给免疫治疗“减毒”“增效”的辅助用药（三）：法莫替丁，老树新芽
Ici是给免疫“松刹车”的治疗，但是“松刹车”的前提基础是首先肿瘤内得有CD8+T细胞这些“车”。所以促进免疫细胞从引流淋巴结出来浸润到肿瘤病灶里去就是个关键问题。法莫替丁，一种治胃病的H2抗组胺药；二十年前有几个尽管规模不大但却是前瞻性的随机临床试验，结果显示法莫替丁对于促进免疫细胞浸润到肿瘤中去，非常有效。那是前ICI时代，没有pd-1i这些松刹车的药，所以光有车也开不快，不算引人注目。
但今天再把它拾起来，老树新芽却是完全可期的。
一、几个前瞻性临床试验
1、《Does Famotidine Enhance Tumor Infiltrating Lymphocytes in Breast Cancer?》
30例乳腺癌患者前瞻性随机分为病例组和对照组，术前分别接受40 mg法莫替丁10-14天和常规术前用药。客观地评估手术标本在肿瘤中心和周围的肿瘤浸润淋巴细胞，同时评估转移性淋巴结的反应性变化。
用法莫替丁的病例组中，有10人（67%）(p = 0.03)的病灶中心显示显著的淋巴细胞浸润，对照组只有4人（27%）；病例组中有11人（77%）(p = 0.03)的病灶外周有显著的淋巴细胞浸润，对照组中只有5人（33%）；病例组中有9人（60%）淋巴细胞反应显著，对照组中只有3人(20%)(p = 0.03)；病例组中78%患者转移性淋巴结中有显著的反应性变化，对照组中只有22%（p <0.01）。种反应与两组患者的肿瘤分期、分级或绝经状态无关。
“Thirty patients with breast cancer were prospectively randomized into case and control groups receiving 40 mg famotidine preoperatively for 10-14 days and routine premedication, respectively. Surgical specimens were evaluated objectively for tumor infiltrating lymphocytes in the center and in the periphery of the tumor along with evaluation of metastatic lymph nodes for reactive changes. Ten famotidine-treated cases (67%) showed significant lymphocytic infiltration in the center compared to 4 controls (27%) (p = 0.03). Eleven cases (77%) had significant lymphocytic infiltration in the periphery (p = 0.03) compared to 5 controls (33%). Considering both sites, lymphocytic response was significant in 9 (60%) cases as opposed to only 3 (20%) controls (p = 0.03). This response did not correlate with the stage, grade of tumor or menopausal status of patients in either group. Seventy-eight percent (78%) of the cases showed significant reactive changes in the metastatic lymph nodes as compared to 22% in controls (p < 0.01). This study suggests that famotidine enhances tumor infiltrating lymphocytes in breast cancer and might have potential as an immunomodulator. A larger confirmatory study is suggested.”
2、《Effect of preoperative short course famotidine on TILs and survival in breast cancer》
45名可手术的乳腺癌患者，分为术前用法莫替丁的病例组（25人）和不用法莫替丁的对照组（20人）。术前短程用法莫替丁后手术，评估手术标本的TIL的浸润情况和生存关系。
病例组中，75% (18/24)观察到病灶中有显著的TIL浸润，对照组中只有35% (7/20)；逻辑回归分析中，发现预测TILs的唯一变量是法莫替丁，优势比为7.324 (1.693-31.686)，P=0.008。在Cox回归分析中，til的存在与中位随访35.56个月的无病生存期的改善有利相关。与TIL阳性患者相比，TIL阴性患者疾病复发的风险比为3.327 (1.174-9.426)，P=0.024。在最初的模型中，单独使用法莫替丁并不显著，然而，在上述多变量模型中，除了其他已确定的预后因素外，纳入受累象限后，其无病生存期的风险比为3.404 (1.005-11.531，P=0.049)，具有临界显著性。
“Method: Forty-five patients with operable breast cancers (25 cases who received preoperative famotidine and 20 controls) were studied for the effect of famotidine in inducing TILs and survival in breast cancer.
Results: Significant TILs were seen in 75% (18/24) of cases as opposed to 35% (7/20) controls. In logistic regression analysis the only variable found to be predictive of TILs was famotidine, odds ratio 7.324 (1.693-31.686) P=0.008. In Cox's regression presence of TILs was favorably associated with improved disease free survival at a median follow up of 35.56 months. The hazard ratio for disease relapse was 3.327 (1.174-9.426) P=0.024 in TIL negative as compared to TIL positive patients. Famotidine use alone was not significant in the original model, however, on incorporation of quadrant of involvement in addition to other established prognostic factors in the above multivariate model, it assumed borderline significance with a hazard ratio for disease free survival 3.404 (1.005-11.531, P=0.049).”
3、《Effect of pre-operative short course famotidine on tumor infiltrating lymphocytes in colorectal cancer: a double blind, placebo controlled, prospective randomized study 》
研究设计:双盲，安慰剂对照，前瞻性随机研究。
方法:23名可切除结直肠癌患者随机接受法莫替丁(n = 11)或安慰剂(n = 12)。术前口服法莫替丁1周，剂量为40mg/天。切除后，由病理学家对两组患者进行组织学分析，确定淋巴细胞浸润。淋巴细胞浸润每个高倍视野超过50个细胞，涉及超过50%的肿瘤-正常组织界面被认为是显著的。
结果:两组在年龄、性别、术前癌胚抗原(CEA)水平和病理分期方面具有可比性。研究组中有63.6%(7/11)的患者出现显著的淋巴细胞浸润，相比之下，安慰剂组中仅有8.5%(1/12)的患者出现显著的淋巴细胞浸润(P = 0.005)。尽管研究组的复发率更低，生存期更长，但差异并不显著。
“Study design: Double blind, placebo controlled, prospective randomized study.
Methods: Twenty-three patients with resectable colorectal cancer were randomized to receive famotidine (n = 11) or placebo (n = 12). Famotidine was given for 1 week pre-operatively in a dose of 40 mg per day p.o. After resection, the specimens were analyzed histologically for lymphocytic infiltration by a pathologist blinded to the two groups. Lymphocytic infiltration more than 50 cells per high power field, involving more than 50% of the tumor-normal tissue interface was considered significant.
Results: The two groups were comparable for age, gender, pre-operative carcino embryonic antigen (CEA) levels and pathological stage. Significant lymphocytic infiltration was seen in 63.6% (7 of 11) patients in the study group compared to only 8.5% (1 of 12) patients in the placebo group (P = 0.005). Despite fewer recurrences and a longer survival in the study group, the difference was not significant.”
二、增效作用
从上面三个小型临床试验结果来看，法莫替丁是有很强的促进淋巴细胞浸润到肿瘤病灶中去的能力的。
首先要有“车”，然后才谈得上“松刹车”（ICI治疗）。
有两点可以考虑。
1、都是短程使用法莫替丁。我认为这是受制于医学伦理--都是等着要手术的病人，不手术只让吃胃药（法莫替丁）或者干脆吃安慰剂，显然时间是不能长的。
不是说法莫替丁只能短程用，或者说法莫替丁只有短程用才有促进淋巴细胞浸润的疗效。
1、至于“差异并不显著”，这是前ICI时代的治疗，只有“车”，没“松刹车”，自然开不快。
此外，《Activity of continuous infusion + pulse interleukin-2 with famotidine in metastatic melanoma》 这篇论文讲了只用了il-2+法莫替丁这两个免疫治疗的辅助用药，没有用ici或者细胞回输这样的主药，也有43% total response rate ；这实际上是很不错的。
“持续静脉输注高剂量白细胞介素-2 (IL-2)可诱导淋巴因子激活的杀伤(LAK)细胞对肿瘤细胞的细胞毒性。当随后用额外的IL-2脉冲这些lak时，它们在体外表现出增强的抗肿瘤细胞毒性。法莫替丁可能通过允许淋巴细胞上的IL-2受体摄取更多的IL-2来增加LAK对肿瘤细胞的细胞毒性。二十三(23)名患者每天两次静脉注射法莫替丁20 mg，连续输注IL-2(18 MIU/米(2)/24小时)72小时，随后休息24小时，然后在15-30分钟内每天1-3次脉冲IL-2剂量18 MIU/米(2)，之前每3周重复法莫替丁20 mg静脉注射周期。最常见的转移部位是肺、淋巴结和皮下/软组织。最常见的毒性为发热、僵硬、恶心/呕吐、低磷血症、低血压、肌酐升高和肺水肿。没有与治疗相关的死亡。观察到1例完全缓解(4%)和9例部分缓解(39%)(总缓解率为43%；95%置信区间:22%-65%)。所有患者的中位生存期为13个月。法莫替丁和大剂量持续输注+脉冲IL-2的组合对转移性黑色素瘤有效。”“High-dose interleukin-2 (IL-2), given via continuous intravenous (i.v.) infusion, induces lymphokine-activated killer (LAK) cell cytotoxicity against tumor cells. These LAKs exhibit enhanced cytotoxicity against tumor cells in vitro when they are subsequently pulsed with additional IL-2. Famotidine may increase LAK cytotoxicity against neoplastic cells by allowing for greater IL-2 uptake at the IL-2 receptor on lymphocytes. Twenty-three (23) patients received famotidine 20 mg i.v. twice per day and continuous-infusion IL-2 (18 MIU/m(2)/24 hours) for 72 hours, followed by a 24-hour rest, then 1-3 daily-pulse IL-2 doses of 18 MIU/m(2) over 15-30 minutes preceded by famotidine 20 mg i.v. Cycles were repeated every 3 weeks. The most common metastatic sites were lung, lymph node, and subcutaneous/soft tissue. The most common toxicities were fever, rigor, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and pulmonary edema. There were no treatment-related deaths. One (1) complete (4%) and 9 partial responses (39%) were seen (43% total response rate; 95% confidence interval: 22%-65%). Median survival for all patients is 13 months. The combination of famotidine and high-dose continuous infusion + pulse IL-2 is active in metastatic melanoma.”
三、减毒作用
《Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm》 这篇论文讲到，法莫替丁可以通过激活炎症反射--这是一种大脑整合的迷走神经机制，通过α7烟碱乙酰胆碱受体(α7nAChR)信号转导抑制炎症，防止免疫风暴。
“法莫替丁IP给药显著降低血清和脾LPS刺激的肿瘤坏死因子(TNF)和IL-6浓度，显著提高存活率。”“双侧膈下迷走神经切断术或α7nAChR基因敲除均可消除法莫替丁的抗炎作用，表明炎症反射是法莫替丁的作用机制。”“Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival.”“Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. ”
我个人认为，免疫毒性里神经毒性最难治疗；法莫替丁的这一消炎作用机制，再结合鞘内注射、脑室药囊注射、腹膜内注射等给药方式，提供了另外一种可能性。
有人用过吗
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