Clinical translation of immunomodulatory therapeutics.
Clinical translation of immunomodulatory therapeutics.
复制标题
免疫调节疗法的临床翻译。
DOI：
10.1016/j.addr.2021.113896
复制
发表时间：
2021-09
影响因子：
16.1
通讯作者：
Veiseh O
中科院分区：
文献类型：
--
作者：
Nash A;Aghlara-Fotovat S;Hernandez A;Scull C;Veiseh O
免疫调节疗法代表了一类独特的药物产品，具有重新平衡功能失调的免疫系统的巨大潜力，并迅速成为制药行业增长最快的领域之一。要使这些药物成为主流药物，它们必须比目前使用的治疗方法提供更多的治疗益处，而不会引起严重的毒性。免疫调节剂、基于细胞的疗法、抗体和病毒疗法都在癌症和/或自身免疫性疾病的治疗中取得了不同程度的成功。然而，在我们看到这些疗法在临床上广泛采用之前，需要解决与精确给药、脱靶效应和制造障碍相关的许多挑战。本文综述了迄今为止免疫刺激和免疫抑制疗法的进展，并讨论了下一代免疫调节疗法临床转化的机遇和挑战。免疫系统周期的示意图。状态1代表免疫系统稳态，其中细胞毒性细胞和调节细胞的活化和增殖之间的平衡自然维持并且不需要干预。状态2a表示局部肿瘤发展，导致免疫抑制微环境，其中细胞毒性细胞如CD 8 + T细胞被抑制。免疫抑制微环境还可导致M2巨噬细胞和调节性T细胞的发育和增殖增加，其通过分泌抗炎分子而有助于免疫抑制。状态3a代表潜在的治疗干预：细胞因子疗法。在该实施例中，可以施用促炎细胞因子如白介素-2以促进细胞毒性T细胞活化和增殖，这可以导致增加的抗肿瘤作用。随着肿瘤细胞被破坏，免疫抑制微环境的程度降低，免疫系统恢复到稳态，如状态4所示。另一方面，状态2b表示将自身抗原错误鉴定为外来抗原，这在自身免疫疾病期间是常见的。在这种状态下，抗原呈递细胞如巨噬细胞标记自身抗原以被免疫系统破坏，这导致M1巨噬细胞、细胞毒性T细胞和B细胞的活化和增殖，从而引起延长的免疫系统活化和组织损伤。状态3b代表潜在的治疗干预：抗体疗法。在该实施例中，施用针对主要促炎细胞因子TNFα的抗体。促炎细胞因子信号传导的阻断通过减少这些信号传导分子与另外的免疫细胞的结合数量来减少免疫系统活化，从而减少炎症并允许免疫系统恢复稳态（状态4）。使用BioRender.com制作示意图
Immunomodulatory therapeutics represent a unique class of drug products that have tremendous potential to rebalance malfunctioning immune systems and are quickly becoming one of the fastest growing areas in the pharmaceutical industry. For these drugs to become mainstream medicines, they must provide more therapeutic benefit than the currently used treatments without causing severe toxicities. Immunomodulators, cell-based therapies, antibodies, and viral therapies have all achieved varying amounts of success in the treatment of cancers and/or autoimmune diseases. However, many challenges related to precision dosing, off-target effects, and manufacturing hurdles will need to be addressed before we see widespread adoption of these therapies in the clinic. This review provides a perspective on the progress of immunostimulatory and immunosuppressive therapies to date and discusses the opportunities and challenges for clinical translation of the next generation of immunomodulatory therapeutics. Schematic representation of immune system cycles. State 1 represents immune system homeostasis where the balance between activation and proliferation of cytotoxic cells and regulatory cells is maintained naturally and does not require intervention. State 2a represents local tumor development causing an immunosuppressive microenvironment in which cytotoxic cells such as CD8+ T cells, are repressed. Immunosuppressive microenvironments can also cause an increase in development and proliferation of M2 macrophages and regulatory T cells which contribute to the immunosuppression by secreting anti-inflammatory molecules. State 3a represents a potential therapeutic intervention: cytokine therapies. In this example, pro-inflammatory cytokines such as interleukin-2 can be administered to boost cytotoxic T cell activation and proliferation which can lead to increased anti-tumor effects. As the tumor cells are destroyed, the extent of the immunosuppressive microenvironment is reduced, and the immune system returns to homeostasis as shown in State 4. On the other hand, State 2b represents misidentification of self-antigens as foreign which is common during autoimmune diseases. In this state, antigen-presenting cells such as macrophages mark self-antigens for destruction by the immune system which leads to activation and proliferation of M1 macrophages, cytotoxic T cells, and B cells causing prolonged immune system activation and tissue damage. State 3b represents a potential therapeutic intervention: antibody therapies. In this example, antibodies against major pro-inflammatory cytokine TNFα are administered. Blockade of pro-inflammatory cytokine signaling reduces immune system activation by decreasing the number binding of these signaling molecules to additional immune cells and thus reducing the inflammation and allowing the immune system to return to homeostasis (State 4). Schematic was made using BioRender.com
登录
查看更多内容
影响因子：
2.2
作者：
Bharadwaj, Pranay;Riekofski, Cassidy;Weiner, Joshua A.
通讯作者：
Weiner, Joshua A.
影响因子：
51.1
作者：
Bockhorn, Maximilian;Jain, Rakesh K.;Munn, Lance L.
通讯作者：
Munn, Lance L.
DOI：
10.4317/medoral.19087
发表时间：
2014-01-01
期刊：
Medicina oral, patologia oral y cirugia bucal
影响因子：
--
作者：
Bascones-Martinez A;Mattila R;Gomez-Font R;Meurman JH
通讯作者：
Meurman JH
影响因子：
16.8
作者：
Alegre ML;Lakkis FG;Morelli AE
通讯作者：
Morelli AE
影响因子：
3
作者：
Azoury, Said C.;Straughan, David M.;Shukla, Vivek
通讯作者：
Shukla, Vivek