*1.5. CTLA-4 Inhibition and Its Potential Use in the Treatment of ACP*

The other major group of immune checkpoint inhibitors that have become increasingly utilized in cancer are the CTLA-4 inhibitors of which ipilimumab is the classic example. One of the first major studies to demonstrate the efficacy of these agents was that by Hodi et al. [47] in 2010. In their study they randomized 676 patients with stage 3 or 4 treatment-resistant melanoma to treatment with ipilimumab plus glycoprotein 100 (gp100) or gp100 alone. They demonstrated a statistically significant, although modest benefit, in terms of survival for patients in the ipilimumab group. Subsequent work by Ji et al. aimed to elucidate what specific factors might be predictive of response to treatment with CTLA-4 blockade [48]. This group utilized gene expression profiling to demonstrate that in pre-treatment samples of patients with metastatic melanoma a higher baseline expression of immune related genes was predictive of an increased response to treatment with ipilimumab [48]. Specifically, they analyzed the gene expression in tumor samples from 45 patients with melanoma both before, and three weeks after treatment with ipilimumab. They found that tumors that had increased expression of immune related genes pre-treatment, were more likely to respond to the therapy. Indeed, when they clustered genes based on biological functions and examined the differential expression of these groups of genes between responders and non-responders, they demonstrated that genes related to the inflammatory response were those that were most differentially expressed between the two groups [48]. This led their group to conclude that a "pre-existing immune-active tumor microenvironment might favor clinical response to ipilimumab". As previously stated, ACPs have been shown to harbor a significant inflammatory/immune component in both the solid and cystic component and there is mounting evidence that this pro-inflammatory environment plays an active

role in tumorigenesis [31]. A 2017 study by Donson et al. [31] utilized various methods to demonstrate upregulation of several pro-inflammatory genes in both the solid and cystic component of these tumors. This begs the question, could the use of a CTLA-4 inhibitor such as ipilimumab lead to improved outcomes in ACP? Furthermore, recent trials have demonstrated that combining different types of immune checkpoint inhibitors can lead to a survival advantage for patients with treatment refractory cancers. Specifically, combining ant-PD1 and anti-CTLA-4 therapy can result in improved survival in treatment-resistant metastatic melanoma, renal cell carcinoma and non-small cell lung cancer [49–52]. Given the expression of PD-L1 and the significant immune cell and inflammatory milieu present in ACP, the use of such combinations in the treatment of this disease would appear promising. As a result, a lot of work remains to be done to fully elucidate the potential of such treatments in ACP. Given the often-aggressive clinical course, and devastating effects this disease can have on patient's quality of life such potential is surely worth investigating.
