Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma.
Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma.
复制标题
BRAF、MEK 和 CDK4/6 抑制剂的免疫调节作用：结合靶向治疗和免疫检查点阻断治疗黑色素瘤的意义。
DOI：
10.3389/fimmu.2021.661737
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Sheppard KE
中科院分区：
文献类型：
--
作者：
Lelliott EJ;McArthur GA;Oliaro J;Sheppard KE
最近出现的靶向和基于免疫的疗法彻底改变了黑色素瘤的治疗，并改变了转移性疾病患者的结局。大多数患者对目前的标准治疗靶向治疗（双重BRAF和MEK抑制）产生耐药性，这促使对包含CDK 4/6抑制剂的新组合进行评价。基于有希望的临床前数据，BRAF、MEK和CDK 4/6联合抑制最近已进入治疗BRAFV 600黑色素瘤的临床试验。有趣的是，虽然BRAF和MEK靶向治疗最初是基于有效的肿瘤内在效应而开发的，但后来发现它具有显著的免疫增强活性。最近的研究还确定了CDK 4/6抑制的免疫相关影响，尽管这些影响不太明确，并且可以是免疫增强和免疫抑制。BRAFV 600黑色素瘤患者也有资格接受免疫治疗，特别是针对PD-1和CTLA-4的检查点抑制剂。BRAF/MEK靶向疗法的免疫调节活性引起了人们对将这些与免疫检查点抑制剂结合的联合疗法的兴趣，然而最近研究这种方法的临床试验产生了不同的结果。在这里，我们总结了BRAF，MEK和CDK 4/6抑制剂的免疫调节作用，阐明了这种组合单独使用和与免疫检查点阻断联合使用的前瞻性效用。了解这些可用疗法的临床疗效的基础机制是优化新型组合和调度方法以对抗黑色素瘤并改善患者结局的关键一步。
The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma and transformed outcomes for patients with metastatic disease. The majority of patients develop resistance to the current standard-of-care targeted therapy, dual BRAF and MEK inhibition, prompting evaluation of a new combination incorporating a CDK4/6 inhibitor. Based on promising preclinical data, combined BRAF, MEK and CDK4/6 inhibition has recently entered clinical trials for the treatment of BRAFV600 melanoma. Interestingly, while BRAF- and MEK-targeted therapy was initially developed on the basis of potent tumor-intrinsic effects, it was later discovered to have significant immune-potentiating activity. Recent studies have also identified immune-related impacts of CDK4/6 inhibition, though these are less well defined and can be both immune-potentiating and immune-inhibitory. BRAFV600 melanoma patients are also eligible to receive immunotherapy, specifically checkpoint inhibitors against PD-1 and CTLA-4. The immunomodulatory activity of BRAF/MEK-targeted therapies has prompted interest in combination therapies incorporating these with immune checkpoint inhibitors, however recent clinical trials investigating this approach have produced variable results. Here, we summarize the immunomodulatory effects of BRAF, MEK and CDK4/6 inhibitors, shedding light on the prospective utility of this combination alone and in conjunction with immune checkpoint blockade. Understanding the mechanisms that underpin the clinical efficacy of these available therapies is a critical step forward in optimizing novel combination and scheduling approaches to combat melanoma and improve patient outcomes.
登录
查看更多内容
影响因子：
4
作者：
Banzi M;De Blasio S;Lallas A;Longo C;Moscarella E;Alfano R;Argenziano G
通讯作者：
Argenziano G
影响因子：
10.1
作者：
Cooper ZA;Juneja VR;Sage PT;Frederick DT;Piris A;Mitra D;Lo JA;Hodi FS;Freeman GJ;Bosenberg MW;McMahon M;Flaherty KT;Fisher DE;Sharpe AH;Wargo JA
通讯作者：
Wargo JA
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
8.4
作者：
Ascierto, Paolo A.;Dummer, Reinhard;Robert, Caroline
通讯作者：
Robert, Caroline
影响因子：
10.1
作者：
Callahan MK;Masters G;Pratilas CA;Ariyan C;Katz J;Kitano S;Russell V;Gordon RA;Vyas S;Yuan J;Gupta A;Wigginton JM;Rosen N;Merghoub T;Jure-Kunkel M;Wolchok JD
通讯作者：
Wolchok JD