Stephan Sirkka B, Taber Alexandria M, Jileaeva Ilona, Pegues Ericka P, Sentman Charles L, Stephan Matthias T
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Technology Access Foundation (TAF) Academy, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Nat Biotechnol. 2015 Jan;33(1):97-101. doi: 10.1038/nbt.3104. Epub 2014 Dec 15.
Although adoptive T-cell therapy holds promise for the treatment of many cancers, its clinical utility has been limited by problems in delivering targeted lymphocytes to tumor sites, and the cells' inefficient expansion in the immunosuppressive tumor microenvironment. Here we describe a bioactive polymer implant capable of delivering, expanding and dispersing tumor-reactive T cells. The approach can be used to treat inoperable or incompletely removed tumors by situating implants near them or at resection sites. Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities. In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect. Scaffold-based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery.
尽管过继性T细胞疗法有望用于治疗多种癌症,但其临床应用因将靶向淋巴细胞输送至肿瘤部位存在问题,以及细胞在免疫抑制性肿瘤微环境中低效扩增而受到限制。在此,我们描述了一种能够递送、扩增和分散肿瘤反应性T细胞的生物活性聚合物植入物。该方法可通过将植入物置于不可切除或未完全切除肿瘤附近或切除部位来治疗这些肿瘤。使用小鼠乳腺癌切除模型,我们表明,与传统递送方式相比,植入物可有效支持肿瘤靶向T细胞在整个切除床和相关淋巴结中发挥作用,并减少肿瘤复发。在多灶性卵巢癌模型中,我们证明聚合物递送的T细胞可引发肿瘤消退,而注射的肿瘤反应性淋巴细胞几乎没有治疗效果。基于支架的T细胞递送可为不可切除肿瘤提供可行的治疗选择,并降低术后转移复发率。