗相关的细胞和组织，这些药物在静脉输注时会产生严重的副作用。

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.