Abstract
Treatment of advanced melanoma with combined immune checkpoint inhibitor (ICI) therapy is complicated in up to 50% of cases by immune-related adverse events (irAE) that commonly include hepatitis, colitis and skin reactions. We previously reported that pre-therapy expansion of cytomegalovirus (CMV)-reactive CD4+ effector memory T cells (TEM) predicts ICI-related hepatitis in a subset of patients with Stage IV melanoma given αPD-1 and αCTLA-4. Here, we develop and validate a 10-color flow cytometry panel for reliably quantifying CD4+ TEM cells and other biomarkers of irAE risk in peripheral blood samples. Compared to previous methods, our new panel performs equally well in measuring CD4+ TEM cells (agreement = 98%) and is superior in resolving CD4+ CD197+ CD45RA- central memory T cells (TCM) from CD4+ CD197+ CD45RA+ naive T cells (Tnaive). It also enables us to precisely quantify CD14+ monocytes (CV = 6.6%). Our new “monocyte and T cell” (MoT) assay predicts immune-related hepatitis with a positive predictive value (PPV) of 83% and negative predictive value (NPV) of 80%. Our essential improvements open the possibility of sharing our predictive methods with other clinical centers. Furthermore, condensing measurements of monocyte and memory T cell subsets into a single assay simplifies our workflows and facilitates computational analyses.
Highlights
Immune checkpoint inhibitor treatment, combined programmed cell death protein 1 (PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade, has dramatically improved treatment response and overall survival rates for patients with inoperable metastatic melanoma [1,2,3,4,5,6]
Various predictive markers of adverse reactions have been reported in recent literature [13,14,15,16,17,18,19,20,21,22,23,24,25], including our own discovery that elevated CD4+ effector memory T cell (TEM) frequency in the blood is strongly associated with hepatitis risk after aPD-1 and aCTLA-4 treatment [26]
Our studies showed that exaggerated cytomegalovirus (CMV)specific memory T cell responses cause liver injury in some patients with advanced melanoma receiving aPD-1 (Nivolumab) and aCTLA-4 (Ipilimumab) therapy
Summary
Combined PD-1/CTLA-4 blockade, has dramatically improved treatment response and overall survival rates for patients with inoperable metastatic melanoma [1,2,3,4,5,6]. Various predictive markers of adverse reactions have been reported in recent literature [13,14,15,16,17,18,19,20,21,22,23,24,25], including our own discovery that elevated CD4+ effector memory T cell (TEM) frequency in the blood is strongly associated with hepatitis risk after aPD-1 and aCTLA-4 treatment [26]. Our studies showed that exaggerated cytomegalovirus (CMV)specific memory T cell responses cause liver injury in some patients with advanced melanoma receiving aPD-1 (Nivolumab) and aCTLA-4 (Ipilimumab) therapy. This surprising discovery stemmed from our observation that pre-treatment expansion of CD4+ effector memory T cells (TEM) in the blood reliably predicts hepatitis. 4 of 4 patients classified as high-risk for hepatitis who received CMV prophylaxis starting from their first exposure to aPD-1/aCTLA-4 did not develop hepatitis [26]
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