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[基础知识] 与ICB免疫治疗相关的部分血液指标

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2349 0 自学自救 发表于 2025-4-14 09:57:20 |

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一些血液指标(基线为主),与ICB免疫治疗的疗效与副作用,有相当的关联性。
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一、中性粒细胞与淋巴细胞比率(NLR)
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/ B( t: N* o9 |( U9 Z  x《Systemic inflammation shapes clinical outcomes in response to immune checkpoint blockade treatment: moving toward optimizing antitumor immunity》. b( r# r/ {) ~5 D3 b

" l5 P8 ^: X: {8 j' c% h0 w% HMethods: This study analyzed a large pan-cancer cohort of 16 cancer types, including 1714 patients with cancer who received ICB treatment. Clinical outcomes in response to ICB treatment were measured by overall survival (OS), progression-free survival (PFS), objective response rate, and clinical benefit rate. The non-linear relationships of NLR with OS and PFS were investigated by a spline-based multivariate Cox regression model. A total of 1000 randomly resampled cohorts were bootstrapped to estimate the variability and reproducibility of NLR-related ICB responses.% q2 t. X/ o/ p, z, F! e5 j% ?  ]
Results: By interrogating a clinically representative cohort, this study revealed a previously unreported finding that the pretreatment NLR levels were associated with ICB treatment outcomes in a U-shaped dose-dependent manner rather than a linear manner. An NLR range between 2.0 and 3.0 was remarkably associated with optimal ICB treatment outcomes, including increased patient survival, delayed disease progression, improved treatment response, and significant clinical benefit. Comparatively, either decreasing (< 2.0) or increasing (>3.0) NLR levels were indicators of worse ICB treatment outcomes.7 \  @5 U4 ]9 u$ z

1 ~$ l% }/ Z! uNLR阈值 2.0 < NLR < 3.0
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4 z. k! z) ~1 p' @4 [( Z二、预后营养指数(prognostic nutritional index, PNI), D3 d7 }! }( ?% n6 F7 [
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1、《Pretreatment "prognostic nutritional index" as an indicator of outcome in lung cancer patients receiving ICI-based treatment: Systematic review and meta-analysis》! q1 P. ]3 y: \
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“We analyzed data from 8 eligible studies (831 patients). Meta-analysis showed that relative to patients with low pretreatment PNI, those with a high pretreatment PNI had better OS (HR = 2.50, 95% CI = 1.44-4.33, P = .001) and better PFS (HR = 1.94, 95% CI = 1.56-2.42, P < .001). Sensitivity analysis indicated these results were robust. There was also no evidence of publication bias.”6 R$ v5 Q! V) ~, a! d( ^1 `
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2、《Prognostic nutritional index as a prognostic biomarker for gastrointestinal cancer patients treated with immune checkpoint inhibitors》
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“In this analysis, a total of 17 articles with 2883 patients were included. Our pooled results indicated that patients with high PNI levels had longer OS (HR: 0.530, 95% CI: 0.456-0.616, p < 0.001) and PFS (HR: 0.740, 95% CI: 0.649-0.844, p < 0.001), as well as higher ORR (OR: 1.622, 95% CI: 1.251-2.103, p < 0.004) and DCR (OR: 1.846, 95% CI: 1.428-2.388, p < 0.001). Subgroup analysis showed that PNI cutoff values of 40 to 45 showed greater predictive potential. Subgroup analysis also confirmed that the above findings still hold true in patients with esophageal cancer, gastric cancer, and hepatocellular carcinomas.”
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3、《Use of the prognostic nutrition index as a predictive biomarker in small-cell lung cancer patients undergoing immune checkpoint inhibitor treatment in the Chinese alpine region》
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; B" e- V4 I* s  H9 Z, DOne hundred and forty patients were included in this study, of which, 60.0% were high PNI (PNI > 49.43) and 40.0% were low PNI (PNI ≤ 49.43). Results indicated that the high PNI group had better PFS and OS than the low PNI group in the patients who received PD-L1/PD-1 inhibitors monotherapy (median PFS: 11.0 vs. 4.8 months, p < 0.001 and median OS: 18.5 vs. 11.0 months, p = 0.004). Similarly, better PFS and OS were associated with an increase in PNI level in the patients who accepted PD-L1/PD-1 inhibitors combined with chemotherapy (median PFS: 11.0 vs. 5.3 months, p < 0.001 and median OS: 17.9 vs. 12.6 months, p = 0.005). Multivariate Cox-regression model showed that high PNI was significantly related to better PFS and OS in patients who accepted PD-L1/PD-1 inhibitors monotherapy or combined with chemotherapy (PD-L1/PD-1 inhibitors monotherapy: PFS: HR = 0.23, 95% CI: 0.10-0.52, p < 0.001 and OS: HR = 0.13, 95% CI: 0.03-0.55, p = 0.006; PD-L1/PD-1 inhibitors combined with chemotherapy: PFS: HR = 0.34, 95% CI: 0.19-0.61, p < 0.001 and OS: HR = 0.53, 95% CI: 0.29-0.97, p = 0.040, respectively). Additionally, Point biserial correlation analysis between PNI and disease control rate (DCR) showed that PNI status was positively correlated with DCR in SCLC patients receiving PD-L1/PD-1 inhibitors or combined with chemotherapy (r = 0.351, p < 0.001; r = 0.285, p < 0.001, respectively).
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4 \( \& _1 H, ]: S8 f; _4、《Prognostic Nutritional Index Predicts Outcome of PD-L1 Negative and MSS Advanced Cancer Treated with PD-1 Inhibitors》( m7 L5 O% \% g) d

# u) \3 ~: t$ v) Q" }2 x' @“Results: Lower level of PNI and poor performance status (ECOG score of 2) was correlated with significantly shorter overall survival (OS) and worse outcome of ICIs. The multivariate analysis revealed that PNI (for OS HR = 0.465, 95% CI: 0.236-0.916, p = 0.027; for PFS HR = 0.493, 95% CI: 0.251-0.936, p = 0.031) and ECOG score (for OS HR = 4.601, 95% CI: 2.676-7.910, p < 0.001; for PFS HR = 2.830, 95% CI: 1.707-4.691, p < 0.001) were independent prognostic factors for OS and PFS. NLR was related to the onset of irAEs.
8 V! t) x7 E6 k5 R$ ?Conclusions: Pretreatment level of PNI and NLR, beyond PD-L1 expression and MSS, can improve the predictive accuracy for immunotherapy outcomes and has the potential to expand the candidate pool of patients for treatment with ICIs.”
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5、《Combined systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) predicts chemotherapy response and prognosis in locally advanced gastric cancer patients receiving neoadjuvant chemotherapy with PD-1 antibody sintilimab and XELOX: a prospective study》
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+ s& h7 l: e! A8 zMethods: We registered a prospective clinical study involving 30 locally advanced gastric cancer patients from March 2020 to July 2021. The pre-treatment SII and PNI were calculated from peripheral blood samples, and the cut-off value was calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 568.5) and low PNI (≤ 52.7); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI.1 t0 E8 E. T( u( G( Q2 m* J, h/ B1 s  Z
Results: All patients were evaluated by RECIST1.1 criteria after four cycles of sintilimab immunotherapy combined with XELOX chemotherapy, including 5 patients with TRG 3 and 25 patients with non-TRG 3. The SII-PNI score of non-TRG 3 patients was significantly lower than that of TRG 3 patients (P = 0.017). The medial progression free survival of patients with low SII-PNI score was significantly better than that of patients with high SII-PNI score (P < 0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting progression-free survival (P = 0.003)., ~6 k4 [- R: s. Z
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三、c反蛋白/白蛋白比值 (C-reactive protein-to-albumin ratio CAR)
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/ r+ q# @& E2 q$ w+ F' _0 n1 |1、《Prognostic role of C-reactive protein to albumin ratio in cancer patients treated with immune checkpoint inhibitors: a meta-analysis》
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Results: A total of 11 studies consisting of 1,321 cases were enrolled into the present meta-analysis. As revealed by combined data, the increased CAR level markedly predicted dismal OS (HR = 2.79, 95% CI = 1.66-4.67, p < 0.001) together with shortened PFS (HR = 1.95, 95% CI = 1.25-3.03, p = 0.003) among carcinoma cases using ICIs. The prognostic effect of CAR was not influenced by clinical stage or study center. Our result reliability was suggested by sensitivity analysis and publication bias test.; [' D8 O/ b8 u2 o0 v2 ^- v
Conclusions: High CAR expression showed marked relation to worse survival outcomes among ICI-treated cancer cases. CAR is easily available and cost effective, which can be the potential biomarker for selecting cancer cases benefiting from ICIs.
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论文建议把 CAR 阈值定为0.3' _' k, A1 d4 d4 `* q

) D  z5 A  N" q2、《Analysis of Early Death in Japanese Patients With Advanced Non-small-cell Lung Cancer Treated With Nivolumab》; G! [' M$ E" l3 z

. h; I( @' s" }0 ^0 N* oResults: A total of 201 patients with NSCLC were enrolled, and 38 (18.9%) died within the first 3 months. Thirty-one (81.6%) patients who experienced early death developed progressive disease, whereas 14 (36.8%) patients who experienced early death demonstrated nivolumab-induced immune-related adverse events, which required corticosteroid intervention, including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic regression demonstrated that an Eastern Cooperative Oncology Group performance status score ≥ 2 (odds ratio [OR], 5.66; 95% confidence interval [CI], 2.01-15.61; P < .001), C-reactive protein-to-albumin ratio > 0.3 (OR, 10.56; 95% CI, 3.61-30.86; P < .001), and the response to prior treatment (OR, 2.07; 95% CI, 1.03-4.14; P = .041) were independent predictors for early death.$ C. Z& e9 b0 D6 V$ _* l
Conclusion: Disease progression and immune-related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology Group performance status score ≥ 2, pretreatment C-reactive protein-to-albumin ratio > 0.3, and poor response to prior treatment were associated with early death.' b  R7 |$ w6 Z  Y
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这篇论文CAR的阈值也是0.3
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四、血小板与淋巴细胞比率 PLR
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2 Y- W. A/ g& X1、《Elevated platelet-to-lymphocyte corresponds with poor outcome in patients with advanced cancer receiving anti-PD-1 therapy》
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* u# W( ], R0 _* G* Q7 {9 A" ~  `“Results: The optimal cut-off value of baseline PLR was 164. Among the total 85 patients, 34 patients presented with PLR ≥ 164, and 51 presented with PLR < 164, respectively. The median OS for the high PLR group was 7.0 months (95% CI: 4.1-9.9 months), and it was not reached for the low PLR group (P < 0.001). The median PFS was 3.0 months (95% CI: 1.9-4.1 months) vs. 9.8 months (95% CI: 6.1-13.5 months) for the high and low PLR groups, respectively (P < 0.001). In multivariate analysis, a PLR > 164 and body mass index (BMI) > 24.0 were independently associated with OS (hazard ratio [HR]: 3.549, 95% confidence interval [CI]: 1.901-6.625, P < 0.001 and HR: 0.496, 95% CI: 0.260-0.945, P = 0.033), meanwhile PLR was also significantly associated with inferior PFS (HR: 2.567, 95% CI: 1.551-4.249, P < 0.001). Disease control rate for high and low PLR group was 38.2% and 74.5%, respectively, and it was also correlated with elevated PLR (P = 0.001).
  S, g% \- j1 d; h" t# uConclusion: This retrospective analysis indicates that PLR could be used as a biomarker to stratify patients who will have a better response to anti-PD-1 agents.”. Y: a! i- f, l  T1 F* ~9 q
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PLR阈值1649 U6 h" ^$ _- Y8 J& |
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2、《Serum neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in prognosticating immunotherapy efficacy》
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Aim: To examine neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in prognosticating immunotherapy efficacy. Methods: A retrospective study of 156 patients with metastatic melanoma and non-small-cell lung cancer on PD-1 inhibitors. Results: Baseline NLR ≥5 was associated with worse progression-free survival (hazard ratio [HR]: 1.53; 95% CI: 1.01-2.31; p = 0.043) but nonsignificant worse overall survival trend (HR: 1.51; 95% CI: 0.98-2.34; p = 0.064). PLR ≥200 was associated with worse overall survival (HR: 1.94; 95% CI: 1.29-2.94; p = 0.002) and worse progression-free survival (HR: 1.894; 95% CI: 1.27-2.82; p = 0.002). NLR or PLR are prognosticating factors regardless of cancer types, with PLR having a stronger association with outcomes than NLR. Conclusion: High baseline NLR or PLR (alone and combined) were associated with worse immunotherapy efficacy regardless of cancer type, indicating their potential role as an agnostic marker for immunotherapy efficacy.
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PLR阈值2000 }1 S6 N% z3 n3 r
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3、《Pretreatment platelet-to-lymphocyte ratio (PLR) as a prognosticating indicator for gastric cancer patients receiving immunotherapy》3 E3 a- _& l4 m7 e! E( h" u
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Results: 237 patients were enrolled for this retrospective investigation. The 6 month and 12 month PFS based on the area under the curve value was 0.60 and 0.65 (p < 0.05). based on a calculated PLR cut-off value of 139.41, The PLR < 139.41 group has a longer OS in contrast with the PLR ≥ 139.41 group (13.46 m vs 10.71 m, HR = 0.57, 95% CI 0.42-0.78, p = 0.004). The PLR < 139.41 group had a PFS of 7.93 m in contrast to the 4.75 m seen in those with PLR ≥ 139.41 group (HR = 0.57, 95% CI 0.43-0.76, p = 0.002). The disease control rate (DCR) and objective response rate (ORR) were 86.17% and 30.85%, respectively, in the PLR < 139.41 group, but were 82.52% and 32.17%, respectively in the PLR ≥ 139.41 group. Both groups did not show any marked differences in terms of ORR and DCR (p = 0.887, p = 0.476). PLR is an independent prognostic indicator for OS and PFS upon uni- and multivariate analyses (p < 0.05).
1 `  v$ n! \- Z1 j1 r1 eConclusions: Pre-treatment PLR correlated significantly with PFS and OS in AGC and MGC patients who received immunotherapy. An elevated PLR may provide guidance on subsequent treatment options.; h0 v4 T- {$ \$ [

8 d# S6 k1 A) mPLR阈值 139.41
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* ?+ U0 Q  @" F2 a, V4、《Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study》! k( b6 \( }6 f' k) n4 k. x
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Results: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes.
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PLR阈值 2001 q  d' i8 R( D5 x. H( u

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5、《Hematological prognosticators in metastatic renal cell cancer treated with immune checkpoint inhibitors: a meta-analysis》
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Results: Fifteen studies comprising 1530 patients were eligible for meta-analysis. High levels of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein and lactate dehydrogenase were significantly associated with worse progression-free survival. High NLR and PLR were significantly associated with worse overall survival. Conclusion: High pretreatment NLR and PLR appear to be hematological prognostic factors of progression and overall mortality in mRCC patients treated with ICIs. These findings might help in the design of correlative biomarker studies to guide the clinical decision-making in the immune checkpoint inhibitor era.
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+ Z: x! l% u. G2 P/ w一、血清铁水平, c+ q) c6 Q& B  C
《Serum iron element: A novel biomarker for predicting PD-1 immunotherapy efficacy》  O1 o$ ^/ l8 w$ {) o
This study aims to explore the relationship between serum iron by inductively coupled plasma-mass spectrometry (ICP-MS) and the efficacy of immune checkpoint inhibitors (ICIs) and potential mechanism. Totally 113 patients from 233 patients with advanced metastatic lung cancer, esophageal cancer, gastric cancer and colorectal cancer who treated with immunotherapy in Shandong Provincial Hospital were divided into training group (n=68) and validation group (n=45), whose patients were divided into clinical benefit response (CBR) and non-clinical benefit (NCB) by RECIST (v1.1) respectively. We found for the first time that high serum iron level (>1036 μg/L) was a novel biomarker of better PFS (10.13 months vs 7.37 months; p = 0.0015) and OS(16.00 months vs 11.00 months; p = 0.0235) by ROC curve (sensitivity: 78.13 %; Specificity: 80.56 %; p < 0.0001) of CBR (n=32) and NCB (n=36) patients in training group. Interestingly, consistently stable and high serum iron level predicted better efficacy during immunotherapy. Noteworthy, the predictive efficacy of PD-L1 expression was significantly inferior than serum iron (accuracy:63.49% vs 79.41%, p=0.0432), while serum iron detected by spectrophotometry did not predict the efficacy of immunotherapy (p=0.0671) indicating higher sensitivity of ICP-MS. Bioinformatics analysis showed that serum iron could enhance innate immunity and cytokine release and was verified by proteomics that KEGG and GO analysis enriched innate immune and cytokine signaling pathways. Flow cytometry showed that IL-17 (p=0.0002) increased and IL-6 (p=0.0112) decreased after immunotherapy. Based on this, Nomogram with better prediction was constructed by multiple clinical and independent factors. Our results revealed that serum iron is positively associated with ICIs efficacy by enhancing innate immunity and cytokine release in advanced metastatic cancers, and can be a biomarker for predicting ICIs response.
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注意:要用inductively coupled plasma-mass spectrometry (ICP-MS) 法检测,不能用 spectrophotometry 法检测
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二、动态CRP
) F+ G$ ?0 r# p: I《C reactive protein flare predicts response to checkpoint inhibitor treatment in non-small cell lung cancer》. m0 A  m+ d3 L
Biomarkers for predicting response to anti-programmed death-1 (PD-1) immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) remain in demand. Since anti-tumor immune activation is a process, early dynamic changes of the acute-phase reactant C reactive protein (CRP) may serve as a predictive on-treatment biomarker. In a retrospective (N=105) and prospective (N=108) ICB-treated NSCLC cohort, early CRP kinetics were stratified after the start of immunotherapy until weeks 4, 6, and 12 as follows: an early doubling of baseline CRP followed by a drop below baseline (CRP flare-responder), a drop of at least 30% below baseline without prior flare (CRP responders), or those who remained as CRP non-responders. In our study, we observed characteristic longitudinal changes of serum CRP concentration after the initiation of ICB. In the prospective cohort, N=40 patients were defined as CRP non-responders, N=39 as CRP responders, and N=29 as CRP flare-responders with a median progression-free survival (PFS) of 2.4, 8.1, and 14.3 months, respectively, and overall survival (OS) of 6.6, 18.6, and 32.9 months (both log-rank p<0.001). Of note, CRP flare-responses, characterized by a sharp on-treatment CRP increase in the first weeks after therapy initiation, followed by a decrease of CRP serum level below baseline, predict ICB response as early as 4 weeks after therapy initiation. Of note, early CRP kinetics showed no predictive value for chemoimmunotherapy or when steroids were administered concurrently. On-treatment CRP kinetics had a predictive value for both major histological NSCLC subtypes, adenocarcinoma and squamous cell carcinoma. The results were verified in an independent retrospective cohort of 105 patients. In conclusion, CRP flare predicted anti-PD-1 monotherapy response and survival in two independent cohorts including a total of 213 patients with NSCLC, regardless of histology. Due to its wide clinical availability, early CRP kinetics could become an easily determined, cost-efficient, and non-invasive biomarker to predict response to checkpoint inhibitors in NSCLC within the first month.
. b+ D" `6 k; v4 l- G+ N! M要注意的是:文中的CRP基线是5 mg/L;平常医院里检测CRP正常值上限是8.2mg/L。
5 M5 \2 O# t0 e: R6 a! O1 h# \四周左右,就可以把绝大部分的CRP快速反应者和反应者鉴别出来了,是早于影像的:Indeed, two-third of the CRP flare-responders and >90% of the CRP responders could be correctly classified 4 weeks after the start of ICB therapy (figure 3B, C). After 6 weeks, >90% of CRP flare-responders had dropped below baseline CRP levels and thus met the criteria for a CRP flare-response (figure 3C).
0 B1 ]5 i- ^5 O" H. I可以用这个办法来鉴别假性进展。
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三、leukemia inhibitory factor (LIF) 白血病抑制因子5 {; ]+ h( I" B! O
《Plasma proteomics identifies leukemia inhibitory factor (LIF) as a novel predictive biomarker of immune-checkpoint blockade resistance》
) F4 r* h' [: R0 tPatients and methods: We analyzed the proteome of plasma samples, collected before treatment onset, from two independent prospective cohorts of cancer patients treated with ICB (discovery cohort n = 95, validation cohort n = 292). We then investigated the correlation between protein plasma levels, clinical benefit rate, progression-free survival and overall survival by Cox proportional hazards models.
4 c! ^! X# }" c2 q2 D% O, VResults: By using an unbiased proteomics approach, we show that, in both discovery and validation cohorts, elevated baseline serum level of leukemia inhibitory factor (LIF) is associated with a poor clinical outcome in cancer patients treated with ICB, independently of other prognostic factors. We also demonstrated that the circulating level of LIF is inversely correlated with the presence of tertiary lymphoid structures in the tumor microenvironment.& \/ u! l0 A2 `7 U6 b
Conclusion: This novel clinical dataset brings strong evidence for the role of LIF as a potential suppressor of antitumor immunity and suggests that targeting LIF or its pathway may represent a promising approach to improve efficacy of cancer immunotherapy in combination with ICB.
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四、基线血细胞计数
$ {4 k7 Z# a/ B$ \, L% ?《Real-world outcomes of 18,186 metastatic solid tumor outpatients: Baseline blood cell counts correlate with survival after immune checkpoint inhibitor therapy》5 N: X$ L' Y6 |
Methods: This retrospective, observational study analyzed baseline demographic, clinical, laboratory, and treatment data versus outcomes of The US Oncology Network adult outpatients. Patients with advanced/metastatic melanoma, NSCLC, or RCC treated between January 1, 2015 and November 30, 2020 were given ICI monotherapy or combination therapy with ipilimumab, pembrolizumab, nivolumab, or atezolizumab. Treatment outcomes (overall survival [OS], time to treatment discontinuation, time to next treatment) were followed longitudinally until May 31, 2021, last patient record, or date of death. Baseline blood cell counts, including absolute monocyte count (AMC), absolute lymphocyte count (ALC), monocyte-to-lymphocyte ratio (MLR), absolute neutrophil count (ANC), and eosinophil count, were subdivided into quintiles for univariate and multivariable Cox regression analyses.: l; ~0 ~0 K5 i9 B" f1 e
Results: Data from 18,186 patients with advanced/metastatic melanoma (n = 3314), NSCLC (n = 12,416), and RCC (n = 2456) were analyzed. Better OS correlated with increased baseline serum albumin concentration, increased eosinophil and lymphocyte counts, and Western United States physician practice location. Decreased OS correlated with increased AMC, MLR, ANC, age, and worse Eastern Cooperative Oncology Group performance status.
. O4 c) |% Z( }8 PKnown covariates, such as high serum albumin concentration as well as investigational covariates, such as high eosinophil levels were associated with longer OS in all tumor types.. a7 R" f, v4 G8 M$ Y+ d
Increased age, non‐Western physician practice location, and increased MLR were risk factors for decreased OS for all cohorts (Figure 4).
5 M4 G' W/ Z5 q0 b* X; n# A4 L4 `Increased baseline monocytes were associated with decreased OS in all cohorts.
; m, n) E6 [( w  @In our large patient series, increased baseline blood monocyte and neutrophil counts were associated with less favorable OS, whereas increased eosinophils and lymphocytes were associated with more favorable OS.
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& Q  w4 [  h8 {7 E五、CXCL12
; \4 O4 i' @- X《Serum cytokine analysis in a cohort of advanced non-small cell lung cancer treated with PD-1 inhibitors reveals predictive markers of CXCL12》/ `' x) U9 ^! G1 M
Results: Higher serum CXCL12 levels (top 33%) were a poor predictive biomarker for durable clinical benefit (DCB) (23.5% vs. 72.1%, p<0.001), progression-free survival (PFS) (3.76 vs. 14.40 months; p<0.001) and overall survival (OS) (12.20 vs. 44.84 months; p=0.008). Compared with PD-L1-negative patients, PD-L1-positive patients had a significantly higher objective response rate (ORR) (70.0% vs. 28.8%, p<0.001) and a prolonged mPFS (25.35 vs. 4.64 months, p=0.003) and tended to have an increased mOS (44.84 vs. 20.42 months, p=0.087). A signature comprising PD-L1<1% and the top 33% CXCL12 level was associated with the lowest ORR (27.3% vs. 73.7%, p<0.001) and DCB (27.3% vs. 73.7%, p<0.001) and the worst mPFS (2.44 vs. 25.35 months, p<0.001) and mOS (11.97 vs. 44.84 months, p=0.007). Area under the curve (AUC) analyses of PD-L1 expression, CXCL12 level and PD-L1 expression plus CXCL12 level to predict DCB or no durable benefit (NDB) showed AUC values of 0.680, 0.719 and 0.794, respectively.1 P" H& h2 @$ L8 @' w# _
Conclusion: Our findings suggest that serum cytokine CXCL12 levels can predict the outcomes of patients with NSCLC receiving ICI. Moreover, the combination of CXCL12 levels and PD-L1 status can predict outcomes with a significantly improved discriminatory power.. u7 p2 p' }7 p$ k. T8 }3 n$ U! z
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六、免疫相关不良反应irAEs的预测标记物
' w  m( l' {+ S+ ^, P《Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors》
8 {- |' G8 D0 j' O) }0 u3 ^Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs.
) m4 n' c: }" ?. b3 A9 k( J6 FMethods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs.
$ }) i! x6 O9 @3 ^+ n& J0 KFindings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs.* x# r7 u- B( I! g6 _% [
Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs.
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