免疫检查点抑制剂Immune Checkpoint inhibitor

免疫检查点抑制剂Immune Checkpoint inhibitor
1 基本知识
免疫细胞（immune cell）是白细胞的俗称，包括淋巴细胞和各种吞噬细胞等，也特指能识别抗原、产生特异性免疫应答的淋巴细胞等，淋巴细胞是免疫系统的基本成分。
淋巴细胞包括 T淋巴细胞（CD3+）、B淋巴细胞（CD3-CD19+）、NK细胞（CD3-CD16+CD56+），其中，T细胞是淋巴细胞的主要组成。
T淋巴细胞：就是胸腺依赖淋巴细胞（thymus dependent lymphocyte），简称T细胞。
抗原提呈细胞：antigen presenting cell（APC），是指具有摄取、处理抗原并将抗原信息提呈给T淋巴细胞的一类细胞，又称为辅佐细胞。
树突状细胞：Dendritic cells, DCs，是一类重要的专职抗原提呈细胞（APC），虽在体内的数量较少，但具有超强的抗原提呈能力，而且能够活化初始T细胞。
从历史角度来看，免疫治疗在肺癌方面的成功先例极少。鲜见的成功先例在某种程度上令人得出肺癌无免疫性的观点。根据文献报道，多数晚期患者出现了免疫抑制现象，此类患者群体的外周淋巴及肿瘤淋巴细胞计数均出现降低。作为一类淋巴细胞，调节性T细胞(Tregs-CD4+)在肿瘤免疫监视的抑制方面发挥了关键性作用，研究发现，与其他T细胞亚群相比，肺癌患者外周血液及肿瘤环境中的调节性T细胞水平较高。CD4+ Tregs 细胞同样可对细胞毒性T淋巴细胞(CD8+ T 细胞)具有抑制作用，而后者则具有肿瘤细胞杀伤、肿瘤免疫监视及免疫记忆功能。
细胞毒性T淋巴细胞相关抗原-4 (CTLA-4)抑制性通路可对T细胞的活化具有抑制作用。CTLA-4为在T细胞活化早期表达于细胞表面的一种受体，可与其配体CD80 或CD86进行结合。该抑制性信号促使T细胞钝化，从而对共刺激信号进行平衡。
癌细胞逃脱免疫系统的另一种方式是，借助于机体或肿瘤特异机制，通过适应性免疫抵抗，引起肿瘤特异性T细胞失能。癌症对抑制性通路，如程序化细胞死亡分子-1 (PD-1)通路的利用即为这类特异机制的一种。业已发现，肺部肿瘤可在其细胞表面表达程序化细胞死亡分子-1 配体(PD-L1)，已知该分子是位于T细胞表面的PD-1受体。该通路可导致T细胞下调及抑制。
PD-1受体可与其配体(PD-L1/B7-H1)进行结合，对T细胞进行抑制，并下调T细胞应答。肿瘤通过在细胞表面上表达PD-L1，从而特异性利用该通路。因而肿瘤可直接抑制具有抗肿瘤能力的细胞毒性T细胞活性，这就是适应性抗性。可通过单克隆抗体阻断PD-1或PD-L1对这种抗性进行阻断，从而增强T细胞应答。

2 免疫检查点抑制剂
2.1 CTLA-4抑制剂
2011年3月，美国FDA批准了一种可特异性中和人细胞毒性T淋巴细胞相关抗原4(CTLA-4)的全人源单克隆抗体易普利姆玛(Ipilimumab，商品名为Yervoy，百时美施贵宝产品)，以用于治疗不可切除的或转移性的黑色素瘤。
在正常情况下，T细胞的激活依赖于第一信号（抗原抗体复合物的形成）和第二信号（B7 介导的活化信号）双活化。而CTLA-4与B7结合将产生抑制性信号并抑制T 细胞活化。
Ipilimumab 可阻断CTLA-4与B7 结合，从而去除免疫抑制效应，并调动特异性抗肿瘤免疫反应。
剂量和给药方法
Ipilimumab推荐剂量为3 mg/kg，在90 min内滴注完毕，每3周1次，连续使用4个周期。
该药起效缓慢，可能在用药12周后才可观察到疗效。约10%~20%的患者在治疗后的初次评效中表现为疾病进展，但在随访过程中显示出疗效，疗效出现的早晚与患者的生存期长短无相关关系，只要能观察到疗效，最终患者都可显著获益。
剂型和规格
50 mg/10 mL (5 mg/mL)（7200美元）和200 mg/40 mL (5 mg/mL)(28800美元)。
对于100kg的病人，一个周期价格是43200美元，四个周期是172800美元。
警告和注意事项
由于T-细胞激活和增殖YERVOY可导致严重和致命性免疫介导不良反应。这些免疫介导反应可能累及任何器官系统；但是，最常见严重免疫介导不良反应是小肠结肠炎、肝炎、皮炎（包括毒性表皮坏死）、神经病变和内分泌病变。这些免疫介导反应大多数在治疗期间最初表现；但是，少数发生在终止YERVOY后几周至几个月。
非小细胞肺癌相关临床结果：
Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.
http://www.ncbi.nlm.nih.gov/pubmed/22547592
实验组收入了204名IIIB/IV的非小细胞肺癌病人，一线化疗方案采用卡铂/紫杉醇方案，按1：1：1分成三组，第一组：四个疗程的Ipilimumab联合卡铂/紫杉醇化疗，再接二个疗程的卡铂/紫杉醇化疗，第二组：二个疗程的卡铂/紫杉醇化疗，再接四个疗程的Ipilimumab联合卡铂/紫杉醇化疗，第三组：六个疗程的卡铂/紫杉醇化疗。
实验结果：免疫相关无进展生存期分别为5.5个月，5.7个月和4.6个月平均无进展生存期分别为4.1个月，5.1个月和4.2个月，平均有效率分别为21%，32%，14%，平均生存期分别为9.7个月，12.2个月和8.3个月，3级以上免疫相关副作用分别为20%，15%和6%（第1组：第2组：第3组）。
2.2 PD-1和PD-L1抑制剂
（1）默克（Merck）的PD-1抑制剂Lambrolizumab（MK-3475）
Phase I Study of Single Agent MK-3475 in Patients With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, and Non-Small Cell Lung Carcinoma
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
http://www.ncbi.nlm.nih.gov/pubmed/23724846
疲劳（22%），皮疹（18%）和瘙痒（14%）是最常见的药物相关不良事件（绝大部分为1/2级）。3/4级不良事件发生率为10%。药物相关肺炎出现了4例，所有的均为1/2级。3/4级的甲状腺机能减退和甲状腺机能亢进各发生1例。
Interim Data for Merck’s MK-3475, an Investigational Anti-PD-1 Immunotherapy, in Previously Treated Patients with Non-Small Cell Lung Cancer to be Presented at 15th World Conference on Lung Cancer
38位患者，单药10mg/kg每三周，客观应答率：irRC->24% RECIST->21%，最常见的AE（发生率16%）：疲劳、皮疹、瘙痒，13%的患者发生1-2级腹泻，1位患者发生药物相关的3级肺水肿。
http://www.yuaigongwu.com/forum.php?mod=viewthread&tid=11868
（2）百时美施贵宝（BMS）的PD-1抑制剂Nivolumab (BMS-936558)
Nivolumab是一种抗PD-1抗体，该抗体可阻断PD-1与PD-L1以及PD-L2相结合。共有129例肺癌患者参加了这项试验，进行了3种不同剂量水平的检测：1mg/kg，3mg/kg和10mg/kg。今年，我们发现，鳞状和非鳞状细胞癌的应答率都非常相似。至少3-mg/kg剂量水平组鳞癌和非鳞癌患者的应答率为20％-25％。去年，鳞癌患者的应答率较高，所以这是包括了2012年欧洲肿瘤内科学会上公布的数据的最新资料。
       我们也公布了生存数据。我们看到，中位总生存期在9个月范围内，如果你观察下不同剂量水平，3-mg/kg剂量水平组似乎表现良好，然而，3-mg/kg剂量组患者数量较少。与1-mg/kg剂量水平组相比，3-mg/kg及10-mg/kg剂量水平组的应答率整体生存率较高。我们也看到2年总生存率在14％左右。这是非常令人兴奋和吸引人的，尤其是这一患者人群中大多数患者既往曾采用至少3或4种疗法治疗。
http://www.yuaigongwu.com/thread-11843-3-1.html
最常见的不良事件，无论因果关系，有乏力，食欲下降，腹泻，恶心，咳嗽，呼吸困难，便秘，呕吐，皮疹，发热，头痛（表S3 - A在补充附录）。常见的治疗相关的不良事件包括疲劳，皮疹，腹泻，皮肤瘙痒，食欲下降，恶心。296例患者中有41例观察到3或4级治疗相关不良事件（14％）。药物相关的严重不良事件发生在32人身上（11％）。
免疫相关副作用，包括肺炎，溃疡性结肠炎，白癜风，肝炎，垂体炎，甲状腺炎。
肝或胃肠道不良事件的处理方式是停药，并在必要糖皮质激素的给药。这些事件（如腹泻33例，其中包括3或4个三级事件和11例患者身上表现的高丙氨酸转氨酶水平，包括两个3或4级事件）在所有情况下是可逆的。内分泌失调的处理是调整治疗。一旦不良事件已成功被控制住，抗PD -1抗体的治疗又重新开始。
药物相关性肺炎的发生有9例（3％） 。 3级或4开发的肺炎3例（1％）。没有发现肺炎的发生和肿瘤类型，剂量水平，或给药次数之间的明显关联。6例患者的早期肺炎治疗通过停药，糖皮质激素给药，或两者同时进行可逆。在3例肺炎中，infliximab, mycophenolate，或二者均用于附加免疫抑制，但是，由于患者数量很小并且结果不一，数目前还不清楚这种治疗的有效性。出现三例与药物相关的因肺炎死亡。
（3）罗氏（Genentech/Roche）的PD-L1抑制剂MPDL3280A
        MPDL3280A是一种基因工程抗体，靶向于肿瘤细胞上的一种名为PD-L1的蛋白，肿瘤利用这种防御机制欺骗机体免疫系统中的T细胞，使之保持失活（inactive）状态。一旦T细胞能够识别肿瘤，它们能够生长和繁殖并更有效地攻击癌细胞。       
在一项由175名肾细胞癌、黑色素瘤、胃癌、肉瘤及淋巴瘤患者参与的Ⅰ期临床试验中，MPDL3280A分三种不同剂量（10,15,20 mg/kg）经静脉注射，每三周给药一次。
Paz-Ares教授说与接受化疗的NSCLC患者还不到10％的有效率相比，这样的有效率相当高了。Soria教授及其团队分析了MPDL3280A在吸烟患者及非吸烟患者中的疗效，发现在吸烟者中的有效率（26％，n=43）高于非吸烟者（10％，n=10）。他解释说同非吸烟患者相比，吸烟患者的病情更为复杂，在基因和分子水平上的变异度更大。Soria教授认为吸烟患者的基因突变率较更高，这可能造成免疫活性增强，因此吸烟患者的免疫系统更易被激活从而攻击癌细胞。
        Soria教授及其团队还利用免疫组化技术（IHC）分析了肿瘤细胞中PDL1的表达，约有半数（n=26）的肿瘤患者存在PD-L1的表达（IHC1,2,3），该组的总有效率为31％（n=8）。在为数不多的高度表达PD-L1（IHC3）的患者（n=6）中有效率高达83％（n=5）。罗氏目前正在开发一种诊断工具，来鉴别哪些患者（如PD-L1蛋白检测阳性）最有可能从MPDL3280A治疗中受益。
        在该项研究中，MPDL3280A耐受性良好，没有出现需要限制剂量的副作用。大多数的不良事件都是短暂性且不严重的。研究中未在任何患者中观察到肺部炎症。罗氏及一些研究人员相信，抗PD-L1药物比抗PD-1药物具有更高的选择性，并可能减少肺脏及其他器官的炎症。
（4）其它：Curetech/Teva的PD-1抑制剂CT-011（黑色素瘤和肾癌2期临床中），阿斯利康（AstraZeneca）旗下Medimmune的PD-L1抑制剂MEDI 4736（1期实体瘤临床中）和百时美施贵宝（BMS）的PD-L1抑制剂BMS-946559（1期实体瘤临床中）。
（5）PD-L1表达与药物疗效的相关性

在旧的或者新的未接受过治疗的由福尔马林固定，石蜡包埋的肿瘤样品上使用小鼠抗人标本PD-L1的单克隆抗体5H1做PD-L1免疫组化分析。PD-L1阳性被定义每一个标本有超过5％的表达，有多个病理样本的患者只要有一个样本达标则被认为是PD-L1阳性。
PD-L1表达检测方法需要改进。
（6）正在进行的临床试验
Study of Nivolumab (BMS-936558) in Combination With Gemcitabine/Cisplatin, Pemetrexed/Cisplatin, Carboplatin/Paclitaxel, Bevacizumab Maintenance, Erlotinib, Ipilimumab or as Monotherapy in First-Line or in Switch Maintenance in Subjects With Stage IIIB/IV Non-small Cell Lung Cancer (NSCLC)
http://www.clinicaltrial.gov/ct2 ... ivolumab&rank=4
2期单药或者联合化疗、单抗、特罗凯一线治疗晚期非小细胞肺癌
临床地点：美国和加拿大

Study of Nivolumab (BMS-936558) in Subjects With Advanced or Metastatic Squamous Cell Non-Small Cell Lung Cancer Who Have Received At Least Two Prior Systemic Regimens
http://www.clinicaltrial.gov/ct2 ... volumab&rank=10
2期单药三线治疗非小细胞鳞癌，单组，无安慰剂
临床地点：美国和欧洲
入组标准：
18岁以上的3B/4期或者复发的非小细胞肺鳞癌病人；
身体评分PS小于2分；
经历了铂类化疗和二线治疗；
有可测量的病灶；
排除标准：
未经治疗的脑转移；
软脑膜转移；
需要激素治疗或者其它免疫治疗的病人；
免疫检查点抑制剂治疗史；
自身免疫性疾病；
间质性肺炎。

Study of BMS-936558 Compared to Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC)
http://www.clinicaltrial.gov/ct2 ... volumab&rank=23
3期单药二线治疗非小细胞鳞癌，双组，对照组为泰素帝
临床地点：美洲、欧洲

A Study Of MPDL3280A in Patients With PD-L1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
http://www.clinicaltrial.gov/ct2 ... PDL3280A&rank=3
2期单药治疗晚期非小细胞肺癌，单组，无安慰剂。
临床地点：美国，欧洲
入组标准：
3B/4期或者复发的非小细胞肺癌病人；
PD-L1表达阳性；
身体评分PS小于2分；
预计生存期大于3个月；
有可测量的病灶；
足够的肝功能和内分泌功能；
排除标准：
3周之内接受了抗肿瘤治疗（指化疗或者激素治疗）；
7天之内接受了抗肿瘤治疗（指激素替代药物或者口服靶向药）；
4周之内接受了临床试验；
组1和组2不接收脑转病人，组3接收治疗过的脑转病人；
软脑膜转移；
控制不了的肿瘤疼痛；
控制不了的高钙血症。

A Study of MPDL3280A Compared With Docetaxel in Patients With Non-Small Cell Lung Cancer After Platinum Failure
http://www.clinicaltrial.gov/ct2 ... PDL3280A&rank=4
2期单药治疗铂类化疗失败的晚期非小细胞肺癌，双组，对照组为泰素帝
临床地点：美国，欧洲，韩国
入组标准：
大于等于18岁的3B/4期或者复发的非小细胞肺癌病人；
代表性的石蜡包块肿瘤组织；
前次铂类化疗在半年内进展；
有可测量的病灶；
身体评分PS小于2分；
排除标准：
活动的或者未处理的脑转移；
自身免疫性疾病史；
非小细胞肺癌之外的原发恶性肿瘤（5年内）；
特发性肺纤维化，药物相关肺炎，机化性肺炎，CT确诊的其它肺炎；
放射性肺炎史（放疗区域内）是允许的；
泰素帝治疗史；
免疫检查点抑制剂治疗史；
活动性肝炎（乙肝和丙肝）。
===============================

这么贵 看来不用期待啦。

贵得不得了，看以后有没有YL了

Ipilimumab in a Phase II trial of melanoma patients with brain metastases
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494644/
Despite historical assumptions that most therapies would not effectively cross an intact blood brain barrier and the poor prognosis of melanoma patients with brain metastases, who de facto have rarely been allowed to participate in trials testing new therapies, objective responses of melanoma brain metastases to interleukin-2 (IL-2)-based approaches have been reported,4-7 suggesting the possibility of an effective control of CNS metastases by T-cell responses to immunomodulatory therapies. Anecdotal reports of ipilimumab responses in the brain raised the possibility that these assumptions should be questioned and that the role of cellular immunotherapy for melanoma brain metastases should be formally evaluated. Although the primary objective of this study was to estimate DCR, safety was also explored considering that initial tumor growth and/or peritumoral inflammatory changes could cause neurologic complications. Despite early concern that ipilimumab-related inflammation and/or edema in brain lesions would increase morbidity, this did not appear to be the case. In fact, there was at least one occasion in which early progressive disease in the CNS was followed by achievement of partial responses - a pattern that has previously been recognized in extracranial disease and is consistent with the mechanism of action and slow kinetics of tumor responses associated with immunomodulatory therapy. The activity of this regimen without an apparent increase in frequency or emergence of unique CNS toxicities was reassuring evidence that, at least for selected patients, treatment with ipilimumab can be administered with similar efficacy and safety in the brain and extracranial sites. While surgery and/or SRT remains the treatment of choice for most patients at the first occurrence of brain metastasis - in particular for large and/or symptomatic single or oligometastatic disease, ipilimumab is a promising therapy for those patients whose disease has recurred following such frontline therapy and/or who present with multiple, small asymptomatic metastases. The potential impact of systemic corticosteroid therapy at the time of initiation of ipilimumab is unknown, but the apparent low level of benefit for such patients (cohort B) in this study suggests that steroid dependence maybe associated with low benefit from ipilimumab.

Ipilimumab in a Phase II trial of melanoma patients with brain metastases.PDF (219.33 KB, 下载次数: 82)

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Hello David. Ipilimumab does not attack tumors itself. It stimulates immune system so that it recognize melanoma and produces lymphocytes that attack tumors. Those lymphocytes can hopefully cross the brain barrier and do the job. At early trials there have been no study references to agree with that statement- however most of them (i think all of them) did not include in the study patients with brain metastases..

However i have come across one study which suggests that ipilimumab has the same level (or at least almost the same) of activity in central nervous system like in extracranial sites.. Here is the link to the study. Look at the conclusion.

Conclusions: Ipi has a similar level of activity in brain and non-CNS lesions. This is the first study to prospectively evaluate Ipi in advanced melanoma pts with brain mets, and the data support its potential use as a treatment for these pts. The analyses are ongoing and final data will be presented.

http://www.melanoma.org/find-sup ... greatly-appreciated

http://meetinglibrary.asco.org/s ... ASCO+Annual+Meeting

Mixed Response to Ipilimumab in a Melanoma P With Brain Meta.PDF (847.02 KB, 下载次数: 125)

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Additional Survival Data on Nivolumab, an Investigational PD-1 Immune Checkpoint Inhibitor, from Lung Cancer Cohort of a Phase 1 Study Presented at 15th World Conference on Lung Cancer


•Across dose cohorts, 42% and 24% of heavily pre-treated patients with non-small cell lung cancer were alive at one and two years, respectively, based on Kaplan-Meier estimates
•Spectrum, frequency and severity of treatment-related adverse events were consistent with those initially reported
•Development program consists of more than 25 studies in broad range of tumors, including seven potentially registrational trials in lung cancer, melanoma and renal cell carcinoma


PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced long-term follow-up results (median follow up of 20.3 months) from the lung cancer cohort (n=129) of the expanded Phase 1 dose-ranging study (003) of nivolumab, an investigational PD-1 immune checkpoint inhibitor. Results showed sustained activity in heavily pre-treated patients with non-small-cell lung cancer (NSCLC) as defined by one- and two-year survival rates of 42% and 24%, respectively, across dose cohorts. These data, which are based on Kaplan-Meier estimates, will be presented on October 29 at the World Conference on Lung Cancer (Abstract # MO18.03).


“Our goal with immuno-oncology is to change survival expectations and the way patients live with cancer,” said Michael Giordano, senior vice president, Head of Development, Oncology & Immunology, Bristol-Myers Squibb. “These are encouraging Phase 1 results from the expanded cohort of patients with lung cancer, the leading cause of cancer deaths globally, and we are seeking to confirm these early data in ongoing Phase 3 trials.”


“Lung cancer is very difficult to treat and there continues to be a high unmet medical need for these patients, especially those who have received multiple treatments,” added Dr. David Spigel, program director of Lung Cancer at Sarah Cannon Research Institute and Study 003 investigator. “With nivolumab, we are investigating an approach to treating lung cancer that is designed to work with the body’s own immune system, and these are encouraging Phase 1 results that support further investigation in larger scale trials.”


Study 003 Results


This analysis is reflective of 129 NSCLC patients, including both squamous and non-squamous histologies. All patients had at least one therapy prior to nivolumab and 54% received three or more therapies prior to nivolumab. Across dose cohorts, the one- and two-year survival rates were 42% and 24%, respectively, based on Kaplan-Meier estimates, and median overall survival (mOS) was 9.9 months. In all treated patients, the objective response rate (ORR) was 17%, as measured by RECIST criteria. An analysis of the 129 NSCLC patients in this study by select patient characteristics demonstrated that nivolumab had activity across a broad range of patients, including those with mutations in key signaling pathways in lung cancer such as EGFR and KRAS.


Data presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting, with all patients having greater than or equal to one year of follow up, demonstrated a spectrum, frequency and severity of treatment-related adverse events (AEs) that were consistent with those initially reported in the study in 2012. As reported at ASCO 2013, common drug-related AEs included fatigue, decreased appetite, diarrhea, nausea, constipation, cough and dyspnea. Drug-related select AEs with potential immunologic etiologies, defined as adverse events that may require more frequent monitoring and/or unique intervention, included rash, diarrhea and pruritus.


About Study 003


Study 003 is a Phase 1 study (n=306) evaluating the safety, antitumor activity and pharmacokinetics of nivolumab in patients with NSCLC (n=129), advanced melanoma (n=107), renal cell carcinoma (n=34), castration-resistant prostate cancer (n=17) and colorectal cancer (n=19). Based on an amendment to the protocol, patients were followed-up for survival.


Eligible patients were administered nivolumab as an intravenous infusion every 2 weeks of each 8-week treatment cycle. Cohorts of three to six patients per dose level (0.1, 0.3, 1.0, 3.0 or 10 mg/kg) were enrolled sequentially. Patients continued treatment ≤2 years (maximum of 12 cycles; 4 doses per 8-week cycle), unless they experienced complete response, unacceptable toxicity, progressive disease or withdrew consent. In clinically stable patients, treatment could be continued beyond apparent initial disease progression until confirmed progression, as defined by proposed immune response criteria. Patients with stable disease or an ongoing objective response (OR) at the completion of treatment were followed for ≤1 year and offered retreatment for one additional year if their disease progressed. OR was defined as complete or partial response.

这系列也是我最关注的。。可是能想象价格会非常的高，也不太可能找到便宜的替代品。。

这数据让我对现行PD-L1检测无信心
Yervoy治脑转令人兴奋
继续关注，马兄弟辛苦了