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。
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：
$ b4 f2 [) `9 h4 u& s% ~. I《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》
  l1 M7 ~2 k, x6 w7 ~& ~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。
0 `8 X2 N2 E$ l( W8 u4 @6 T$ a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.........
0 z/ ?1 s0 s7 z& F) V, O, K2 E“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. ”

! [% t; b# I4 b' I* i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。
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。

0 V% T/ y, a. V, ]+ d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。
; D/ K) i6 j2 j* e
4 O: V% H. F9 \: D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。
& T) \5 Y: M: d

. x- E% e% N. t- x5 l5 IH1受体拮抗剂抗组胺药

" s" u3 n- r% q' J) r( H! P( G一、几个回顾性的研究

$ x. I7 a5 N# Z: n- y0 e9 ~8 i% A! M( Q" [1、《Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors》
! M$ T; U1 g6 }! Z
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.”
' ?. c4 S5 X* f7 L* [4 `+ j, U% E
7 [8 Y) w) r9 R# }. t( _& I. o
5 g/ U* @8 R8 W' L' V8 J! S4 Y2、《Impact of antihistamines use on immune checkpoint inhibitors response in advanced cancer
( x" ~& @6 `  t5 Wpatients》

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。

( v) k6 l) }8 ]“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”

* F% p3 m5 j* g4 W" L7 S
5 O+ X2 x% u' W! x  t2 y3、《Concomitant medication of cetirizine in advanced melanoma could enhance anti-PD-1 efficacy by promoting M1 macrophages polarization》
. W" `/ |9 O% G  v! O. m, B/ @3 e, W
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). ”
# Q! {: Z2 _9 z
  g& ^# i9 R; g0 a" Y
4、《The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1》
, L0 g; D! i9 ?7 U1 C$ ?4 v
) a( t0 e6 P& v' N* y1 ?7 R& T$ `, {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。

“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.”

7 w/ ]2 y' B$ ]3 u二、增效的作用机制
) T& t0 ?+ G, T- P: v2 E8 m5 [
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。
4 o; o1 Q" i8 ^1 E
  J8 c( T3 T* C2、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）

" p& k7 b& Z3 s. v- q# bTAM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。

" x4 I* J2 D9 q9 A: O: C7 i
1 R3 J! `2 h# P9 v三、减毒的作用机制
) u! Y4 s& Z! N0 `6 v& o9 ?* [
' Z( S! k* \7 e4 c8 t( N3 @' S1、抑制IL-1β、 IL6、IL8等促炎细胞因子。

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》）
$ u( ^+ E( @5 Q" ?* R. a& w6 Q
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》）
; \9 N( i& Q6 Z- h: r1 v0 O