Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy.
Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy.
复制标题
DOI：
10.1126/scitranslmed.aaw2614
复制
发表时间：
2019-06-26
影响因子：
17.1
通讯作者：
Wittrup KD
中科院分区：
文献类型：
--
作者：
Momin N;Mehta NK;Bennett NR;Ma L;Palmeri JR;Chinn MM;Lutz EA;Kang B;Irvine DJ;Spranger S;Wittrup KD
由于严重的不良反应和治疗效果不足，细胞因子疗法在癌症治疗中的临床应用仍然受到限制。尽管通过肿瘤内施用进行细胞因子定位可以解决这两个问题，但可溶性细胞因子从肿瘤中的快速逃逸总是会破坏这一努力。我们发现，瘤内施用与胶原结合蛋白 lumican 融合的细胞因子可延长局部保留时间并显着减少全身暴露。在同基因肿瘤模型和 BrafV600E/Ptenfl/fl 基因工程黑色素瘤模型中，将局部给予 lumican-细胞因子融合物与全身免疫疗法（肿瘤靶向抗体、检查点阻断、癌症疫苗或 T 细胞疗法）相结合可提高疗效，而不加剧毒性。值得注意的是，局部治疗引发的保护性和全身性 CD8+ T 细胞反应也观察到了对非细胞因子注射肿瘤的治疗性远隔效应。细胞因子胶原蛋白锚定构成了一种简便的、与肿瘤无关的策略，可以安全地增强原本效果有限的全身免疫疗法。胶原蛋白定位的 IL-2 和 IL-12 细胞因子可增强不同的全身癌症免疫疗法，同时最大限度地减少多种肿瘤模型的毒性。
The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although cytokine localization by intratumoral administration could address both issues, the rapid escape of soluble cytokines from the tumor invariably subverts this effort. We find that intratumoral administration of a cytokine fused to the collagen-binding protein lumican prolongs local retention and dramatically reduces systemic exposure. Combining local administration of lumican-cytokine fusions with systemic immunotherapies (tumor-targeting antibody, checkpoint blockade, cancer vaccine, or T cell therapy) improves efficacy without exacerbating toxicity in syngeneic tumor models and the BrafV600E/Ptenfl/fl genetically engineered melanoma model. Notably, curative abscopal effects on non-cytokine-injected tumors were also observed as a result of a protective and systemic CD8+ T cell response primed by local therapy. Cytokine collagen-anchoring constitutes a facile, tumor-agnostic strategy to safely potentiate otherwise marginally effective systemic immunotherapies. Collagen-localized IL-2 and IL-12 cytokines potentiate disparate systemic cancer immunotherapies while minimizing toxicity in several tumor models.
登录
查看更多内容
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1007/s40259-013-0048-z
发表时间：
2013-12
期刊：
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
影响因子：
--
作者：
Corti A;Curnis F;Rossoni G;Marcucci F;Gregorc V
通讯作者：
Gregorc V
影响因子：
158.5
作者：
Gogas, H;Ioannovich, J;Kirkwood, JM
通讯作者：
Kirkwood, JM
影响因子：
6
作者：
Conklin, Matthew W.;Eickhoff, Jens C.;Keely, Patricia J.
通讯作者：
Keely, Patricia J.
影响因子：
6.2
作者：
Eton, O;Rosenblum, MG;Benjamin, RS
通讯作者：
Benjamin, RS