Acute Phase Proteins as Early Predictors for Immunotherapy Response in Advanced NSCLC: An Explorative Study

Abstract

In the last decade, targeting the immune system became a promising therapy in advanced lung cancer stages. However, in a clinical follow-up, patient responses to immune checkpoint inhibitors widely differ. Peripheral blood is a minimally invasive source of potential biomarkers to explain these differences. We blindly analyzed serum samples from 139 patients with non-small cell lung cancer prior to anti-PD-1 or anti-PD-L1 therapies to assess whether baseline levels of albumin (ALB), alpha-1 acid glycoprotein (AGP), alpha1-antitrypsin (AAT), alpha2-macroglobulin (A2M), ceruloplasmin (CP), haptoglobin (HP), alpha1-antichymotrypsin (ACT), serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP), have a predictive value for immunotherapy success. Disease progression-free survival (PFS) was calculated based on RECIST 1.1 criteria. A multivariate Cox regression analysis, including serum levels of acute-phase proteins and clinical parameters, revealed that higher pre-therapeutic levels of HP and CP are independent predictors of a worse PFS. Moreover, a combined panel of HP and CP stratified patients into subgroups. We propose to test this panel as a putative biomarker for assessing the success of immunotherapy in patients with NSCLC.

Multi-omic analysis identifies hypoalbuminemia as independent biomarker of poor outcome upon PD-1 blockade in metastatic melanoma

“…A recent pan-cancer study with 1,714 patients has shown that hypoalbuminemia predicts poor survival upon ICI treatment, but this work lacked a melanoma-speci c analysis placing these associations into the context of other melanoma-speci c biomarkers (14). Multiple studies on NSCLC showed that hypoalbuminemia was associated with poor survival after immunotherapy, which held in a multivariate analysis adjusting for treatment line, prior radiotherapy, NLR, and ECOG PS (39,40). Another study comparing several laboratory and clinical factors in metastatic melanoma reported that albumin was an independent predictor for immunotherapy response after adjustment for LDH, CRP, NLR, brain metastasis, sex, and age (41,42).…”

Molecular & Translational Biology of the Blood-Based VeriStrat® Proteomic Test Used in Cancer Immunotherapy Treatment Guidance

“…SAA proteins increase expression up to 1000-fold during the acute phase response, which is part of an attempt to restore homeostasis after an immune response or tissue insult [44]. SAA is prognostic of outcomes in NSCLC and other cancers [29,30,32], as well as efficacy and outcomes of ICI therapy [45,46]. One important point to note is that it is not yet determined how the different SAA proteins and their proteoforms individually have roles in prognosis or prediction.…”

The Association Between Albumin Levels and Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis

“…The 3.5 gr/dL was the most frequently used albumin cut-off in the included studies (n = 20) [25, 31-33, 37, 38, 40-43, 45-52, 54, 56-64], while eight studies evaluated the effect of albumin levels on survival by using albumin as a continuous measure [34,39,44,53,55,[65][66][67]. All but two studies reported HR for OS [25,36,49], while data for PFS was available in the 15 studies [25, 32, 33, 36, 40-42, 48-50, 52, 53, 57, 60, 63, 66]. Most studies tested the prognosis in patients treated with ICI monotherapy and nivolumab was the most commonly used ICI in the studies (n = 21) (Table -…”

“…The sample sizes were variable and spanned from 44 [39] to 1714 [33]. More than half of the studies were reported from Far East (n = 15) [32, 39-52], followed by Europe (n = 12) [25,31,37,38,[53][54][55][56][57][58][59][60]]. The 3.5 gr/dL was the most frequently used albumin cut-off in the included studies (n = 20) [25, 31-33, 37, 38, 40-43, 45-52, 54, 56-64], while eight studies evaluated the effect of albumin levels on survival by using albumin as a continuous measure [34,39,44,53,55,[65][66][67].…”

“…Similar to the peripheral blood-based biomarkers derived from the blood count, albumin levels are signi cantly affected from the in ammatory pressure [23]and lower albumin levels are seen in cases of chronic in ammatory disorders and cancer as a negative acute phase reactant [24,25]. Additionally, the albumin levels are correlated the nutritional status with lower albumin levels are an important denominator of malnutrition and general condition [26,27].…”