给免疫治疗“减毒增效”的辅助用药（一）

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。
7 w) R+ r+ K4 p- Q1 L8 |9 J) b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。
比如下面这例：
《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》
5 \; E" T1 q4 Z# k$ n' X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。
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。
但是患者第三次治疗的时候就因为严重的肺炎死了。
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.........
“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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4 s" h. J9 I( L9 S, _3 O3 [) ^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。
# y' J7 w# M: E: @% h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。

. K/ |% U0 H7 q& [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。

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。
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H1受体拮抗剂抗组胺药

) C' Q# V; s: t5 p. ?2 M3 j一、几个回顾性的研究

2 `+ b+ ]" H  N5 F1、《Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors》
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ICI+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])。
“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.”
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2、《Impact of antihistamines use on immune checkpoint inhibitors response in advanced cancer
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( W3 t: J+ r# M1 j) T0 {1 o6 w; P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。
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) C: L6 n$ ^7 ]* N, ]* b" m“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”


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).

“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). ”


4、《The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1》

8 c5 ?2 W  K  `- Q/ H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。

7 V& `) R, `. `0 j6 ^# K( ^5 }“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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& g9 H$ ~4 y9 D+ R9 x1 G二、增效的作用机制
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1、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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! I/ e0 Q/ R9 k0 I: U# [/ \$ Y2、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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5 A  C9 }( u' T+ R# F9 b: y  xTAM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。


三、减毒的作用机制
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7 [: q) j) F) F  C2 X5 @5 _1、抑制IL-1β、 IL6、IL8等促炎细胞因子。
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0 W- a8 ^8 N: o+ X1 m% `  F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》）

2、抑制 NF-KB

“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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