Cytokine conjugation to enhance T cell therapy.
Cytokine conjugation to enhance T cell therapy.
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DOI：
10.1073/pnas.2213222120
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发表时间：
2023-01-03
影响因子：
11.1
通讯作者：
Mooney, David J.
中科院分区：
文献类型：
--
作者：
Liu, Yutong;Adu-Berchie, Kwasi;Brockman, Joshua M.;Pezone, Matthew;Zhang, David K. Y.;Zhou, Jingyi;Pyrdol, Jason W.;Wang, Hua;Wucherpfennig, Kai W.;Mooney, David J.
ACT和CAR-T疗法在治疗实体肿瘤方面遇到了重大障碍。在这里，我们展示了一种简单的方法，通过将低剂量的抗肿瘤细胞因子偶联到细胞表面来提高过继转移T细胞的功效。这种方法可以很容易地集成到当前的T细胞制造过程中，而不会对制造过程或时间产生重大变化。这种方法允许局部递送原本有毒的细胞因子，增加T细胞浸润到实体瘤，并通过激活宿主免疫反应诱导抗原扩散。总的来说，这种方法改善了对侵袭性实体瘤的控制，显著减少了治疗反应所需的car -T剂量，对当前T细胞制造和过继性T细胞转移治疗的过程改变最小。过继性T细胞转移（ACT）疗法存在许多局限性（例如，对实体瘤的控制较差），而将ACT与细胞因子疗法结合可以提高疗效，但也会导致显著的副作用。在这里，我们描述了一种纳米技术方法，通过用非天然糖纳米颗粒代谢标记T细胞来提高ACT治疗的疗效，允许在制造过程中将抗肿瘤细胞因子直接结合到T细胞表面。这允许局部的，集中的活动，否则有毒的细胞因子。这种方法增加了T细胞对实体瘤的浸润，激活宿主免疫系统产生1型反应，促进抗原扩散，改善了对侵袭性实体瘤的控制，并通过CAR-T细胞的非治愈剂量实现了血癌的完全消退。总体而言，该方法为当前ACT制造工艺提供了一种有效且易于集成的方法，以提高各种设置下的效率。
ACT and CAR-T therapies have met significant obstacles in treating solid tumors. Here, we demonstrate a simple method to increase the efficacy of adoptively transferred T cells by conjugating low-dose antitumor cytokines onto cell surfaces. This method can be easily integrated into the current T cell manufacturing process without significant changes to the manufacturing process or time. This method allows local delivery of otherwise toxic cytokines, increases T cell infiltration into solid tumors, and induces antigen spreading by activating host immune responses. Overall, this method improves control over aggressive solid tumors and significantly reduces dosage of CAR-Ts needed for a curative response with minimal changes to the current processes for T cell manufacturing and adoptive T cell transfer therapies. Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings.
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影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
7
作者：
Lanitis E;Irving M;Coukos G
通讯作者：
Coukos G
影响因子：
3.7
作者：
Pogue SL;Taura T;Bi M;Yun Y;Sho A;Mikesell G;Behrens C;Sokolovsky M;Hallak H;Rosenstock M;Sanchez E;Chen H;Berenson J;Doyle A;Nock S;Wilson DS
通讯作者：
Wilson DS
影响因子：
--
作者：
Fallon JK;Vandeveer AJ;Schlom J;Greiner JW
通讯作者：
Greiner JW
影响因子：
8
作者：
Geyer, Mark B.;Riviere, Isabelle;Brentjens, Renier J.
通讯作者：
Brentjens, Renier J.