免疫检查点抑制剂Immune Checkpoint inhibitor

Novel Immunotherapy Combinations in NSCLC
http://www.onclive.com/peer-exch ... mbinations-in-NSCLC
The CTLA-4 inhibitor ipilimumab showed promising early results in a first-line phase II study for patients with non-small cell lung cancer (NSCLC) in combination with carboplatin plus paclitaxel, explains Everett E. Vokes, MD. In this trial, carboplatin and paclitaxel were administered along with placebo, concurrently with ipilimumab, or with phased ipilimumab after two cycles.

This trial was a proof of principle for checkpoint inhibition in NSCLC, explains Vokes. The phased treatment approach for ipilimumab is being investigated further in a definitive trial based on response rates in the phase II investigation. In this treatment approach, patients initially received two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin.

In addition to anti-CTLA-4 approaches, there is a phase I multiplex study under way that is examining the anti-PD-1 agent nivolumab in various combinations for patients with NSCLC, explains Vokes. One of the arms in this trial will explore nivolumab plus ipilimumab, a combination that demonstrated promising data in melanoma.

The most common adverse events associated with these immunotherapies are rash, diarrhea, nausea, headache, and pruritus, notes Anne S. Tsao, MD. Occasionally, serious adverse events, such as hepatitis, colitis, and fatal pneumonitis may also occur. As a result, vigilance is required when managing these side effects, Tsao notes.

These agents result in very unique immune-related toxicities that may require a multidisciplinary treatment team that includes an endocrinologist, believes Roy S. Herbst, MD, PhD. In general, if properly managed, the overall side effects associated with these agents are well tolerated.

There are currently two ongoing trials comparing nivolumab to docetaxel in patients with squamous and non-squamous metastatic NSCLC, points out Herbst. Also, in addition to treatment as a monotherapy, nivolumab shows potential as a backbone agent for combinations with cytotoxics and targeted therapies.

There is a great deal of potential for combinations with targeted therapies, specifically since the immunotherapies seem to impact not only the tumor cells but also the microenvironment, believes Karen L. Reckamp, MD, MS. Moreover, Vokes notes, the likelihood of achieving a cure increases as you treat patients in earlier stages. As a result, these agents may demonstrate the greatest potential in patients with minimal disease burden.

Anti-PD-L1 MAb or MEDI4736

Programmed cell death ligand 1 (PD-L1) is part of a complex system of receptors and ligands that are involved in controlling T-cell activation. Nonclinical research suggests that tumors can evade immune detection and elimination by expressing PD-L1.

Nonclinical studies of MEDI4736, a human monoclonal antibody directed against PD-L1, have demonstrated its ability to block the interaction between PD-L1 and its receptors, PD-1 and CD80 (PD-1). This blockade may help to overcome the immunosuppressive effects of PD-L1 signaling in anti-tumor T cells.



Abstract LB-158: MEDI4736: Delivering effective blockade of immunosupression to enhance tumour rejection: Monoclonal antibody discovery and preclinical development

Cancerous cells emerge within the body following accumulation of deleterious genetic mutations. These mutations alter the phenotype of a cancer cell marking it as distinct from the surrounding host; an immunological state termed "altered self". These cells, like other non-self entities such as viruses and bacteria, are recognised by the immune system and marked for destruction, a process known as "immune surveillance". B7-H1 expression by tumour cells is believed to aid tumours in evading detection and elimination by the immune system. B7-H1 functions in this respect via several alternative mechanisms including driving exhaustion and anergy of tumour infiltrating T lymphocytes, stimulating secretion of immune repressive cytokines into the tumour micro-environment, stimulating repressive regulatory T cell function and protecting B7-H1 expressing tumour cells from lysis by tumour cell specific cytotoxic T cells.

Using hybridoma technology and high throughput screening MedImmune has identified a series of fully human antibodies specific for human B7-H1. Further characterisation of these antibodies led to the identification of a single high affinity antibody, MEDI 4736, with the ability to relieve B7-H1 mediated suppression of T cell activation in vitro and to enhance sub-optimal T cell activation in a mixed lymphocyte reaction. In vitro testing shows that MEDI 4736 does not trigger non-specific cytokine release in whole blood, and is only able to activate T cells in the context of an active T cell receptor signal.

A surrogate anti-mouse B7-H1 antibody shows significant anti-tumour activity in a syngeneic model when dosed in combination with chemotherapy. Similarly MEDI 4736 is able to inhibit tumour growth in a novel in vivo xenograft model, via a mechanism that is dependent on the presence of tumour specific human T cells.

A Phase I, Open-Label, Multicentre Study to Evaluate the Safety, Tolerability and Pharmacokinetics of MEDI4736 in Japanese Patients With Advanced Solid Tumors
http://clinicaltrials.gov/ct2/show/NCT01938612

A Phase 1 Study to Evaluate MEDI4736
http://clinicaltrials.gov/ct2/show/NCT01693562

A Phase 1b Study of MEDI4736 in Combination With Tremelimumab in Subjects With Advanced Non-small Cell Lung Cancer (D4190C00006)
http://clinicaltrials.gov/ct2/show/NCT02000947

A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab
http://clinicaltrials.gov/ct2/show/NCT01975831

MedImmune strengthens immune-mediated cancer therapy portfolio with acquisition of Amplimmune

AstraZeneca today announced that MedImmune, its global biologics research and development arm, has entered into a definitive agreement to acquire Amplimmune, a privately-held, Maryland, US-based biologics company focused on developing novel therapeutics in cancer immunology.

The acquisition will bolster MedImmune’s oncology pipeline by obtaining multiple early-stage assets for its immune-mediated cancer therapy (IMT-C) portfolio, including AMP-514, an anti-programmed cell death 1 (PD-1) monoclonal antibody (mAb). AMP-514 is currently in late-stage pre-clinical development with the aim of an investigational new drug (IND) filing before the end of 2013. Other Amplimmune assets include multiple preclinical molecules targeting the B7 pathways. MedImmune’s oncology research is focused on IMT-C, a promising therapeutic approach that may lead to durable and prolonged response rates across a range of cancer types. IMT-Cs are being designed to empower the immune system to counteract the tactics employed by cancer cells to avoid detection and attack the body.

Under the terms of the agreement, MedImmune will acquire 100 per cent of Amplimmune’s shares for an initial consideration of $225 million and deferred consideration of up to $275 million based on reaching predetermined development milestones.

“MedImmune’s focus on harnessing the power of the patient’s own immune system to fight cancer will be complemented by Amplimmune’s innovative work in this area. It will allow us to strengthen our arsenal of potential cancer therapies,” said Dr. Bahija Jallal, Executive Vice President, MedImmune. “We are excited to be working with the Amplimmune team to help find new treatments to address areas of unmet medical need.”

MedImmune, with its clinical stage programmes – tremelimumab, anti-OX40 mAb and MEDI-4736 (anti-PD-L1 mAb) - and a robust pre-clinical pipeline, is building one of the most comprehensive programmes in IMT-C. The acquisition of the Amplimmune technology and pipeline significantly strengthens the AstraZeneca and MedImmune portfolio, enabling the pursuit of the most effective data-driven combinations of IMT-C molecules as well as combinations with highly targeted small molecules. Because of the complexity of cancer biology, combination therapies have the potential to be one of the most effective ways of treating this disease.

“Both companies are passionate about developing new cancer therapies for patients and are excited about the potential of immunotherapies. We are pleased to be joining MedImmune, who will work to further advance the pioneering work we’ve been conducting in this area,” said Michael Richman, Amplimmune's President and Chief Executive Officer. “The synergy achieved by combining our pipelines provides an important path towards developing novel immunotherapy products.”

The proposed transaction is subject http://clinicaltrials.gov/ct2/show/NCT02013804to customary regulatory approvals and is expected to close in the third quarter of 2013.



AMP-514

The PD-1 pathway is clinically validated and an important target for the treatment of cancer, as well as potentially infection. Amplimmune is leveraging its translational capabilities to rapidly advance a unique and mechanistically differentiated anti-PD-1 antibody. By combining its immunology expertise along with a comprehensive biologics development infrastructure, Amplimmune is well positioned to develop a best-in-class anti-PD-1 antibody and move this program efficiently through clinical proof-of-mechanism. An IND filing for the first candidate is expected in 2013. This program is currently unpartnered.

http://www.amplimmune.com/proddev.html


A Phase 1 Study to Evaluate AMP-514
http://clinicaltrials.gov/ct2/show/NCT02013804

Merck Collaborates with GlaxoSmithKline to Evaluate Novel Combination Regimen for Advanced Renal Cell Carcinoma

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the initiation of a clinical trial to evaluate the combination of the company’s investigational anti-PD-1 immunotherapy, MK-3475, and GlaxoSmithKline’s orally administered kinase inhibitor, pazopanib, in advanced renal cell carcinoma.

“Collaborations like this are central to Merck’s strategy to evaluate the potential of MK-3475 for the treatment of cancer,” said Iain Dukes, senior vice president, Licensing and External Scientific Affairs, Merck Research Laboratories. “We look forward to initiating further collaborations to investigate MK-3475 in combination with other anti-cancer agents across a range of tumor types.”

Merck and GlaxoSmithKline entered a collaboration to study MK-3475 with pazopanib and other agents in the GlaxoSmithKline portfolio in the future. This Phase I/II clinical trial is designed to evaluate the safety and efficacy of a combination of MK-3475 and pazopanib in treatment naïve patients with advanced renal cell carcinoma. Further details of the collaboration were not disclosed.

Update on immune checkpoint inhibitors in lung cancer


Abstract
BACKGROUND: The immune checkpoint proteins, including the B7/CD28 receptor superfamily, have become increasingly important targets for pharmacologic blockade. Several classes of new agents have impressive clinical activity, and their eventual approval for treatment of lung cancer seems likely.

METHODS: This article discusses the current development of these agents, including the CTLA-4, PD-1, and PD-L1 inhibitory pathways, killer immunoglobulin receptor (KIR ) inhibition, and other checkpoint proteins.

RESULTS: Ipilimumab in combination with chemotherapy has exhibited encouraging results in small-cell and non-small-cell lung cancer alike. Reported phase I trials of the monoclonal antibodies nivolumab, MK-3475, MEDI4736, and MPDL3280A are demonstrating durable overall radiological response rates in the 20% to 25% range in lung cancer. This exceptional activity includes squamous lung cancers, a population historically bereft of significant therapeutic advances. Retrospective examination of tumor PD-L1 expression suggests that PD-L1 may eventually be evaluable as a predictive biomarker. Dual checkpoint blockade strategies, such as those combining anti-CTLA-4, anti-LAG-3, or anti-KIR, are being tested to increase the proportion and durability of tumor responses. Examination of acquired immune resistance and post-immunotherapy relapse strategies are underway.

CONCLUSIONS: These emerging antibodies hold great potential for the systemic control of epithelial cancers such as lung cancer.



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A Randomized Study of Nivolumab or Nivolumab Combined With Ipilimumab Versus Bevacizumab in Adult Subjects With Recurrent Glioblastoma(GBM)(CheckMate 143)

http://clinicaltrials.gov/show/NCT02017717

贵的不是一般呀，求大神们赶紧出YL吧！

5 Key Points on Immune Checkpoint Inhibitors for Lung Cancer: Game Changer or Just Leveling Up?
http://cancergrace.org/lung/2014 ... munotherapy-for-lc/
Just last week, I ranked the development of immunotherapies as the leading development in lung cancer in 2013. I don’t consider 2013 to be the clear turning point for immunotherapies in lung cancer: they have been the subject of interest and research for many years, and ASCO 2012 really marks their breakout from niche idea to more widespread credibility. But if 2012 was the real launchpad, 2013 saw the rocket really take off. The question is where is it really going?

I’ve had the opportunity to put more than a dozen patients on immune checkpoint inhibitors (anti-PD1, anti-PDL1) over the past 12-18 months, and in that time I’ve been able to combine my real life clinical experience with more data from other agents. At this point, I’d like to offer some preliminary projections on what we should expect from immunotherapies.

1) They work very well for a few patients. As is seemingly always the case, the first patient you try on a new therapy does remarkably well, and that has been the case with me putting my first patient on the trial of nivolumab, the anti-PD1 therapy from BMS, vs. Taxotere (docetaxel) as second line therapy. Clinically, her symptoms improved so quickly I had trouble believing it was from the treatment (within days), and the response has lasted a year and is still ongoing.

2) Immunotherapies are not going to replace conventional chemotherapy and fundamentally overhaul all lung cancer treatment. I mentioned that this phenomenal response was in my first patient, but I haven’t seen that kind of benefit in patients after my first. The phase I/II trial results we’ve seen thus far have indicated a response rate of 20-25% for immune checkpoint inhibitors, but frankly, I expect the objective response rate in the larger phase III studies with nivolumab, for instance,  to be below 15%, and very possibly below 10%. That’s just the pattern of what happens with drugs that go from very limited testing in one or a few centers to widespread testing in a multicenter national or international trial. The currently plain Jane combination of carboplatin and Taxol (paclitaxel) had a response rate as high as 50% reported in initial phase II testing for first line treatment of advanced NSCLC, and now we know to expect more like 20-25% at most in a big phase III experience. Second line Taxotere (docetaxel) had a response rate initially reported at 25% in phase II research, then settled in at the 5-10% response rate we have seen in study after study over the past decade.

With broad study, I expect that we’ll find that immune checkpoint inhibitors are very far from a replacement for current standard therapies. The 25-35% response rate we typically see from standard chemotherapy +/- Avastin (bevacizumab) in the first line setting is likely to eclipse the response rate with a single immune checkpoint inhibitor given in a broad, unselected population.

3) Immune checkpoint inhibitors can lead to prolonged responses. A major appeal of immunotherapies is that they can lead to very sustained responses.  As I alluded to earlier, my best responding patient on nivolumab is continuing to do well for a year after the start of treatment.  Dr. Julie Brahmer reported that many of the responding patients on her initial landmark study presented at ASCO 2012 continue to respond as of ASCO 2013. We don’t know how long they will respond, but it appears that immunotherapies do hold a realistic promise of a treatment that can lead to a benefit that is at least in the range of what we see with targeted therapies like EGFR and ALK inhibitors in patients with these respective driver mutations, well exceeding the typical duration of benefit from standard chemotherapy.

We don’t know how long their benefit might last, but it looks as if it’s feasible to see years of benefit. My best responding patient needed to come off of treatment for a couple of months due to side effects (more on this below), during which time her scans continued to look good, with no progression of her cancer, which had previously progressed at a rapid pace through standard chemotherapy, so it isn’t just a very indolent cancer. The folks from BMS informed me that in some of their trials of nivolumab in other cancer settings, patients continued to do very well for a long time after a fixed duration of treatment, without further infusions of the inhibitory antibody.  This pattern suggests that the immune system continues to exert an inhibitory effect on the cancer, so it may well be possible for some patients to do very well with immune checkpoint inhibitors for a very long time (how long? indefinitely? we don’t know yet) without requiring ongoing infusions.

4) We are still working on identifying which patients are the major beneficiaries of these treatments. While the early nivolumab research and subsequent phase III trials do not restrict by expression of PDL1 protein (overexpressed in somewhere in the range of 40-50% of people with advanced NSCLC), some work with MPDL3280A, an anti-PDL1 immune checkpoint inhibitor from Genentech/Roche suggests that response rates are particularly high for those with PDL1 overexpression (~80% vs. <20% in those without it). Some studies being conducted with various immune checkpoint inhibitors are now restricting enrollment to those patients with PDL1 overexpression, though there isn’t any standard assay for defining this as a binary result of high expression or not.  Presumably, this is because the companies want to get a fast approval for a drug if it shows a response rate over 50% in a defined population. That may work, but it’s clear that the potential benefit of these agents is not restricted to just a subgroup with any biomarker being used right now.

There have also been some early findings that efficacy of immune checkpoint inhibitors may be particularly favorable in those with squamous NSCLC and smokers or ex-smokers (as opposed to never-smokers who are far more likely to have a cancer harboring a driver mutation like EGFR, ALK, or ROS1), but we definitely need to learn more about these preliminary leads before using them to guide enrollment or treatment recommendations.

5) Immunotherapies are not non-toxic. They have different side effects than standard chemotherapy, but it would be a grave mistake to oversimplify and presume that immune-based treatments, including immune checkpoint inhibitors, will let us treat cancer effectively while sparing the patient treatment-related complications.

We’ll require a careful assessment of the results from a large pool of patients to see what patterns emerge, but my patient sailing along on nivolumab had a scary period of months in which she was experiencing very high fevers, up to 104F, and low blood pressure that landed her briefly in an ICU. She had persistently low lymphocyte counts that could leave her vulnerable to some infections.  She developed newly enlarged lymph nodes in her chest and under her arms that were biopsied to determine whether they represented progressing cancer, a new lymphoma, or some other process, and the biopsy showed what seemed to be an overly dramatic immune response killing off the nodes. She’s doing remarkably better since I worked with BMS and followed a recommendation from one of their immunotherapy experts and put her on Celebrex (celecoxib), but I’ve had several conversations with other colleagues who have treated a growing number of patients with immune checkpoint inhibitors and who have developed a greater respect for the potentially significant curve ball side effects we might see with them. Pneumonitis has been reported in up to about 3% of patients receiving nivolumab (seemingly more prevalent among those with squamous NSCLC), and we may well see other significant auto-immune mediated side effects as we learn more.  

In fact, most of my patients haven’t had significant side effects from immune checkpoint inhibitors, but we can’t presume that immunotherapies will represent a freebie in terms of effective cancer treatment that is free of side effects.



I’m very happy to see these agents tested not only in previously treated patients with advanced NSCLC but also in other settings, alone or in combinations. I stand by my earlier designation of the momentum of immunotherapies as the most significant development in lung cancer over the past year, but we won’t move to a new era in which our world of treatments before immunotherapy is considered the dark ages of cancer care. As much as I believe that not one but several immune-based treatments will likely find their way into treatment of lung cancer, they will add to but not fundamentally replace everything that came before them.

免疫检查点抑制剂治疗肺癌的5个要点：革命性的新药还是仅仅改良？
        就在上周，我认为免疫治疗处于2013年肺癌治疗进展的领先位置。我不认为2013年是肺癌免疫治疗的一个明显转折点：免疫治疗已经研究了许多年，ASCO 2012已经公布了它们的效果，2013年是导弹发射。现在的问题是免疫检查点抑制剂存在哪些要点？
1) 少数病人取得了良好的疗效.
我的一个病人参加百时得施贵宝nivolumab （PD1抑制剂）Vs泰素帝的非小细胞肺癌二线治疗临床试验，令人难以置信的是，他几天就显效，症状明显改善。无进展时间超过了一年，持续到今天。
2) 免疫检查点抑制剂并不准备取代传统的化疗和整个治疗模式.
我前面提到的病人是我的第一个参加这个临床试验的病人，但我的其它参加临床的病人们没有观察到这样的良好效果。Nivolumab的1/2期临床结果显示有效缓解率是 20-25%，但坦率地说，我估计Nivolumab3期大型临床的有效缓解率会低于15%，非常有可能是低于10%。这在药物临床中很常见。例如紫杉醇联合卡铂2期临床的有效缓解率是50%，到了3期，有效缓解率平均只有20-25%。泰素帝的单药2线有效缓解率在2期临床是25%，但过去10年它的平均有效缓解率只有5-10%。
        因此我认为免疫检查点抑制剂要取代现有的治疗药物还需要很长的路要走。对于未经选择的大样本临床，阿瓦斯汀联合标准化疗药物一线有效缓解率（25-35%）是免疫检查点抑制剂单药治疗难以超越的。
3) 免疫检查点抑制剂的响应时间很长。
免疫检查点抑制剂最吸引人的地方是它有效响应时间很持久。我的一个病人应用Nivolumab长达一年以上，至今仍有效。Julie Brahmer 医生报道她的一个临床中，在ASCO2012里公布的很多有效响应病人到ASCO2013仍然有效。. 我们不知道他们还能响应多久，但看上去免疫检查点抑制剂至少能达到EGFR抑制剂和ALK抑制剂的水平，超过标准化疗药物的无进展时间。我们不知道他们的受益时间是多久，但看上去至少是一年。我那个效果最好的病人因为严重的副作用中断治疗几个月，空窗期间，他的影像检查是稳定的，而他并不是一个肿瘤缓慢进展的病人，之前他化疗后迅速进展。施贵宝公司的一人说Nivolumab治疗其它类型的肿瘤，有些病人几个疗程后有非常好而且持久的效果，即使不再注射Nivolumab。 这说明病人不再注射Nivolumab后，体内改造过的免疫系统仍可能持久有效，然而这时间是多久仍是未知数。
4) 我们仍在努力确定哪些患者是这些治疗的主要受益者。
Nivolumab的早期临床和3期临床没有对病人的PDL1表达（晚期非小细胞肺癌病人中有40-50%存在PDL1高表达）有特别要求。 罗氏/基因泰克的PDL1抑制剂MPDL3280A 的临床针对PDL1表达情况做了一些研究，结果显示这些具有PDL1高表达的病人会有较高的有效缓解率（(~80%)，而PDL1低表达的病人的有效缓解率小于20%。尽管目前还没有一个关于PDL1表达的可靠检测标准，一些免疫检查点抑制剂的临床试验已经对入组病人的PDL1表达情况做了限定。很可能，药厂们认为一个药物如果在特定人群里能取得超过50%的有效率缓解率，将更快地得到批准。这也许能行，但显然这些药物的潜在好处并不局限于这个生物标志物亚组。以及，前期结果显示免疫检查点抑制剂的有效缓解率更偏向于非小细胞鳞癌病人，或者有抽烟史的病人。但我们必须在确定入组条件或者提出治疗建议前对这些初步的线索进行进一步研究。
5) 免疫检查点抑制剂并非无副作用。
免疫检查点抑制剂的副作用与标准化疗不同，但如果轻视它们的副作用，或者认为免疫治疗（包括免疫检查点抑制剂）的副作用是微不足道的，将造成严重的后果。
我们需要仔细评估大样本的临床数据来找出相似的模式。我的一个病人使用Nivolumab期间经历了可怕的几个月，40度高烧、低血压，甚至进了ICU，长期淋巴细胞偏低，经常感染。她的胸腔和腋下几个淋巴结肿大了，穿刺结果显示，这些并不是肿瘤转移，而是因为免疫响应过于强烈。我听从了施贵宝公司的一位免疫专家的建议，给她上了西乐葆，她感觉好多了。我与其他参与临床的同事几次交流后，发现可能会有一些潜在的明显的毒性副作用。接受Nivolumab治疗的病人中约有3%得了肺炎（鳞癌病人比例更高），其它异常自身免疫反应介导的副作用仍在关注中。
        事实上，绝大多病人使用免疫检查点抑制剂没有产生明显的副作用，但我们还不能认为免疫检查点抑制剂是一种低毒高效的治疗方法。