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。
/ @4 l' D" f: C% x! W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。
: ?9 F6 l* w' W% ^" E0 R比如下面这例：
5 V# d! x% @( j( s. w9 V《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》
% F4 v! `0 k  }: e1 l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。
$ A( x. C1 s! e( r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.........
! j4 x  k% Z! {' M- V. t“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. ”
8 m3 N+ j. Z- k- o) M7 Z
7 f9 G+ A' i  \# T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。
: E8 m& X/ [3 V9 ^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。
. O& ^' [, S+ Z4 ~
+ e8 r- W. R1 |" }! R9 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。
0 o# a7 Y0 \* R
/ ]( S9 r9 I8 P' |: n4 i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 w) E3 z, F( D" ]+ X
% C: O, K; S2 i( {4 I' s6 B
" Z6 P* p9 e; JH1受体拮抗剂抗组胺药
+ E# w, Y2 |% P4 a$ c8 ~
6 M, A. t  l3 C2 L. n. m" U一、几个回顾性的研究

- ]/ X/ {/ n( D2 ~5 m. e* U1、《Efficacy of cationic amphiphilic antihistamines on outcomes of patients treated with immune checkpoint inhibitors》

9 @- R4 m) l9 Y: N/ ^- GICI+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.”


2、《Impact of antihistamines use on immune checkpoint inhibitors response in advanced cancer
6 h7 {* F; J/ _8 Wpatients》

) R/ o- g5 Z" K2 P: n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。

$ H* a+ S& N* j( d. G“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”


  d$ d$ U! {8 ?8 {1 Y1 X* C3、《Concomitant medication of cetirizine in advanced melanoma could enhance anti-PD-1 efficacy by promoting M1 macrophages polarization》

1 h% e$ D6 ~( N6 m5 {1 a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).
) ?0 W" Z, j( P% ?7 @7 N) g
“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). ”

" t4 |) S1 ]- z/ g- i& @8 y
) ]5 o* j7 q. o& J- V4、《The allergy mediator histamine confers resistance to immunotherapy in cancer patients via activation of the macrophage histamine receptor H1》
7 U2 V2 C9 R8 H7 _( ?( F2 ~
5 V5 V: s# H1 ?* N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。
" w5 u# D$ R# O8 s- n. u" O
1 u% p+ c- S& W' h0 R. A“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.”

; {5 b# k& c/ y# J- O+ e0 \二、增效的作用机制
3 [  A$ b0 A( i: a  s% L
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。
  i4 u' m6 l2 e; M
3 y- B2 i( u1 y. W9 c9 i2、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）
5 y' U' X, g1 |
1 h  D- D9 S5 H5 r5 l, j" D& TTAM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。

' i1 u% {# t7 m6 d5 S, A
三、减毒的作用机制
; z& s) B  T/ G' G1 [$ U
3 E0 q, |, W, @5 j, q: w* ?1、抑制IL-1β、 IL6、IL8等促炎细胞因子。
) Y! H. B) p% N' e) r7 U! o" D
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》）
& A3 d; ]+ q4 y9 \9 P
- ]! o0 y# P2 S. H1 Y0 h9 B2 F- S2、抑制 NF-KB
5 f, [: R9 o, N% P. n, [5 K6 n/ I
' t/ G: O3 {% v0 F“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》）
: r- d+ M3 q. e( @4 }9 g