A variant of the CTLA-4 gene associated with autoimmune disease was found to be more frequent in non-small cell lung cancer (NSCLC) patients who experienced an exceptionally high response to anti-PD-1 immunotherapy and higher immune-related side effects than in a comparable cohort of lung cancer patients and healthy individuals, according to data presented during theAACR Annual Meeting 2022，4月8日至13日举行。

“免疫检查点蛋白PD-1/PD-L1的抑制剂已改变了癌症治疗局势。然而，在接受这种治疗的NSCLC患者中，反应和不可预测的不良事件（包括自身免疫反应）仍然存在很大的差异。“目前有限的生物标志物可以有效地预测这种可变性，而患者的遗传构成对反应的贡献的程度尚不清楚。”

与免疫相关的不良事件（IRAE）的发生 - 已知通过免疫疗法激活免疫系统而产生的副作用，与NSCLC患者的抗PD-1治疗的反应更高，对抗PD-1治疗的反应更高。

In addition, Allen explained, combined blockade of PD-1 and a second immune checkpoint protein, such as CTLA-4, often results in better treatment outcomes but at the cost of increased irAEs, including autoimmunity.

“This suggests a shared mechanism behind the predisposition that drives autoimmunity and better response to cancer immunotherapy,” said Allen. “We hypothesized that patients who exhibit increased response may be harboring genetic mutations within the autoimmune-linked gene CTLA-4, and that these might work to drive better outcomes.”

To test this hypothesis, the authors of this study performed whole genome sequencing on germline DNA from 35 NSCLC patients exhibiting exceptional response to anti-PD-1 therapy, defined as progression-free survival of at least two years and one or more irAEs of grade 2 or higher. In these patients, the frequency of certain single nucleotide polymorphisms (SNPs) in the genetic region encompassing the CTLA-4 gene was analyzed and compared to that in patients with lung cancer within the publicly accessible Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort and to cancer- and dementia-free elderly individuals included in the Medical Genome Reference Bank (MGRB).

艾伦（Allen）及其同事确定了与其他两个队列相比，在异常响应者中更频繁的几个SNP。特别是，在15.7％的特殊响应者中，有一个SNP的频率是PCAWG队列中的患者的两倍，而MGRB队列中的患者的频率几乎高四倍。

艾伦说：“据报道，该SNP会影响CTLA-4免疫检查点蛋白的功能，以提高对自身免疫性疾病的敏感性，例如1型糖尿病和类风湿关节炎。”“我们队列中这种变体的富集提出了一种机制，可以通过这种机制来提出对治疗的反应。因此，该CTLA-4变体可用于识别将受益于抗PD-1治疗的患者。”

According to Allen, the identification of this genetic variant through genomic sequencing could be used alongside existing biomarkers to help select NSCLC patients who may experience better response to anti-PD1/PD-L1 checkpoint therapy and those at risk of more severe autoimmune side effects.

作者目前正在将遗传反应生物标志物的搜索扩展到其他自身免疫连接基因，包括CTLA-4的相邻基因，例如CD28和ICOS。

“Further analysis into the immunological impact of such genetic variants could also help us better understand the mechanisms underlying current variability in response and why some patients develop more severe autoimmune side effects following immune checkpoint therapy,” said Allen. “Understanding the mechanisms of response to these drugs is paramount to broadening their potential clinical benefit.”

这项研究的一个重要局限性是与非反应者缺乏直接比较，他们目前正在招募并正在进行测序以进行未来分析。此外，正如艾伦（Allen）所指出的那样，与整个基因组测序以及具有特殊免疫疗法反应的患者的稀有性相关的成本极大地限制了样本量。其他局限性包括患者人口统计学的差异，包括性别，年龄和吸烟状况，以及例外响应者队列与比较队列（MGRB和PCAWG）之间招募过程的差异，尽管在比较中考虑了这些差异。

这项研究由澳大利亚Bioplatforms，Kinghorn基金会和Garvan Institute资助。作者宣称没有利益冲突。

Reference:Allen, I. 665 - Correlation between a CTLA-4 single nucleotide polymorphism and high response to anti-PD1/PDL1 immunotherapy in advanced non-small cell lung cancer.AACR年会；2022年4月8日至13日；路易斯安那州新奥尔良。https://www.aacr.org/meeting/aacr-anual-meeting-2022。2022年4月4日访问

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