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[基础知识] 给免疫治疗“减毒增效”的辅助用药(一)

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5159 0 自学自救 发表于 2025-4-23 09:31:43 | 查看全部 | 阅读模式 来自: 上海闵行区

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以ICI为代表的免疫治疗单药有效率太低,尤其是对所谓冷肿瘤;联合做增敏增效治疗是主要出路。1 B1 r8 p% G; {/ ?, K  O$ a
但人的免疫系统是个整体,那些免疫细胞相关的因素也并非只管肿瘤,增敏增效治疗有可能增加全身炎症;即便是直奔肿瘤去的,过于放飞自我的免疫细胞掀起的免疫活动的强度,患者也未必能耐受得了;ICI治疗本身就风险巨大,再叠加这些风险因素,有时候就表现为“怕你死得不够快”了。- n3 G: G# S% F& S) O0 q
比如下面这例:
9 T6 A4 q7 w' }; T3 S9 f9 f3 e《Anti-PD-1 Immunotherapy Combined With Stereotactic Body Radiation Therapy and GM-CSF as Salvage Therapy in a PD-L1-Negative Patient With Refractory Metastatic Esophageal Squamous Cell Carcinoma: A Case Report and Literature Review》! }8 `/ D. l& G1 C- B
这篇论文讲了一个很时髦的疗法,“布拉格疗法”---ici+放疗+特尔立(gm-csf),治疗一位食管癌患者。
7 c% S2 k2 @+ b+ t2 _0 G# K增敏增效的疗效肯定是有的,因为这位患者pd-l1是阴性的,布拉格治疗也起效了。; Y9 q8 v- Z( l; w. [
但是患者第三次治疗的时候就因为严重的肺炎死了。- `' Z& N0 }7 ~+ L) X- b
直接对肺病灶放疗,肺炎本身就不可避免;会急剧加重炎症的pd-1i、gm-csf再联着用;再配上只会用激素的一言难尽的治疗措施.........% \5 D; Y. A- z1 D1 K: Y
“This study aimed to report a case of a patient about advanced unresectable ESCC negative expression of PD-L1, who experienced tumor progression after chemoradiotherapy and targeted therapy.A significant systemic effect was seen after PD-1 inhibitor combined with GM-CSF and stereotactic body radiotherapy (SBRT) for metastatic lesions, however, severe pneumonia occurred after the triple-combination therapy. ”
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9 M0 Z: ?2 J7 {4 V# o  k所以一切给免疫增敏增效的治疗,“减毒”要与“增效”并重,甚至“减毒”要在“增效”之前。
  }, ]& l" u; e6 ~; k' t这里的“减毒”,主要指的是 1、尽量不增加不可控的炎症风险 2、最好能对那些不利的促炎细胞因子、趋化因子之类的有所抑制。) d: {( K1 j# P+ r; ?: a

$ }, a/ a3 D8 T# i' B5 B简化的办法就是从消炎药中去找增敏增效药。当然消炎药也要看其具体作用机制,如果是增加treg等四座大山来消炎的,那也有免疫抑制促肿瘤发展的风险,那也不能用。
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- N1 `4 o7 a- y) ^从今天开始陆续介绍一些给免疫治疗“减毒”“增效”的辅助用药。4 X" Z3 ~$ P4 G: L7 T6 ^, W& ?+ E  a
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H1受体拮抗剂抗组胺药8 c# g1 S9 b/ |
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一、几个回顾性的研究
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1、《Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors》
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3 h, a/ }; z0 i6 Z+ w2 C# kICI+地氯雷他定或者赛庚啶或者依巴斯汀这三种H1受体拮抗剂抗组胺药的患者与只用ICI患者相比,中位总生存期显著延长(24.8个月对10.4个月;Log-rank,p = 0.018),无进展生存期显著延长(10.6对4.93个月;对数秩,p = 0.004);全因死亡率降低了约50%(HR,0.55 [95% CI: 0.34-0.91])。5 f7 g' F. _# `% ?, j
“Compared with non-cationic amphiphilic antihistamine users, patients who received cationic amphiphilic antihistamines had a significantly longer median overall survival (24.8 versus 10.4 months; Log-rank, p = 0.018) and progression-free survival (10.6 versus 4.93 months; Log-rank, p = 0.004). The use of cationic amphiphilic antihistamines was associated with an approximately 50% lower risk of all-cause mortality (HR, 0.55 [95% CI: 0.34-0.91]). Survival benefits were not seen in patients who received cationic amphiphilic antihistamines before immune checkpoint blockade.”0 a2 C5 L: o8 M" P0 u- [

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* J* C. T/ T, [, J2、《Impact of antihistamines use on immune checkpoint inhibitors response in advanced cancer
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6 g/ ~9 ~2 u% e) F* H% k一共纳入133名已经发生转移并使用ici治疗的肿瘤患者,其中黑色素瘤(33.1%)患者最多。最常见的ICI是nivolumab (63.2%)。55名(38.4%)患者在接受ICIs的同时接受了抗组胺药。最常见的抗组胺药是pheniramine(85.5%)。同时接受抗组胺药和ICIs的患者,中位无进展生存期(PFS) (8.2比5.1个月,log-rank p = 0.016)和总生存期(OS) (16.2比7.7个月,log-rank p = 0.002)更长。在多变量分析中,在校正混杂因素(如表现状态、骨或肝转移和同步化疗)后,这些患者的PFS(风险比(HR) = 0.63,95% CI:0.40–0.98,p = 0.042)和OS (HR = 0.49,95% CI:0.29–0.81,p = 0.006)也更好。2 [$ b+ M2 y' T, i* x+ o
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“A total of 133 patients receiving ICIs in the metastatic setting were included. Melanoma (33.1%) was the most common tumor type. The most common ICI was nivolumab (63.2%). Fifty-fi ve (38.4%) patients received antihistamines concomitantly with ICIs. The most common antihistamine was pheniramine (85.5%). The median progression-free survival (PFS) (8.2 vs. 5.1 months, log-rank p = 0.016) and overall survival (OS) (16.2 vs. 7.7 months, log-rank p = 0.002) were longer in patients receiving antihistamines concomitantly with ICIs. In multivariate analysis, PFS (Hazard Ratio (HR) = 0.63, 95% CI:0.40–0.98, p = 0.042) and OS (HR = 0.49, 95% CI:0.29–0.81, p = 0.006) were also better in those patients after adjusting for confounding factors, such as performance status, bone or liver metastasis, and concurrent chemotherapy”- _) q; Z6 X* u5 c+ O( X" M
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3、《Concomitant medication of cetirizine in advanced melanoma could enhance anti-PD-1 efficacy by promoting M1 macrophages polarization》
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接受西替利嗪联合抗PD-1药物治疗的患者无进展生存期显著延长(PFS平均无病生存期:28个月对15个月,风险比0.46,95%可信区间:0.28-0.76;p = 0.0023)和OS(平均OS为36比23个月,HR为0.48,95% CI为0.29-0.78;p = 0.0032)。伴随治疗与ORR和DCR显著相关 (p < 0.05).% N" X# Y! O% r
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“atients treated with cetirizine concomitantly with an anti-PD-1 agent had significantly longer progression-free survival (PFS; mean PFS: 28 vs 15 months, HR 0.46, 95% CI: 0.28-0.76; p = 0.0023) and OS (mean OS was 36 vs 23 months, HR 0.48, 95% CI: 0.29-0.78; p = 0.0032) in comparison with those not receiving cetirizine. The concomitant treatment was significantly associated with ORR and DCR (p < 0.05). ”: x4 w" _2 x; Z+ J" C/ ^+ v! Q

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( t! s, `6 P8 n( N0 c! C. E4、《The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1》
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血浆组胺水平低的癌症患者对抗PD-1治疗的客观缓解率是血浆组胺水平高的患者的三倍以上。2 x2 b0 }  b6 b$ o

4 {$ C  w. q: R# l5 Y“cancer patients with low plasma histamine levels had a more than tripled objective response rate to anti-PD-1 treatment compared with patients with high plasma histamine.”
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二、增效的作用机制
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. @. _' `. t* x1、2021年的《Allergic Mediator Histamine Confers Immunotherapy Resistance in Cancer Patients via Histamine Receptor 1 on Macrophage》这篇论文讲,组胺受体H1 (HRH1)在肿瘤微环境里的TAM肿瘤相关巨噬细胞上表达,这种表达会诱导TAM极化成促癌的M2表型,抑制CD8+T细胞的功能。
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2、2022年的《Concomitant medication of cetirizine in advanced melanoma could enhance anti-PD-1 efficacy by promoting M1 macrophages polarization》这篇论文验证了上述观点。用了H1抗组胺药cetirizine后,与接受西替利嗪的患者的血液样品中的基线相比,巨噬细胞的特异性标记物FCGR1A/CD64的表达在治疗后增加,但在仅接受抗PD1的患者中没有增加,并且与干扰素途径相关的基因如CCL8的表达正相关(rho = 0.32p = 0.0111),ifit 1(rho = 0.29;p = 0.0229),ifit 3(rho = 0.57;p %3C 0.0001),ifi 27(ρ= 0.42;p = 0.008),MX1(ρ= 0.26;p = 0.0383)和RSA D2(ρ= 0.43;p = 0.0005)。“he expression of FCGR1A/CD64, a specific marker of macrophages, was increased after the treatment in comparison with baseline in blood samples from patients receiving cetirizine, but not in those receiving only the anti-PD1, and positively correlated with the expression of genes linked to the interferon pathway such as CCL8 (rho = 0.32; p = 0.0111), IFIT1 (rho = 0.29; p = 0.0229), IFIT3 (rho = 0.57; p < 0.0001), IFI27 (rho = 0.42; p = 0.008), MX1 (rho = 0.26; p = 0.0383) and RSAD2 (rho = 0.43; p = 0.0005).” FCGR1A/CD64是M1型巨噬细胞的特异性标志物。(https://www.uniprot.org/uniprot/ UniProtP12314)
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TAM是肿瘤微环境中免疫抑制的四座大山之一,属于普遍共性问题。
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三、减毒的作用机制- v6 y+ H' J; G% E' h" N
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1、抑制IL-1β、 IL6、IL8等促炎细胞因子。2 m# S+ W! x8 o9 h" J& F
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例如 “Both H1 antihistamines reduce all symptoms of allergic rhinitis, including nasal congestion and the plasmatic level of IL-1β, IL-6, IL-8 and TNF-α, after 4 weeks of treatment. ” (《In Vivo Anti-Inflammatory Effect of H1 Antihistamines in Allergic Rhinitis: A Randomized Clinical Trial》)
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/ f8 ^) t5 }" D5 b. {( E2、抑制 NF-KB
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“H1 antihistamines reduced basal NF-kappaB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine).” (《Desloratadine inhibits constitutive and histamine-stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor》)
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