给免疫治疗“减毒增效”的辅助药物（十八）--乙酰左旋肉碱

一、cxcl12高表达是icb免疫治疗不良预后的生物标志物
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8 ^: d5 M$ m# p2 w5 Q! `, [1、《Serum cytokine analysis in a cohort of advanced non-small cell lung cancer treated with PD-1 inhibitors reveals predictive markers of CXCL12》
6 @4 z; _' @2 ~) O! L9 qBackground: The circulating predictive factors for the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) remain elusive. We aimed to assess the predictive value of circulating cytokines for outcomes.
3 Q4 Y( E, `$ H8 K- a$ b+ L6 O5 eMethods: Serum samples of 102 advanced-stage NSCLC patients who underwent immunotherapy were collected at baseline. The relative levels of 37 cytokines were detected. PD-L1 expression was also analyzed.
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.
/ q$ T& N$ E" wConclusion: 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.

2、《CXCL12 expression and PD-L1 expression serve as prognostic biomarkers in HCC and are induced by hypoxia》
Anti-PD-1 treatment increases anti-tumour immune responses in animal models of hepatocellular carcinoma (HCC). Sorafenib, the mainstay of treatment of HCC patients, however, leads to tumour hypoxia and thereby abrogates the efficacy of anti-PD-1 treatment. This served as a rationale to implement CXCR4 inhibition as adjunct to sorafenib and anti-PD-1 treatment in murine HCC models. We studied the relationship between tumour hypoxia, PD-L1 and CXCL12 expression in human HCC, aiming to test the rationale for triple therapy combining sorafenib, PD-1 immune checkpoint inhibitors and CXCR4 inhibitors. Expression of CXCL12, PD-L1 and of surrogate markers for tumour hypoxia was evaluated at messenger RNA (mRNA) level in a cohort of HCC patients from The Cancer Genome Atlas and immunohistochemically in an independent cohort from the University Hospital of Bonn. Retrospective survival analyses were conducted. CXCL12 mRNA level significantly correlated with markers indicating tumour hypoxia in HCC (HIF1-α ρ = 0.104, p = 0.047). PD-L1 expression was significantly increased in tumours with a high number of tumour-infiltrating lymphocytes (ρ = 0.533, p < 0.001). In Cox proportional hazard analyses, high PD-L1 expression and loss of nuclear CXCL12 expression showed significant prognostic value in terms of overall survival (hazard ratio (HR) = 3.35 [95%CI 1.33-8.46], p = 0.011 for PD-L1; HR = 2.64 [95%CI 1.18-5.88], p = 0.018 for CXCL12, respectively). This study supports the rationale to combine CXCR4 inhibitors and PD-1 immune checkpoint inhibitors in patients with HCC, as sorafenib-induced tumour hypoxia leads to upregulation of PD-L1 and CXCL12.
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3、《Chemokine level predicts the therapeutic effect of anti-PD-1 antibody (nivolumab) therapy for malignant melanoma》
* k7 y( l6 U( G; z: ^Anti-programmed cell death protein 1 (PD-1) antibody drugs, nivolumab and pembrolizumab, are regarded as first-line therapies for advanced malignant melanoma. Anti-PD-1 therapy suppresses tumor immunity, and the therapeutic effect is frequently correlated with the number of tumor-infiltrating lymphocytes (TIL) and tumor mutation burden (TMB). However, sampling tumor tissues from the metastatic sites to examine the number of TILs and TMB level is often challenging. Herein, we focused on chemokines in blood to determine whether they can predict the therapeutic effect of anti-PD-1 (nivolumab) therapy. First, we measured 44 types of chemokines and cytokines in the blood of 8 advanced malignant melanomas before anti-PD-1 (nivolumab) treatment and examined the relationship between the levels of these proteins and therapeutic effect of the drug treatment, which suggested that C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine ligand 12 (CXCL12) were candidates for biomarkers to predict the therapeutic effect of anti-PD-1 therapy. Next, we measured the blood levels of CCL5 and CXCL12 in 22 patients with advanced malignant melanomas before the administration of anti-PD-1 antibody. We evaluated tumor infiltration of CD8-positive T cells by immunostaining in nine patients in whom the metastatic site could be sampled at the beginning of the treatment. The patients with lower than average levels of CCL5 and CXCL12 had a large number of TILs (P = 0.04) and good disease-specific survival rate (P = 0.04). Therefore, CCL5 and CXCL12 could likely be used as biomarkers to predict the therapeutic effect of anti-PD-1 (nivolumab) therapy.

" G; e/ ]+ _8 N' Y( C) ^二、乙酰左旋肉碱是抑制CXCR4/CXCL12的廉价替代药物
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+ `6 X) M' U7 k6 p0 D1、CXCR4/CXCL12有专门的靶向药普乐沙福，但普乐沙福很贵；乙酰左旋肉碱是抑制CXCR4/CXCL12的廉价替代药物。
《Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: rationale for prevention and interception strategies》
Background: Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR.
4 h' S& a* R8 H4 [7 J0 yMethods: The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts.
Results: We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo.
Conclusions: Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible "repurposed agent' for cancer prevention and interception, similar to aspirin, metformin or beta-blockers.

& v6 Y: ^. g. \2 S6 X0 h' F2、乙酰左旋肉碱可参考下面这个临床试验的用法：
《Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy》
A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted.