医药魔方 / 最新资讯 / 正文

肿瘤免疫疗法2.0时代,如何让免疫检查点抑制剂更有效?

偶数 偶数 来源:医药魔方Pro
2019-01-08
免疫检查点
原文

2013年,《科学》杂志将癌症免疫疗法评为“年度最重大突破”。癌症治疗迎来了变革,从之前着眼于肿瘤细胞本身,到现在开启针对免疫系统的新疗法,癌症治疗思路发生了巨大变化。

 

2018年,诺贝尔生理学或医学奖分别授予两位研究人员:日本京都大学Tasuku Honjo博士和安德森癌症中心James Allison博士。

 

近日,国际顶级医学期刊JAMA回顾了过去几年我们在癌症免疫治疗中取得的成果及存在的困惑,并对未来可能的研究方向进行了展望。用作者M.J. Friedrich的话来说,免疫治疗已经进入了2.0时代。

 

1、免疫治疗2.0时代:成功&难点

 

日本京都大学Tasuku Honjo博士和安德森癌症中心James Allison博士的获奖源于分别发现了两个免疫检查点通路,这两个通路会抑制CD8 + T细胞,防止其破坏癌细胞。


20世纪90年代中期,Allison证明:阻断CTLA-4蛋白(细胞毒性T淋巴细胞蛋白4)可以缩小小鼠的肿瘤。大约在同一时间,Honjo发现了第二个免疫检查点通路,即PD-1(程序性细胞死亡蛋白)通路。活化的T细胞表面含有PD-1蛋白。癌细胞会用自己表面的配体和PD-1蛋白结合,使得T细胞的活性受到抑制。



这些免疫检查点通路最初是为了防止T细胞攻击健康组织,但是却被肿瘤细胞利用,逃避T细胞的围捕。这些研究促使科学家开始了免疫检查点抑制剂的研发。

 

现有的免疫检查点抑制剂包括抗PD-1单克隆抗体、抗PD-L1单克隆抗体以及抗CTLA-4单克隆抗体等。

 

代表性的抗PD-1单克隆抗体包括pembrolizumab和nivolumab。两者都与T细胞上的PD-1蛋白结合,并阻止其与癌细胞表面的配体蛋白PD-L1(程序性细胞死亡配体)结合,从而使癌细胞暴露在免疫系统的视野中。其他检查点抑制剂,例如atezolizumab,通过靶向癌细胞表面的配体PD-L1实现相同的效果。CTLA-4抗体,包括ipilimumab,通过类似于抗PD-1 / PD-L1的方式起作用。T细胞的激活依赖于第一个信号(抗原/抗体复合物形成)和第二信号(B7介导的活化信号)双活化,而CTLA4与B7结合可抑制T细胞的活化。靶向免疫治疗药物Ipilimumab正好可以阻断CT-LA4与B7的结合,去除免疫抑制从而调动特异性抗肿瘤免疫反应。这些免疫检查点抑制剂以及其他几种抑制剂现已获得美国FDA的批准。

 

尽管这些免疫检查点抑制剂具有巨大的潜力,但目前仅能对某些特定类型的癌症起作用,诸如黑素瘤、肺癌、肾细胞癌和膀胱癌,以及具有高突变负荷的微卫星不稳定性的癌症。甚至在这些肿瘤类型中,也并非所有肿瘤都对检查点抑制剂有反应。


因此,摆在研究人员面前的有两大难点:1)如何才能使用才能使免疫检查点抑制剂的功效发挥到最大,并且将毒性降到最低;2)如何将免疫检查点抑制剂的应用扩大到更广泛的癌症类型。


2、用于预测疗效的生物标志物:CD8 +T细胞浸润和肿瘤突变负荷

 

目前正在进行的单药和组合治疗的免疫检查点抑制剂临床试验将近2000项。


为了增强免疫疗法的功效,许多试验将CTLA-4和PD-1 / PD-L1的免疫检查点抑制剂联合使用。尽管这种组合疗法通常比单一疗法更有效,但其带来的不良事件风险也同样不可小觑。医学界迫切需要可靠的生物标志物来筛选出适合单药和组合治疗的患者。

 

安德森癌症中心的Padmanee Sharma博士及其丈夫 Allison致力于开发和改进检查点抑制剂多年。她正在进行一项新的研究,以评估肿瘤中CD8 + T细胞浸润是否可以作为生物标志物,预测免疫检查点抑制剂的疗效。

 

这项研究的前提是高CD8 +T细胞浸润的“热”肿瘤将对诸如nivolumab这样的PD-1抑制剂产生回应,而低水平CD8 + T细胞的“冷”肿瘤可能需要CTLA-4抑制剂额外助力,使T细胞进入肿瘤。基于这一前提,Sharma博士将志愿者分成两组,分别使用nivolumab单一疗法或nivolumab和ipilimumab组合疗法,分组原则取决于志愿者的肿瘤中CD8 + T细胞浸润是高还是低。

 

临床试验中涉及了所有类型的晚期转移性癌症患者。Sharma及其同事假设,所有实体肿瘤(甚至那些像胰腺和前列腺癌一样被认为是“冷”的实体肿瘤)中有一定比例可能具有高CD8 + T细胞的特性,这可能使它们对检查点阻断有反应。


目前由FDA评估的另一种生物标志物是肿瘤突变负荷(TMB)。纪念斯隆·凯特琳癌症中心的Matthew Hellmann博士表示,肿瘤中的每个突变都有可能产生“新抗原”,这些“新抗原”可以作为免疫系统的“警示灯”,提醒它注意癌细胞入侵。


几年前,Hellmann及其同事证明,对于TMB较高的非小细胞肺癌患者,使用pembrolizumab治疗效果良好。Hellmann表示,“此后,在研究的大多数癌症类型中均发现了高TMB和免疫检查点抑制剂反应之间的正相关性。”


这种情况的一个主要例子可见于由错配修复基因缺乏引起遗传病的患者,这种错配修复基因缺乏还会导致高微卫星不稳定性肿瘤的发展。2017年,pembrolizumab获得FDA批准用于高微卫星不稳定性肿瘤,无论癌症的起源位置在哪儿。这是FDA首次基于生物标志物而非单一肿瘤适应症批准。


但是,并没有哪个生物标志物是完美的。例如,用于检测高PD-L1肿瘤表达的4种不同的免疫组织化学测试已经获得FDA批准用于某些癌症适应症(包括非小细胞肺癌),但是PD-L1表达并不总是能准确地预测哪些患者将对免疫检查点抑制剂产生回应或者不产生回应。


Hellmann指出,“综合考虑,各种生物标记物可能从不同角度预测疗效。”


3、肠道微生物作为生物标志物和调节剂

 

据休斯顿,芝加哥和法国研究人员最近的几项研究显示,肠道微生物组的多样性和组成是影响免疫检查点抑制剂反应的另一个因素。研究人员现在已经开始在研究使用肠道微生物作为检查点阻断反应的生物标志物和调节剂。


安德森癌症中心的Jennifer Wargo博士将和帕克研究所以及Seres Therapeutics公司合作,开展I期临床试验,探索这两种可能性。该研究将在开始抗PD-1治疗前将患有转移性黑色素瘤的患者随机分配至使用3种疗法中的1种:含有来自抗PD-1应答者的粪便微生物群的口服药片; 含有特定微生物混合物(模仿抗PD-1应答者中发现的微生物成分)的口服药片或安慰剂。


在另一项II期试验中,匹兹堡大学的Hassane Zarour博士正在研究长期抗PD-1应答者的粪便微生物群移植是否能改善PD-1抑制剂对于抵抗PD-1黑色素瘤患者的疗效。


与Wargo研究团队类似,Zarour及其合作者的研究目的也是为了确定哪种特定的微生物群可以调节对免疫检查点抑制剂的反应。


4、打破限制疗效的“天花板”

 

贝塞斯达NCI泌尿生殖系统恶性肿瘤分部主任James Gulley博士表示,“对免疫检查点抑制剂产生反应,需要使T细胞进入肿瘤微环境中。如果T细胞早已不在肿瘤微环境中,无论如何也要将T细胞置于肿瘤微环境中。”许多肿瘤逃避T细胞浸润,科学家们正在探索各种方法来解决这个问题。


阻止T细胞进入肿瘤微环境的一个分子标记是转化生长因子β(TGF-β),这种细胞因子具有很多功能,其中就包括免疫抑制。为了克服这一障碍,Gulley一直在对M7824进行研究。M7824就是PD-L1的增强版,能同时拮抗TGF-β与PD-L1,两个系统同时起效又具有协同作用。


Gulley及其团队已经开始了M7824用于转移性去势抵抗性前列腺癌患者的I期和II期试验,转移性去势抵抗性前列腺癌是一种冷肿瘤。这项新型试验设计加速了针对5种不同免疫靶点的4种不同实验试剂的评价。Gulley表示,“如果我们在后续的II期研究中单独研究每种药物,那就需要很长时间。”


在这项试验中,Gulley研发团队设置了3个研究组,3个研究组的入组将依次推进,在前一研究组中使用的药物组合的安全性得到证实后,随后一个研究组将添加新的免疫疗法制剂。所有患者都使用了M7824治疗。


“这是一种适应性试验设计,我们不断推进,添加另一种药物,直到我们得到明确的临床信号,”Gulley说。


另一种创新方法是使用CD40抗体疗法来激发免疫系统并使肿瘤对免疫检查点抑制剂敏感。宾夕法尼亚大学艾伯拉姆森癌症中心主任Robert Vonderheide博士表示,其实验室数据表明,CD40可以作为一种“转换器”,将无法产生足够的免疫反应的冷肿瘤转化为可以产生免疫反应的热肿瘤。CD40抗体正是打开此开关的激动剂。另外,还有其他科学家的实验数据予以佐证。


Vonderheide正在和帕克研究所合作开展Ib期和II期临床试验,研究抗CD40抗体是否可以改善胰腺癌患者的免疫检查点阻断效果。胰腺癌是对免疫疗法最不“感冒”的一种。这些患者将被随机分配接受抗CD40抗体,nivolumab或抗CD40抗体和nivolumab组合。另外,在这个过程中,之前没有接受过转移性疾病治疗的所有患者还会进行标准化疗。


另外,测试抗CD40抗体与nivolumab的组合用于检查点阻断无效的转移性黑素瘤和肺癌患者的临床试验也在有条不紊的进行。科学家希望即使在最难治的癌症中,这种方法也会起效。


Vonderheide,“我们用这些方法试图打破免疫检查点抑制剂可以实现的“玻璃天花板。”


5、免疫检查点抑制剂用于早期肿瘤


研究人员也正在研究早期癌症使用免疫检查点抑制剂的效果,科学家认为早期肿瘤可能尚未产生针对免疫攻击的良好防御,所以免疫检查点抑制剂用在早期肿瘤上可能反应更好。


约翰霍普金斯大学医学院Bloomberg-Kimmel癌症免疫疗法研究所的Suzanne Topalian博士指出,去年,nivolumab已经获得FDA批准用于黑色素瘤患者手术切除后淋巴结转移的辅助治疗。


Topalian和一些其他科学家也在积极探索免疫检查点抑制剂对于各种类型癌症的新辅助治疗中的应用。这次免疫检查点抑制剂从手术后走向了手术前。Topalian的研究小组最近公布了一项初步研究结果,这项研究首次报道了术前使用nivolumab治疗未经治疗的早期NSCLC患者的数据。


6、安全性值得关注


另外,免疫相关不良事件(irAEs)也是目前科学家正在研究的重点。免疫相关不良事件可能发生于任何器官,但最常见的还是皮肤,胃肠道,内分泌腺和肝脏。


根据临床实践指南,大多数irAE可以通过剂量修改,中断治疗或使用类固醇来减轻。但是,仍然可能发生罕见和不可逆的病症,例如1型糖尿病。加州大学旧金山分校教授、帕克研究所CEO Jeffrey Bluestone博士表示,帕克研究所正在制定一项战略计划,试图解决围绕irAE的一些难题。


Bluestone还表示,这项战略计划的目的是更深入地了解这些不良事件背后的生物学、生物化学和遗传学基础,从而确定哪些患者产生不良事件的风险最大,并设法避免。在此过程中,还可以更深入地了解在没有这些疗法的情况下导致1型糖尿病的原因。


尽管种种障碍限制了检查点抑制剂的疗效和安全性,但Bluestone强调了这些药物彻底改变了癌症治疗。最重要的是,这并不是结束,一切才刚刚开始。

 

原文:Immunotherapy 2.0: Improving the Response to Checkpoint Inhibitors

作者:M.J. Friedrich

机器翻译

In 2013, Science ranked cancer immunotherapy as "the most significant breakthrough of the year".Cancer treatment has ushered in changes, from the previous focus on the tumor cells themselves, to now open new therapies for the immune system, cancer treatment ideas have changed dramatically.

In 2018, the Nobel Prize in Physiology or Medicine was awarded to two researchers, respectively: Dr. Tasuku Honjo, Kyoto University, Japan, and Dr. James Allison, Anderson Cancer Center.

Recently, the top international medical journal JAMA reviewed the achievements and perplexities we have achieved in cancer immunotherapy in the past few years, and looked forward to possible future research directions.With author M.J.In Friedrich's words, immunotherapy has entered 2.Time 0.

1, immunotherapy 2.Time 0: Success & Difficulty

The awards of Dr. Tasuku Honjo and Dr. James Allison of the Anderson Cancer Center at Kyoto University in Japan stem from the discovery of two immune checkpoint pathways that inhibit CD8 + T cells and prevent them from destroying cancer cells.

In the mid-1990s, Allison demonstrated that blocking CTLA-4 protein (cytotoxic T-lymphocyte protein 4) can shrink tumors in mice.Around the same time, Honjo discovered a second immune checkpoint pathway, the PD-1 (programmed cell death protein) pathway.Activated T cells contain PD-1 protein on their surface.Cancer cells bind to the PD-1 protein with their own surface ligands, resulting in inhibition of T cell activity.

These immune checkpoint pathways were originally designed to prevent T cells from attacking healthy tissues, but were exploited by tumor cells to evade the encirclement of T cells.These studies prompted scientists to begin the development of immune checkpoint inhibitors.

Existing immune checkpoint inhibitors include anti-PD-1 monoclonal antibody, anti-PD-L1 monoclonal antibody, and anti-CTLA-4 monoclonal antibody.

Representative anti-PD-1 mAbs include pembrolizumab and nivolumab.Both bind to the PD-1 protein on T cells and prevent it from binding to the ligand protein PD-L1 (programmed cell death ligand) on the surface of cancer cells, thereby exposing the cancer cells to the view of the immune system.Other checkpoint inhibitors, such as atezolizumab, achieve the same effect by targeting PD-L1, a ligand on the surface of cancer cells.CTLA-4 antibodies, including ipilimumab, work in a manner similar to anti-PD-1/PD-L1.Activation of T cells depends on dual activation of the first signal (antigen/antibody complex formation) and the second signal (B7-mediated activation signal), whereas binding of CTLA4 to B7 inhibits T cell activation.Ipilimumab, a targeted immunotherapy drug, can just block the binding of CT-LA4 to B7, remove immunosuppression and mobilize specific anti-tumor immune responses.These immune checkpoint inhibitors, as well as several others, are now approved by the US FDA.

Despite the great potential of these immune checkpoint inhibitors, it is currently only possible to act on certain specific types of cancer, such as melanoma, lung, renal cell, and bladder cancers, as well as cancers with microsatellite instability with high mutational load.Even in these tumor types, not all tumors respond to checkpoint inhibitors.

Therefore, there are two major difficulties facing researchers: 1) how to use it to maximize the efficacy of immune checkpoint inhibitors and minimize toxicity; 2) how to expand the use of immune checkpoint inhibitors to a wider range of cancer types.

2, Biomarkers used to predict efficacy: CD8 + T cell infiltration and tumor mutation burden

There are currently nearly 2,000 clinical trials of immune checkpoint inhibitors for single and combination therapies.

To enhance the efficacy of immunotherapy, many trials have combined immune checkpoint inhibitors of CTLA-4 and PD-1/PD-L1.Although this combination therapy is usually more effective than monotherapy, the risk of adverse events should not be underestimated.There is an urgent need for reliable biomarkers in the medical community to screen out patients suitable for single and combination therapies.

Dr. Padmanee Sharma of the Anderson Cancer Center and her husband Allison worked on developing and improving checkpoint inhibitors for many years.She is conducting a new study to assess whether CD8 + T cell infiltration in tumors can be used as a biomarker to predict the efficacy of immune checkpoint inhibitors.

The premise of this study is that "hot" tumors with high CD8 + T cell infiltration will respond to a PD-1 inhibitor such as nivolumab, whereas "cold" tumors with low levels of CD8 + T cells may require additional help with CTLA-4 inhibitors to allow T cells to enter the tumor.Based on this premise, Dr. Sharma divided the volunteers into two groups using nivolumab monotherapy or nivolumab and ipilimumab combination therapy, and the grouping principle depended on whether the CD8 + T cell infiltration was high or low in the volunteers' tumors.

All types of patients with advanced metastatic cancer are involved in clinical trials.Sharma and colleagues hypothesized that a proportion of all solid tumors (even those considered "cold" like pancreas and prostate cancer) may have the properties of high CD8 + T cells, which may make them responsive to checkpoint blockade.

Another biomarker currently evaluated by the FDA is tumor mutation burden (TMB).Dr. Matthew Hellmann, who commemorates the Sloan Kettering Cancer Center, said that every mutation in the tumor has the potential to produce "new antigens" that can act as "warning lights" for the immune system to alert it to cancer cell invasion.

A few years ago, Hellmann and colleagues demonstrated that treatment with pembrolizumab works well in NSCLC patients with higher TMB.Hellmann said, "Since then, a positive correlation between high TMB and immune checkpoint inhibitor response has been found in most cancer types studied.A prime example of this situation can be found in patients with genetic disease caused by a deficiency of mismatch repair genes, which can also lead to the development of tumors with high microsatellite instability.In 2017, pembrolizumab received FDA approval for high microsatellite instability tumors, regardless of where the cancer originated.This is the first FDA approval based on a biomarker rather than a single tumor indication.

However, no biomarker is perfect.For example, four different immunohistochemical tests for detecting high PD-L1 tumor expression have received FDA approval for certain cancer indications (including non-small cell lung cancer), but PD-L1 expression does not always accurately predict which patients will or will not respond to immune checkpoint inhibitors.

Hellmann states, "Taken together, various biomarkers may predict efficacy from different perspectives."

3, gut microbiota as biomarkers and modulators

According to several recent studies by Houston, Chicago and French researchers, the diversity and composition of the gut microbiome is another factor influencing the response to immune checkpoint inhibitors.Researchers are now beginning to investigate the use of gut microbes as biomarkers and modulators of the checkpoint blockade response.

Dr. Jennifer Wargo at Anderson Cancer Center will collaborate with the Parker Institute and Seres Therapeutics to conduct phase I clinical trials to explore both possibilities.The study will randomize patients with metastatic melanoma to use 1 of 3 therapies before starting anti-PD-1 therapy: oral tablets containing fecal microbiota from anti-PD-1 responders; oral tablets containing a specific mixture of microorganisms (mimicking the microbial components found in anti-PD-1 responders) or placebo.

In another phase II trial, Dr. Hassane Zarour of the University of Pittsburgh is investigating whether fecal microbiota transplantation in long-term anti-PD-1 responders can improve the efficacy of PD-1 inhibitors in patients with resistant PD-1 melanoma.

Similar to the Wargo research team, the aim of the study by Zarour and coworkers was also to determine which specific microbiota could modulate the response to immune checkpoint inhibitors.

4, breaking the "ceiling" that limits efficacy

Dr. James Gulley, Director, Division of Urogenital Malignancies, NCI, Bethesda, said, "Responding to immune checkpoint inhibitors requires T cells to enter the tumor microenvironment.If T cells are no longer in the tumor microenvironment, they must be placed in the tumor microenvironment anyway."Many tumors escape T cell infiltration, and scientists are exploring ways to solve this problem.A molecular marker that prevents T cells from entering the tumor microenvironment is transforming growth factor beta (TGF-β), a cytokine that has many functions, including immunosuppression.To overcome this obstacle, Gulley has been working on M7824.M7824 is an enhanced version of PD-L1 that can antagonize both TGF-β and PD-L1, and both systems have a synergistic effect at the same time.

Gulley and his team have started phase I and II trials of M7824 for patients with metastatic castration-resistant prostate cancer, a cold tumor.This novel experimental design accelerates the evaluation of four different experimental reagents targeting five different immune targets.Gulley said, "If we study each drug separately in a subsequent phase II study, it will take a long time."

In this trial, the Gulley R & D team set up three study groups, the enrollment of the three study groups will be sequentially advanced, and after the safety of the drug combination used in the previous study group is confirmed, a new immunotherapy formulation will be subsequently added by one of the study groups.All patients were treated with M7824.

"This is an adaptive trial design, and we keep advancing, adding another drug until we get a clear clinical signal," Gulley said.

Another innovative approach is to use CD40 antibody therapy to prime the immune system and sensitize tumors to immune checkpoint inhibitors.Dr. Robert Vonderheide, director of the Alberramson Cancer Center at the University of Pennsylvania, said that his laboratory data show that CD40 can be used as a "converter" to convert cold tumors that do not produce enough immune responses into hot tumors that can produce immune responses.The CD40 antibody is the agonist that turns this switch on.In addition, there are experimental data from other scientists to support this.

Vonderheide is collaborating with the Parker Institute in Phase Ib and Phase II clinical trials to investigate whether anti-CD40 antibodies can improve immune checkpoint blockade in patients with pancreatic cancer.Pancreatic cancer is the least "cold" type of immunotherapy.These patients will be randomly assigned to receive anti-CD40 antibody, nivolumab or anti-CD40 antibody and nivolumab combination.In addition, during this process, all patients who have not previously received treatment for metastatic disease will also undergo standard chemotherapy.

In addition, clinical trials testing the combination of anti-CD40 antibodies with nivolumab for metastatic melanoma and lung cancer patients with ineffective checkpoint blockade are also in progress.Scientists hope that this approach will work even in the most difficult cancers.

Vonderheide, "We used these methods to try to break the" glass ceiling that can be achieved by immune checkpoint inhibitors."

5, Immune Checkpoint Inhibitors for Early Tumors

Researchers are also studying the effect of using immune checkpoint inhibitors in early cancers. Scientists believe that early tumors may not have developed a good defense against immune attacks, so immune checkpoint inhibitors may respond better to early tumors.

Dr. Suzanne Topalian of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, noted that last year nivolumab had received FDA approval for the adjuvant treatment of lymph node metastases after surgical resection in melanoma patients.

Topalian and some other scientists are also actively exploring the use of immune checkpoint inhibitors for the neoadjuvant treatment of various types of cancer.The immune checkpoint inhibitor moved from surgery to pre-surgery.Topalian's group recently published the results of a pilot study that reported for the first time data on the preoperative use of nivolumab in patients with untreated early stage NSCLC.

6, safety deserves attention

In addition, immune-related adverse events (irAEs) are also the focus of current research by scientists.Immune-related adverse events may occur in any organ, but most commonly in the skin, gastrointestinal tract, endocrine glands, and liver.

Most irAEs can be mitigated by dose modification, interruption of treatment, or use of steroids according to clinical practice guidelines.However, rare and irreversible conditions such as type 1 diabetes may still occur.Dr. Jeffrey Bluestone, professor at the University of California, San Francisco and CEO of the Parker Institute, said that the Parker Institute is developing a strategic plan to try to solve some of the problems surrounding irAE.

Bluestone also stated that the purpose of this strategic plan is to gain a deeper understanding of the biological, biochemical, and genetic basis behind these adverse events, thereby identifying which patients are at greatest risk of adverse events and trying to avoid them.In the process, a deeper understanding of the causes of type 1 diabetes in the absence of these therapies is also possible.

Although various barriers limit the efficacy and safety of checkpoint inhibitors, Bluestone highlights that these drugs have revolutionized cancer therapy.Above all, it's not over, it's just beginning.

Original: Immunotherapy 2.0: Improve the response to Checkpoint Inhibitors

Author: M.J. Friedrich

扫码实时看更多精彩文章

版权及免责声明 本文由医药魔方原创,版权归医药魔方所有。未经许可,严禁任何媒体或个人以任何形式摘编、改写、复制、转载本文内容。对于恶意侵权行为,医药魔方保留采用法律手段追究的权利。媒体内容及商务合作请联系医药魔方工作人员(微信号:medicube)

魔方微信公众号