Checkpoint Inhibition in Myeloma: Opportunities and Challenges.
Checkpoint Inhibition in Myeloma: Opportunities and Challenges.
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DOI：
10.3389/fimmu.2018.02204
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发表时间：
2018
影响因子：
7.3
通讯作者：
Dhodapkar MV
中科院分区：
文献类型：
--
作者：
Costa F;Das R;Kini Bailur J;Dhodapkar K;Dhodapkar MV
尽管治疗前景有了重大改善，但大多数多发性骨髓瘤（MM）患者最终死于潜在的恶性肿瘤。免疫疗法由于其特异性和长期记忆能力而代表了实现持久缓解的有吸引力的策略。免疫细胞的活化通过表面和细胞内受体的激动和抑制信号的平衡来控制。包括PD-1/PD-L1在内的这种抑制性免疫受体（称为“免疫检查点”）的阻断导致了几种癌症中令人印象深刻的肿瘤消退。临床前研究表明，这些免疫检查点也可能在调节MM中的肿瘤免疫中发挥作用。实际上，骨髓瘤是在临床前模型中证明阻断PD-1轴的治疗功效的首批肿瘤之一。PD-L1在肿瘤和免疫细胞上的表达也与恶性转化的风险相关。然而，单药PD-1阻断的早期临床研究并未导致有意义的肿瘤消退。免疫调节药物（IMiD）现在是大多数MM治疗的支柱。有趣的是，IMiD的免疫激活机制还涉及抑制性检查点的释放，例如Ikaros介导的IL-2抑制。PD-1靶向药物与IMiD的联合治疗产生了有前景的临床活性，包括在一些IMiD治疗难治性患者中的客观缓解。然而，其中一些研究在2017年暂时停止，原因是担心IMiD-PD 1联合用药可能存在安全性信号。免疫系统控制MM的能力已经通过最近成功的过继细胞疗法（例如通过嵌合抗原受体（CAR-T）重定向的T细胞）得到进一步加强。仍然存在未满足的需求，以更好地理解检查点阻断的免疫学作用，描述对这些疗法的抗性机制，并确定激动性信号传导、检查点抑制剂以及包括CAR-T在内的其他疗法的最佳组合，以实现免疫系统控制和预防MM的潜力。
Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as “immune checkpoints”) including PD-1/PD-L1 has led to impressive tumor regressions in several cancers. Preclinical studies suggest that these immune checkpoints may also play a role in regulating tumor immunity in MM. Indeed, myeloma was among the first tumors wherein therapeutic efficacy of blockade of PD-1 axis was demonstrated in preclinical models. Expression of PD-L1 on tumor and immune cells also correlates with the risk of malignant transformation. However, early clinical studies of single agent PD-1 blockade have not led to meaningful tumor regressions. Immune modulatory drugs (IMiDs) are now the mainstay of most MM therapies. Interestingly, the mechanism of immune activation by IMiDs also involves release of inhibitory checkpoints, such as Ikaros-mediated suppression of IL-2. Combination of PD-1 targeted agents with IMiDs led to promising clinical activity, including objective responses in some patients refractory to IMiD therapy. However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM.
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影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
20.3
作者：
Badros, Ashraf;Hyjek, Elizabeth;Singh, Zeba
通讯作者：
Singh, Zeba
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John
DOI：
10.1016/j.clim.2010.12.010
发表时间：
2011-08
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Dhodapkar MV;Richter J
通讯作者：
Richter J
影响因子：
50.3
作者：
Chauhan D;Singh AV;Brahmandam M;Carrasco R;Bandi M;Hideshima T;Bianchi G;Podar K;Tai YT;Mitsiades C;Raje N;Jaye DL;Kumar SK;Richardson P;Munshi N;Anderson KC
通讯作者：
Anderson KC