New melanoma antibody drug Keytruda (pembrolizumab / MK-3475) demonstrates utility in advanced lung and bladder cancer patientsAntibodies, such as Keytruda, that target T-cell inhibitory / checkpoint pathways are emerging as an important class of cancer therapeutics. Keytruda along with Opdivo and Yervoy are the first examples of these next generation immunomodulatory therapies which target inhibitory pathways; PD-1 and CTLA-4 respectively. Alternative inhibitory pathways currently being developed include the B7-H4, B7-H3, TIM-3, LAG-3, VISTA, while antibodies targeting co-stimulatory pathways are also actively being pursued (e.g. CD27, CD137, GITR, OX40).
Preclinical research as well as preliminary data from clinical studies suggests that targeting these immune system checkpoint pathways can induce long term / durable clinical responses in patients suffering from a variety of tumour types other than melanoma, including, lung, bladder, and colon cancer.
Other cancers that may benefit from these treatments based on their high PD-L1 cell surface expression levels include:
- Glioblastoma/mixed glioma
- Nasopharyngeal cancer
- Hepatocellular carcinoma
- Urothelial cancer
- Multiple myeloma
- Ovarian cancer
- Gastric carcinoma
- Esophageal cancer
- Pancreatic cancer
- Breast cancer
- Prostate cancers – The suggestion that prostate cancers may benefit from this therapy comes with a caveat though, given that PD-L1 has only been reported in approximately 1% or less of prostate tumour samples. However, one study found that although prostate cancer lesions were PD-L1-negative (i.e. do not express this protein on their cell surface), they were surrounded by clusters of PD-1-positive and PD-L1-positive immune cells (lymphocytes). This observation fits well with the notion that low PD-L1 expression levels on tumour cells do not automatically preclude a positive response to PD-1 antibody treatment (as per clinical trial observations in other types of cancer).
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The therapeutic targeting of a significant but 'forgotten' Hallmark of Cancer that is making a comeback - Immune Evasion and InhibitionMany people are likely to be familiar with the 6 Hallmarks of Cancer as eloquently described in a 2000 publication by Hanahan & Weinberg. In their often cited paper they describe these six hallmarks of cancer as six biological capabilities which have been acquired by the tumour and / or metastases during the development of cancer. In essence it provides the framework for categorising a complex disease such as cancer in a more rational manner.
These six hallmarks of cancer include the following:
- sustaining proliferative signaling
- evading growth suppressors
- resisting cell death
- enabling replicative immortality
- inducing angiogenesis
- activating invasion and metastasis
Given the heterogeneous and complex nature of tumour microenvironments, which are invariably laden with various types of paralysed immune cells (e.g. T-cells, macrophages, etc...), recognition of acquired tumour Immune Evasion and Inhibition capabilities (as a hallmark of cancer) seemed like a certain eventuality by those involved in immunology, even then. Fast forward 15 years from the time Hanahan and Weinberg wrote their paper and it is clear that science and pharma have collectively embraced the development of cancer therapeutics targeting immunological aspects at the molecular level of tumour development. In fact, some astonishing results in end-stage cancer patients were reported in 2014 – Keytruda (PD-1 antibody) is just one example of many promising next generation cancer treatments aimed at curbing the Immune Evasion and Inhibition capabilities of cancer.
However, throughout its history, and despite several successes, immunotherapy has faced a lot of skepticism (e.g. Coley's Toxin or Mixed Bacterial Vaccines). Nevertheless, in the past few years it has started to gather momentum, primarily as a result of the vastly improved understanding, the continued characterisation of immune checkpoints and the success of next generation immunotherapies targeting those checkpoints. In addition, most physicians and scientists now agree that cancer cells have the acquired ability to evade the patient's immune response and that it ultimately manifests itself as uncontrolled proliferation of tumours (and metastases) as well as resistance to cancer therapies. This has resulted in the recognition of the hugely important role the immune system can play (with the help of targeted immunotherapies) in bringing about a durable response or long term complete remission.
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FDA approved immunotherapy offers vastly improved outlook for patients suffering from the deadliest form of skin cancerUp until very recently (September 4, 2014 to be precise), there were very few options for late stage melanoma patients and their physicians - none of them appealing because of rather severe side effects and / or little clinical benefit. However, that situation changed considerably upon the FDA approval of a new immunotherapy drug called Keytruda (tradename), otherwise known as pembrolizumab, lambrolizumab or its code name MK-3475 (a monoclonal PD-1 antibody).
What is melanoma?Melanoma is the most deadly form of skin cancer and according to 2012 figures from the World Health Organisation (WHO) approximately 232.000 people will be diagnosed with melanoma per year while more than 55.000 will die of melanoma each year. Nevertheless, melanoma is the rarest type of skin cancer, while the estimated lifetime risk of developing the disease is 1 in 55 people. There are 4 stages (I - IV) in melanoma. Unfortunately, the survival rate statistics paint a remarkably grim picture for patients suffering from stage IV melanoma. The vast majority (85%) of patients with distant metastases were not expected to survive beyond 5 years, between 2001 and 2007. In fact, the median survival for patients with stage IV disease is less than 1 year.
The Yervoy FDA approval for the treatment of metastatic melanoma, in March 2011, represented the first new treatment for advanced melanoma in more than a decade. Yervoy (otherwise known as ipilimumab) is an IgG1 monoclonal antibody developed by Bristol-Myers Squibb. This particular immunotherapy consisted of a monoclonal antibody that was targeting one of two known inhibitory checkpoint pathways (CTLA-4 and PD-1) that regulate the patient's own immune system by controlling T-cell function. Yervoy targets Cytotoxic T-Lymphocyte-associated Antigen 4 (CTLA-4) signaling (see figure below).
Despite their immune evasion and inhibitory capabilities, tumours express tumour-associated antigens. As such, it is theoretically possible that the patient's own immune system mounts an effective immune response against a tumour with the use of this antibody therapy (on the grounds that CTLA-4 serves as an “immune checkpoint” which down regulates T-cell activation (in a normal scenario this prevents autoimmunity). A relatively close analogy would be releasing the brakes on a car. When ipilimumab binds to CTLA-4, it blocks the interaction of CTLA-4 with its ligands (CD80 and CD86) and as such releases the "brakes". Effectively, ipilimumab potentiates the anti-tumour T-cell response. This then results in unrestrained T-cell proliferation. Hence, ipilimumab’s effect in patients with melanoma is indirect, and most likely due to T-cell mediated anti-tumour immune responses. However, the patient outcome with anti CTLA-4 antibodies is limited while it is coupled with potentially significant toxicities (side effects such as auto immune responses).
What is the difference between an antibody blocking the CTLA-4 T-cell checkpoint or an antibody blocking the PD-1 T-cell checkpoint?As can be seen in the figure below, the devil is in the detail - the PD-1 checkpoint is in essence "further down the T-cell activation pathway" as there is both a spatial and temporal difference between PD-1 and CTLA-4 signaling. Thus, unlike CTLA-4 antibodies, the PD-1 and / or Programmed cell Death-Ligand 1 (PD-L1) antibodies aim to potentiate the antitumor T-cell response at a more tumour specific level. This relatively tumour specific activity is accomplished by impairing the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumour cells.
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Does the PD-1 antibody treatment represent a paradigm shift in how we treat melanoma as well as other cancers, such as lung cancer?In an effort to answer the above question, I will discuss the following points in this article:
- What is Keytruda?
- Are there any alternatives to Keytruda (e.g. Opdivo) and do they work in a similar way?
- What is BMS-936559 and what is the difference between PD-1 and PD-L1?
- Will Keytruda (or other PD-1 antibody) bring about remission in late stage lung cancers?
- Current PD-1 antibody (Keytruda / Opdivo / BMS-936558 / CT-011) clinical trials that are being conducted (2015 and onwards)
- Current PD-L1 antibody clinical trials (BMS-936559 / MPDL3280A / RG7446) clinical trials that are being conducted (2015 and onwards)
What is Keytruda?Keytruda / Lambrolizumab (MK-3475) is a humanized monoclonal IgG4 PD-1 antibody, that was developed by the Medical Research Council (MRC) from the UK (for Merck / MSD) and represents 1 of 55 antibodies that have been humanized by this organisation to date (examples of other well known humanized antibodies by the MRC in the UK include Tysabri®, Actemra® and Entyvio®).
Keytruda is an IgG4 antibody, which refers to the subclass of the antibody isotype (IgG). The four subclasses, IgG1, IgG2, IgG3, and IgG4, differ predominantly in their hinge regions (which includes the corresponding disulphide bonds) and upper CH2 domains – other segments of the Fc portion (CH and CL domains) are invariably conserved. However, even though they are more than 90% identical at the amino acid level, each subclass has a unique profile in terms of immune complex formation, complement activation, triggering of effector cells, half-life, and placental transport. Therefore, these Fc regions are pivotal in coordinating different immune responses given that they selectively bind to IgG-Fc receptors (FcγR) and / or C1q (complement system). Thus, whether an immune response results in phagocytosis, cell-mediated cytotoxicity, and / or activation of the complement system, is very much dependent on the IgG subclass. Please note: all recombinant monoclonal antibodies currently in clinical development belong to the IgG class / isotype because it has the highest serum half-life among all the antibody classes (IgA, IgD, IgE, IgM).
However, given that antibodies such as Keytruda or Opdivo target immune cells, triggering any of the above mentioned immune responses has been deemed undesirable. Which is why many of these immunomodulatory IgG antibodies have been engineered to have low, or no binding to the Fcγ receptors (FcγRs) that trigger the aforementioned cytotoxic effector functions such as Antibody Dependent Cellular Cytotoxicity (ADCC) and Antibody Dependent Cellular Phagocytosis (ADCP). These antibody specifications are acquired (in part) by selecting a subclass such as IgG2, but are often the result of genetic modifications (point mutations) in the Fc portion (hinge region as well as the Fc domains) of the antibody. However, these genetic modifications are not as trivial as it would seem at first sight, given that conformational changes / flexibility and steric hindrance as a result of such modifications may lead to small (but significant) changes in antigen affinity (Fab domains) or effector functions (Fc domains) - see Tian et al., 2015 for an indepth analysis of IgG antibody and subclass-specific conformational structures (using small-angle X-ray scattering (SAXS), structure modelling, and shape clustering).
The antigen to which Keytruda (or Opdivo) binds is called Programmed Cell Death 1 (PD-1 is also known as CD279). PD-1 is a receptor which is primarily expressed on the surface of activated T cells. The binding of this PD-1 receptor to one of its ligands (PD-L1 or PD-L2), inhibits a cytotoxic T-cell response (i.e. “switches the T-cell off”). The PD-L1 and PD-L2 ligands are expressed on the surface of Antigen Presenting Cells (APCs), such as dendritic cells or macrophages, in order to suppress T-cell activation.
However, many tumour cells (and / or tumour microenvironment) acquire the ability to also express high levels of PD-L1 / PD-L2 on their cell surface. In other words, they utilise this pathway to “paralyze” T-cells that have been primed to recognise and kill those tumour cells, even though tumours are often immunogenic (this means your immune system can recognise tumours). Anti-PD-1 antibodies, such as Keytruda (Pembrolizumab), Opdivo (Nivolumab), etc... are highly selective, humanized monoclonal IgG antibodies against PD-1, which disrupt the engagement of PD-1 with tumour-expressed PD-L1 ligand. As a consequence, the inhibitory signals in T cells are blocked, which ultimately results in tumour recognition by cytotoxic T-cells and the subsequent killing of tumour cells.
Keytruda is currently used to treat advanced skin cancer (melanoma) that has spread to other parts of the body, or skin cancers that cannot be surgically removed. It is usually given after other cancer medicine has failed.
Please note: Keytruda can cause your immune system to attack normal organs and tissues in other areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening.
Are there any alternatives to Keytruda (e.g. Opdivo) and do they work in a similar way?There are currently seven therapeutic agents (that block the PD-1/PD-L1 pathway) under clinical evaluation:
- MDX-1106 / BMS-936558 / ONO-4538 (fully human IgG4 anti-PD1 mAb from BMS),
- MEDI-4736 (a modified fully human IgG1 anti-PD-L1 antibody developed by MedImmune and AstraZeneca),
- Pidilizumab, formerly CT-011 (humanized IgG1 anti-PD1 mAb developed by CureTech in partnership with Medivation),
- MPDL3280A/ RG7446 (anti-PD-L1 from Genentech),
- BMS-936559 (fully humanized PD-L1 IgG4 mAb inhibiting ligation to both PD-1 and B7.1) by Bristol-Myers Squibb
- AMP-224 (a B7-DC/ IgG1 fusion protein licensed to GSK),
- Keytruda / MK-3475 (human IgG4 anti-PD1 mAb from Merck / MSD).
Common toxicities that have been reported include rash, diarrhea, fatigue, and pruritis. Grade 3/4 toxicities may occur in patients (i.e. lymphopenia, fatigue, diarrhea, nausea and anemia (in approximately 21% of patients). Pneumonitis has also been reported, but is a very rare, although significant adverse event, which may result in death.
The other antibodies listed above are similar, but in terms of development (i.e. FDA approval) considerably behind the anti- PD-1 antibodies that are currently marketed by Merck/MSD and Bristol-Myers Squibb. RG7446 (although targeting the ligand (PD-L1) rather than PD-1 itself – i.e. similar to BMS936559) is likely to be the third company to obtain an FDA / EMA approval for an antibody targeting the PD-1 checkpoint.
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What is BMS-936559 or RG7446 and what is the difference between PD-1 and PD-L1?BMS-936559, is a fully human IgG4 PD-L1 antibody that demonstrates a RECIST response rate of approximately 20% (in melanoma). Initial trial data indicates that toxicity is in most cases mild although some patients have experienced higher grade adverse events (e.g. rash, hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, and diabetes mellitus).
The anti-PD-L1 antibodies in development (e.g. BMS-936559 by Bristol-Myers Squibb or RG7446 by Roche / Genentech) also target the “PD-1 checkpoint” but, unlike Keytruda or Opdivo, accomplish this by binding to the PD-L1 ligand (a small molecule that upon forming a complex with the PD-1 receptor (found on T-cells), serves as an inhibitory signal which results in “switching-off” a T-cell).
Will Keytruda (or another PD-1 / PD-L1 antibody) bring about remission in late stage lung cancers?Unfortunately, the estimated mortality for lung cancer is 1.589.925 deaths per year as a result of this disease (based on the latest data from Globocan 2012). Moreover, the estimated incidence of 1.824.701 lung cancer cases world wide (every year), demonstrates that new medicines (in addition to prevention) are urgently required.
Investigators (physicians) conducting clinical trials with PD-1 targeting antibodies in lung cancer patients have observed remarkable results in some lung cancer patients - results they would have not thought possible.
A recent example relates to a British man in his forties who was diagnosed with metastatic lung cancer (i.e. his cancer had spread to various other organs in his body, including his liver, brain, bones and adrenal glands). Following treatment with Bristol-Myers Squibb's Opdivo / Nivolumab (BMS-936558, MDX-1106, ONO-4538), the cancer completely disappeared.
The above result stands in stark contrast to the usual expectations (and observations) of physicians in terms of outcome for patients who have been diagnosed with metastatic lung cancer (cancer which has spread to other organs). Sadly, metastatic lung cancer is often the rule rather than the exception by the time lung cancer is spotted and as such patients often die within months following diagnosis.
Needless to say, that some people have labelled the PD-1 antibodies (Nivolumab, Pembrolizumab, etc...) as a potential cure for lung cancer. While in some patients the drug may lead to no detectable cancer / tumours, calling the drug a cure would be somewhat presumptuous, given that the clinical trial statistics indicate that a partial response rate of approximately 20 – 30 % can be expected in late stage lung cancers (e.g. one clinical trial in malignant pleural mesothelioma (lung cancer caused by asbestos) reported a 28% response rate in patients who had received chemotherapy previously, while another study in advanced non-small cell lung cancer reported a 20% response. The reported median Overall Survival (OS) also increases in NSCLC (9.9 months with Opdivo and approximately 12 months for Keytruda according to initial data published in 2014). In addition, clinical trial data demonstrates that PD-1 and its ligand PD-L1 expression in T-cells and tumour cells respectively, are not the only factors playing a role in the success of this particular immunotherapy (e.g. the amount of tumour-associated lymphocytes also appears to be an important aspect). As such, combination therapies are likely to be of benefit to the majority of patients to derive the most from this next generation cancer treatment (e.g. Antibody Drug Conjugates (ADC) , Dendritic Cell Therapy (AV0113), and CTLA-4 antibody therapy, etc...).
Nevertheless, the PD-1 antibody treatment as a monotherapy is already a huge step forward over the standard of care that has changed little in the past few decades for this particular cancer!
Please note that Opdivo (manufactured by Bristol-Myers Squibb) was approved by the FDA in December 2014 to treat advanced melanoma and that in March 2015, Bristol-Myers Squibb received clearance for Opdivo to treat a common form of lung cancer.
On the 24th of April 2015, the European Medicines Agency (EMA) approved Opdivo as a first-line treatment for advanced melanoma and in previously treated patients. However, the EMA has not yet approved PD-1 antibodies for the treatment of lung cancer. Patients from the UK may possibly gain access to PD-1 antibodies (for e.g. lung cancer) through a UK initiative called EAMS - More information is available on the MHRA website at https://www.gov.uk/apply-for-the-early-access-to-medicines-scheme-eams).
For patients in other European contries (and the rest of the world) it may be useful to get in contact with a charity called MyTomorrows as they can possibly facilitate access to new drugs (that have not yet been approved) through compassionate use programmes http://www.pvanuden.com/2014/03/my-tomorrowsfor-access-to.html
Current PD-1 antibody (Keytruda / Opdivo / BMS-936558 / CT-011 / clinical trials that are being conducted (2015 and onwards).*Please note: I am ONLY listing lung cancer trials on this particular page. There are many trials currently taking place and many others are planned with PD-1 antibody treatments for most types of cancer (e.g. colon cancer, glioblastoma, bladder cancer, melanoma, kidney cancer, etc...). If you are unable to find a PD-1 antibody clinical trial for a particular cancer, then please leave a comment at the bottom of this article and I will try to assist you.
Europe (EU) - Keytruda clinical trials for lung cancer patients
- Czech Republic
- United Kingdom (UK)
- Czech Republic
United States of America (USA) - Keytruda clinical trials for lung cancer patients
Europe (EU) - Opdivo / Nivolumab clinical trials for lung cancer patients
- United Kingdom (UK)
- Czech Republic
- Great Britain (UK)
- Finland / Suomi
- Czech Republic
United States of America (USA) - Opdivo / Nivolumab clinical trials for lung cancer patients
Current PD-L1 antibody clinical trials (BMS-936559 / MPDL3280A / RG7446) clinical trials that are being conducted (2015 and onwards)United States of America (USA) - BMS-936559 / MDX1105-01 (Bristol-Meyers Squibb) or MPDL3280A / RG7446 (Roche – Genentech) Anti-PD-L1 clinical trials for lung cancer patients
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