Nobel Prize in Physiology or Medicine 2018 – Unleashing the Body’s Dogs of War in the Fight Against Cancer

This blog post is part of a series of articles on the scientific research that led to this year’s Nobel Prizes. The official Nobel Prize Award Ceremony will take place in Stockholm on 10 December 2018.


This year’s Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo. Their breakthroughs in cancer research have allowed scientists to fashion highly effective drugs which reactivate the body’s own defences against cancer cells.

The war on cancer has generally been thought of and presented as a battle that is waged between scientists and doctors armed with either chemotherapeutics, radiotherapy or other approaches on the one side and the malignant cells on the other. But what if cancer therapy wasn’t focused on targeting the tumours directly – in reality often a messy and imprecise approach – but on reactivating the body’s latent ability to identify and eliminate cancerous cells?

We humans possess highly sophisticated and complex immune systems that protect us from foreign invaders such as bacteria and viruses but also from cancer, the enemy within. Scientists have long appreciated that cancer and the immune system are intimately linked with each other. Paul Ehrlich, who shared the 1908 Nobel Prize in Physiology or Medicine with Ilya Ilyich Mechnikov for elucidating the fundamentals of immunity, already hypothesised that cancer cells can be both recognised and eliminated by the immune system. In the 1950s and 60s, Lewis Thomas and the Nobel Laureates in Physiology or Medicine in 1960, Frank MacFarlane Burnet and Peter Brian Medawar, built on this idea and developed the concept of cancer immunosurveillance, which states that cancer cells express specific proteins on their surfaces that can be recognised by circulating cells of the immune system, leading to the mounting of powerful immune reactions directed against the tumour cells.

However, owing to its destructive potential, immune system function must be tightly regulated in order to ensure that it doesn’t do damage to the body’s own cells. Further, cancer cells actively suppress the immune system in order to promote their survival and spread. By gaining a molecular understanding of the brakes that act on T cells, specialised cells of the immune system that attack and destroy foreign invaders as well as cancer cells, James P. Allison and Tasuku Honjo have figured out ways to disable these brakes, thus directing the immune system to kill cancer cells.

As with many important scientific discoveries, the road was a long one, and while attractive to many, the concept of stimulating the immune system to attack and eliminate cancer remained an unconventional research niche for many years. Already in the 1970s, Allison and colleagues had found a mechanism whereby the immune system was inhibited from efficiently targeting cancer cells, one which involved the interaction of tumour proteins with other proteins. Then, in the late 1980s, a novel protein called CTLA-4 was discovered on the surface of T cells. James Allison and his laboratory could show that it keeps the immune system in check by restricting T cell responses. Allison then hypothesised that if the function of the CTLA-4 protein could be blocked then this might release the brake that was preventing the immune system from eliminating cancer cells. He went on to use an antibody to block CTLA-4 function in mice with cancer. This had the effect of reactivating T cell function and led to a complete eradication of cancer in the mice.  

In parallel to Allison’s research, Tasuku Honjo and colleagues in Japan had in the early 1990s discovered another protein expressed on the surface of T cells that they termed PD-1. Further experiments showed that PD-1 also restricted T cell function. Following the same rationale as for CTLA-4, blocking PD-1 function and thus relieving the brake on T cell function was adopted as an anti-cancer strategy.

Legend: Illustration of the mode of action of immune checkpoint inhibitors targeted at CTLA-4 or PD-1. Left panel: CTLA- 4 functions as a brake on T cells by inhibiting the function of an accelerator cells required for T cell activation. Antibodies (in green) against CTLA-4 release the brake and prompt T cells to attack on cancer cells. Right panel: The PD-1 brake also prevents T cell activation, and antibodies against PD-1 release this brake allowing T cells to effectively kill cancer cells. Image source: Press release: The Nobel Prize in Physiology or Medicine 2018. Nobel Media AB 2018. Mon. 19 Nov 2018.

However, it still remained unclear whether approaches targeting these proteins could be effective in treating cancer in humans. In 2010, a clinical study using an inhibitor of CTLA-4 showed impressive results in patients with melanoma, while the results of a 2012 study in which PD-1 function was inhibited in lung and other cancers showed similarly dramatic recovery rates. The results of these and other trials are particularly exciting as lifting immune blockade can also lead to complete eradication of cancer in patients with metastasis, i.e. with cancer that has already spread through the body from its primary site. Such advanced-stage cancers are notoriously difficult to treat using conventional cancer therapies.

The overwhelming weight of evidence was by now too much to ignore, and the journey of cancer immunotherapy from the sidelines to the mainstream was complete. By 2013, Science magazine had named it as their breakthrough of the year, and six so-called immune checkpoint therapies that target CTLA-4, PD-1 and another protein on the surface of T cells, PD-L1, have now been approved for use in patients. Allison and Honjo’s equal share of this year’s Nobel Prize in Physiology or Medicine is also apt for very practical reasons, as the effectiveness of immune checkpoint therapies seems to be increased further when both CTLA-4 and PD-1 are targeted simultaneously.

Is there a catch to all this? One major caveat associated with these therapies is that side-effects resulting from enhanced immune system function, such as inflammation, must be carefully monitored and controlled. Nevertheless, cancer immunotherapy has brought about a revolution in how we think about and treat cancer and in the years to come will surely save countless lives.

Additional Note: An interesting Topic Cluster on the history of immunology can be found in our mediatheque.

Tackling the Silent Crisis in Cancer Care

For those receiving a life-changing diagnosis of cancer, the lottery of birth is a decisive factor in survival. Breast cancer survival rates in the West, for example, are over double that in low-income countries.

Fixing this inequality, however, demands multiple interventions – from preventative public health measures to improved access to treatment. Other issues include a shortage of medical professionals and inadequate education and training. Technology is one important area where researchers can contribute.


An IAEA global directory of treatment machines per million people shows the radiotherapy ‘gap’. Senegal, for example, has two while Switzerland has 74 for around half the population. Credit: DIRAC Project, IAEA

Linear accelerators, or linacs, are the workhorses of radiotherapy and a case in point. While it’s estimated that around 50% of people with cancer would benefit from radiotherapy, only 10% of people in low income countries have access – dubbed the ‘silent crisis’ by the International Atomic Energy Agency (IAEA).

That need is only set to get bigger. An increase to 25 million annual cases by 2035, a 67% jump on 2015, has been predicted. Around two thirds will be in low-middle income countries (LMIC).

The problem with accelerators

Linacs, however, are complex creatures costing several million dollars. They demand regular checks and services to deliver radiation safely and accurately. Consequently, stories of linacs sitting idle following a breakdown through a lack of money or support are not unusual in LMIC.


Linacs at the Lake Constance Radiation Oncology Centre in Singen are exclusively powered by solar panels in the summer. Credit: Holger Wirtz

Tackling this, researchers are working towards more robust and affordable linacs. One coordinated global effort is bringing together experts, including from CERN, the IAEA and eight LMIC. In its early days, the collaboration is developing specifications for a complete radiotherapy treatment system and a conceptual design.

Lack of power is a critical problem. Linacs devour electricity and need a stable supply, something not always available in LMIC. One potential solution can be found near Lindau at the Lake Constance Radiation Oncology Centre in Singen. The clinic’s linacs are the only ones in the world to be powered directly by solar panels – entirely so in summer.  Chief physicist Holger Wirtz plans to build a 100% off-the-grid clinic in Germany, using existing battery technology, as a demonstration site for clinics in LMIC.

A more robust linac

Other projects are working to simplify linac hardware. Applying a concept invented at UCLA, US firm RadiaBeam is developing an affordable linac that uses less power, is more robust, but should still deliver high-quality treatment. “[Research shows] the developing world doesn’t want a second-class product,” says CEO Salime Boucher.

One major innovation is the linac’s collimator – the beam-shaping aperture that shields healthy tissue during treatment. Conventional collimators are complex, typically comprising more than 100 individually driven finger-like metal leaves and are responsible for a significant share of linac-downtime. The new design uses just eight leaves controlled by larger, sturdier motors to form a single, moving aperture that paints the tumour with radiation.

In another project, a simpler gantry, the structure from which radiation is fired, is being developed at the University of Sydney, Australia. While conventional gantries rotate around the patient to zap the tumour from all directions, the Nano-X gantry is fixed and fires into the floor. Instead, the smaller, lighter patient is rotated – a much easier engineering problem.

Precision imaging and processing algorithms make the switch possible. As the patient rotates, X-rays detect the tumour’s new position and deformation caused by the rotation. The data is then used to update the beam settings, ensuring accurate treatment. The design is compact and reduces the shielding needed in the walls and ceiling of the treatment room. An associated start-up, also in Sydney, is working on a similar solution.


The smaller Nano-X gantry (L) compared to a conventional linac and associated room shielding (R). This was originally published in Advances in Radiation Oncology, Vol 1, Feain et al, Functional imaging equivalence and proof of concept for image-guided adaptive radiotherapy with fixed gantry and rotating couch, 365–372, (c) the Authors, 2016.

Computing to improve imaging

Imaging, such as ultrasound, CT and MRI, has several jobs in cancer care, from screening populations to monitoring treatment response. Here, computational techniques that reconstruct images and automate their analysis could ease workloads in hospitals across the globe.

Harshita Sharma of the University of Oxford, a young scientist who attended the 68th Lindau Nobel Laureate Meeting, develops such methods in her research. They include machine learning techniques, a hot topic in biomedical imaging. “We want to develop these applications for medical professionals so that it saves them time and effort,” says Sharma. The benefits could be particularly great in LMIC, where staff shortages and over-loaded clinicians are more common, adds Sharma.

Computational analyses can also save money. Focusing on digital pathology,  Sharma investigated during her PhD whether a more affordable, efficient staining technique for gastric carcinoma, H&E, could provide better analyses using machine learning. Currently, it is not the preferred choice of pathologists, as certain types of cancers are not easy to differentiate by eye using the technique. Initial accuracies of 75-80% are promising.

Machine learning is set to have a large global impact on radiology, says Ge Wang of Rensselaer Polytechnic Institute, New York. In essence, it shifts the complexity of imaging from the hardware to the software. “By using artificial intelligence for tomographic reconstruction, cheaper scanners can make better images,” says Wang.

Wang is developing a compact, mobile CT scanner that uses simpler hardware to acquire less data from the patient than a conventional scanner, compensated by sophisticated image reconstruction. In an audacious vision, AVATAR, he sees the scanner on an autonomous self-driving truck taking imaging to remote communities.


A low-quality, low-dose CT scan (L) is improved using machine learning into a version (R) comparable to a standard-dose CT image (M). Machine learning could enable simpler, cheaper, safer scanners. Credit: Ge Wang, in a collaboration between RPI, Sichuan Univ. & MGH/Harvard

Altogether, there is great potential for effective, more accessible technologies. However, innovation must be part of a bigger movement if it is to make a difference. Funding and governmental will to address the silent crisis, for example, are critical. According to a recent WHO report, long-term efforts to reduce premature deaths by non-communicable diseases, including cancer, are not on track. Can the boat be turned around? Watch this space. 


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CRISPR-Cas: The Holy Grail Within Pandora’s Box

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“With great power comes great responsibility” – although most often attributed to the Marvel comic Spider-Man, this phrase has since become synonymous with new discoveries and techniques that harbour great potential but could also go terribly awry if not met with enough care. What might happen if the novel gene-editing tool CRISPR-Cas was employed without the greater good in mind, can be seen in the new Hollywood movie ‘Rampage’. This movie adaptation based on a video game portrays the disastrous, albeit not scientifically accurate, consequences of reckless gene editing, which results in the hero having to fight former friendly pet animals that have been turned into monsters with the help of CRISPR. Undoubtedly, CRISPR-Cas is one of the most ground-breaking scientific developments in recent years, but it is also still heavily debated among scientists and the public. So much so that even Hollywood took note.

But what exactly is CRISPR-Cas and how does it work? CRISPR (pronounced “crisper”) stands for Clustered Regularly Interspaced Short Palindromic Repeats, which are part of the bacterial “immune” system. Jennifer Doudna and Emmanuelle Charpentier, together with their postdocs Martin Jinek and Krzysztof Chylinski, developed the gene-editing tool, which uses RNA guide sequences specific to the target gene as well as the bacterial enzyme Cas9 to cut the target sequence out of the genome. If different Cas-enzymes accompany the RNA guide sequences, the system can also be programmed to insert or replace specific gene sequences. With these systems, researchers are able to permanently modify genes in most living cells and organisms. The break-through discovery was published in a Science paper in August 2012. The beauty of the technique: it is fast, cheap and relatively simple. As a consequence, the scientific community has seen a massive increase in CRISPR-related projects, papers and patents in the years since 2012.

In particular the medical research community adopted this new tool early on in the hope that precise DNA editing could eliminate genetic diseases and allow for targeted gene therapies to treat genetic causes of disease. In fact, recently, researchers managed to reduce the disease burden of such debilitating diseases as Huntington’s disease and muscular atrophy via targeted gene editing in mice. What is especially impressive about these first successful trials, is that the researchers have found a way to introduce the CRISPR-Cas system directly into the body. Previous approaches to improve immune therapies for certain cancers followed a different approach: blood or immune cells were isolated, their genetic code altered to better fight the tumour cells and then reintroduced to the body. For most tissues, however, this approach was not feasible. Thus, both guide RNA and enzyme had to be introduced directly into the body and aimed at their target tissue. However, both RNA and enzyme are large molecules, that don’t diffuse into cells easily and don’t survive well in blood. Therefore, some pharmaceutical companies have successfully started pairing the two components to fatty particles in order to facilitate their uptake into the cells. If these trials prove feasible, virtually any disease – from hepatitis B to high cholesterol – could potentially be eradicated by the CRISPR-Cas system.


Illustration of genetically modified lymphocytes attacking a cancer cell. Credit: man_at_mouse/


Moreover, the CRISPR system not only proves tremendously useful for treating diseases, it is also being used as a promising new diagnostic tool: SHERLOCK – another pop-culture icon, but here the acronym stands for Specific High Sensitivity Reporter unLOCKing.

In 2017, a team of researchers in Boston first described an adapted CRISPR-system in which the guide sequence targets RNA (rather than DNA) as a rapid, inexpensive and highly sensitive diagnostic tool. The end product is a miniature paper test that visualizes the test result via a colourful band – similar to a pregnancy test. According to the scientists, SHERLOCK can detect viral and bacterial infections, find cancer mutations even at low frequencies, and could even detect subtle DNA sequence variations known as single nucleotide polymorphisms that are linked to a plethora of diseases.

In a new study, published earlier this year, the researchers used SHERLOCK to detect cell-free tumour DNA in blood samples from lung cancer patients. Moreover, their improved diagnostic tool is supposed to be able to detect and even distinguish between the Zika and the dengue virus.

The detection rather than editing of genetic information is based on the Cas13a enzyme, a CRISPR-associated protein, which can also be programmed to bind to a specific piece of RNA. Cas13 could even target viral genomes, genetic information underlying antibiotic resistance in bacteria or mutations that cause cancer. After Cas13 has cut its target, it will continue cutting additional strands of synthetic RNA, which are added to the test solution. Once these additional strands are cut by Cas13, they release a signalling molecule which finally leads to the visible band on the paper strip. The researchers have developed their diagnostic test to be able to analyse and indicate up to four different targets per test.

However, it is also this seemingly tireless activity of the cutting enzymes of the CRISPR toolbox that have led many researchers to question just how targeted and controlled this enzymatic reaction can be. In May 2017, a paper in Nature Methods reported a huge number of unexpected off-target effects, essentially labelling the gene-editing tool as unsafe. The paper brought the heated debate surrounding the predictability and safety of this new tool to the forefront of the field; however, in March 2018, the paper was retracted, after several researchers called the methods and in particular the controls of the first paper into question. The off-target effects observed earlier might have been due to different genetic backgrounds of the mice rather than the employed CRISPR-Cas method.

Nevertheless, many researchers caution their colleagues that the CRISPR-system and its possible side-effects are not yet fully understood. Another piece of the puzzle could be a natural off-switch for Cas9 that has been found in another bacterium and that could help control the enzymatic gene-editing system in the future.

However, possible side- or off-target effects are by no means the only fodder for heated debates surrounding the CRISPR tool box: in 2015, Chinese scientists reported that they had edited the genome of a human embryo. Although the embryo was not viable, it sparked a heated ethical discussion and conjured up many negative connotations regarding genetically engineered humans.

Leaving possible medical applications aside, CRISPR-Cas also holds great potential for agriculture. The gene-editing tool could help to generate plants that are resistant or at least more tolerant concerning fungi, insects or extreme weather phenomenon such as heat, drought or massive downpour, which occur more often in recent years due to climate change and can wreck entire harvests. The plants could also be made to produce higher yields or provide certain vitamins (e.g. golden rice), thus providing a huge relief in the fight against world hunger. However, the debate is still ongoing whether CRISPR-induced genetic modifications result in a genetically modified product (GMO) that should be labelled as such. GMO products are viewed critically by many customers and will thus be difficult to market.

The fact remains that the CRISPR-Cas system is a significant milestone in modern science with seemingly endless potential from diagnostic tests to curing nearly any disease there is, including a shortage of transplant organs, to alleviating world hunger. And yet, a system as complex and complicated as CRISPR-Cas needs to be met with due diligence and care in order to minimise risks and side effects. Moreover, the decision of altering the genetic code of (human) embryos requires in-depth ethical and moral deliberations.



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The Hungry Brain

Gut brain Axis Feature Credited


Under normal, healthy conditions we eat whenever we are feeling hungry. In addition to the feeling of hunger, we also often have an appetite for a specific kind of food, and sometimes we simply crave the pleasure a certain food like chocolate or pizza may provide us. This pleasure is part of the hedonic aspect of food and eating. In fact, anhedonia or the absence of experiencing pleasure from previously pleasurable activities, such as eating enjoyable food, is a hallmark of depression. The hedonic feeling originates from the pleasure centre of the brain, which is the same one that lights up when addicts ‘get a fix’. Hedonic eating occurs independently of the gut-brain axis, which is why you will keep eating those crisps and chocolate, even when you know, you’re full. Hence, sayings like “These chips are addictive!” are much closer to the biological truth than many realise.  

But how do we know that we are hungry? Being aware of your surrounding and/or your internal feelings is the definition of consciousness. And a major hub for consciousness is a very primal brain structure, called the thalamus. This structure lies deep within the brain and constantly integrates sensory input from the outside world. It is connected to cognitive areas such as the cortex and the hippocampus, but also to distinct areas in the brainstem like the locus coeruleus, which is the main noradrenergic nucleus in the brain and regulates stress and panic responses. Directly below the thalamus and as such also closely connected to this ‘awareness hub’ lies the hypothalamus.

The hypothalamus is a very complex brain area with many different functions and nuclei. Some of them are involved in the control of our circadian rhythm and internal clock – the deciphering of which was awarded the 2017 Nobel Prize in Physiology or Medicine. But the main task of the hypothalamus is to connect the brain with the endocrine system (i.e. hormones) of the rest of the body. Hormones like ghrelin, leptin, or insulin are constantly signalling your brain whether you are hungry or not. They do so via several direct and indirect avenues, such as blood sugar levels, monitoring energy storage in adipose cells, or by secretion from the gastrointestinal mucosa.

There are also a number of mechanosensitive receptors that detect when your stomach walls distend, and you have eaten enough. However, similarly to the hormonal signals, the downstream effects of these receptors also take a little while to reach the brain and be (consciously) noticeable. Thus, the slower you eat, the less likely you will be to over-eat, because the satiety signals from hunger-hormones and stomach-wall-detectors will reach your consciousness only after about 20 to 30 minutes.

Leaving the gut and coming back to the brain, the hypothalamus receives endocrine and neuropeptidergic inputs related to energy metabolism and whether the body requires more food. Like most brain structures, the hypothalamus is made up of several sub-nuclei that differ in cell-type and downstream-function. One of these nuclei, the arcuate nucleus of the hypothalamus, is considered the main hub for feeding and appetite control. Within it there are a number of signalling avenues that converge and that – if altered or silenced – can induce for instance starvation. Major signalling molecules are the Neuropeptide Y, the main inhibitory neurotransmitter GABA, and the peptide hormone melanocortin. The neurons in the arcuate nucleus are stimulated by these and other signalling molecules in order to maintain energy homeostasis for the entire organism. There are two major subclasses of neurons in the arcuate nucleus that are essential for this homeostasis and that, once stimulated, cause very different responses: activation of the so-called POMC neurons decreases food intake, while the stimulation of AGRP neurons increases food intake. And this circuit even works the other way around: researchers found that by directly infusing nutrients into the stomach of mice, they were able to inhibit AGRP neurons and their promotion of food intake.

Given this intricate interplay between different signalling routes, molecules, and areas it is not surprising then that a disrupted balance between all of these players could be detrimental. Recent studies identified one key player that can either keep the balance or wreak havoc: the gut microbiome


Bacteria colonising intestinal villi make up the gut microbiome. Picture/Credit: ChrisChrisW/

Bacteria colonising intestinal villi make up the gut microbiome. Picture/Credit: ChrisChrisW/


The gut microbiome is the entirety of the microorganisms living in our gastrointestinal tract, and they can modulate the gut-brain axis. Most of the microorganisms living on and within us are harmless and in fact are very useful when it comes to digesting our food. However, sometimes this mutually beneficial symbiosis goes awry, and the microbes start ‘acting out’. For instance, they can alter satiety signals by modulating the ghrelin production and subsequently induce hunger before the stomach is empty, which could foster obesity. They can also block the absorption of vital nutrients by taking them up themselves and thereby inducing malnutrition. A new study which was published only last month revealed that Alzheimer patients display a different and less diverse microbiome composition than healthy control subjects. Another study from Sweden even demonstrated that the specific microbiome composition occurring in Alzheimer’s patients induces the development of disease-specific amyloid-beta plaques, thereby establishing a direct functional link between the gut microbiome and Alzheimer’s disease – at least in mice. Similarly, the composition and function of the microbiome might also directly affect movement impairments in Parkinson’s disease. In addition, there is also mounting evidence that neuropsychiatric diseases such as anxiety or autism are functionally linked to the microbiome

Moreover, even systemic diseases such as lung, kidney and bladder cancers have been recently linked to the gut microbiome. Albeit, in this case, not the disease development and progression seem to be directly related to our gut inhabitants. Instead, the researchers found that if the microbiome of the cancer patients was disrupted by a recent dose of antibiotics, they were less likely to respond well to the cancer treatment and their long-term survival was significantly diminished. It seems that the treatment with antibiotics disrupts specific components of the microbiome, which then negatively affects the function of the entire composition. 

While the cause or consequence mechanisms between these different afflictions and an altered microbiome have not been solved yet, it seems certain that it is involved in more than digestion. Hence, the already intricate gut-brain axis is further complicated by the gut microbiome, which not only affects when and what we eat, but can also determine our fate in health and disease.  

Immunotherapy: The Next Revolution in Cancer Treatment

Over the past 150 years, doctors have learned to treat cancer with surgery, radiation, chemotherapy and vaccines. Now there is a new weapon for treatment: immunotherapy. For some patients with previously incurable cancer, redirecting their immune system to recognise and kill cancer cells has resulted in long-term remission, with cancer disappearing for a year or two after treatment.


Lymphocytes attacking cancer cell. Credit: selvanegra/

Lymphocytes attacking a cancer cell. Credit: selvanegra/


Cancer immunotherapy has been used successfully to treat late stage cancers such as leukaemia and metastatic melanoma, and recently used to treat mid-stage lung cancer. Various forms of cancer immunotherapy have received regulatory approval in the US, or are in the approval process in the EU. These drugs free a patient’s immune system from cancer-induced suppression, while others engineer a patient’s own white blood cells to attack cancer. Another approach, still early in clinical development, uses antibodies to vaccinate patients against their own tumours, pushing their immune system to attack the cancer cells.

However, immunotherapy is not successful, or even an option, for all cancer patients. Two doctors used FDA approvals and US cancer statistics to estimate that 70 percent of American cancer deaths are caused by types of cancer for which there are no approved immunotherapy treatments. And patients that do receive immunotherapy can experience dramatic side effects: severe autoimmune reactions, cancer recurrence, and in some cases, death.

With such varied outcomes, opinions vary on the usefulness of immunotherapy. Recent editorials and conference reports describe “exciting times” for immunotherapy or caution to “beware the hype” about game-changing cancer treatment. Regardless of how immunotherapy could eventually influence cancer treatment, its development is a new revolution in cancer treatment, building on detailed biochemical knowledge of how cancer mutates and evades the immune response. Academic research into immunotherapy is also being quickly commercialised into personalised and targeted cancer treatments.


T-cells (red, yellow, and blue) attack a tumour in a mouse model of breast cancer following treatment with radiation and a PD-L1 immune checkpoint inhibitor, as seen by transparent tumour tomography. Credit: Steve Seung-Young Lee, National Cancer Institute\Univ. of Chicago Comprehensive Cancer Center

T-cells (red, yellow, and blue) attack a tumour in a mouse model of breast cancer following treatment with radiation and a PD-L1 immune checkpoint inhibitor, as seen by transparent tumour tomography. Credit: Steve Seung-Young Lee, National Cancer Institute\University of Chicago Comprehensive Cancer Center

Checkpoint inhibitors

Twenty years ago, James Allison, an immunologist at MD Anderson Cancer Center, was the first to develop an antibody in a class of immunotherapy called checkpoint inhibitors. These treatments release the immune system inhibition induced by a tumour. The drug he developed, Yervoy, received regulatory approval for the treatment of metastatic skin cancer in the US in 2011. By last year, Yervoy and two newer medications had reached 100,000 patients, and brought in $6 billion a year in sales.

In general, immunotherapy tweaks T-cells, white blood cells that recognise and kill invaders, to be more reactive to cancer cells. Tumours naturally suppress the immune response by secreting chemical messages that quiet T-cells. Cancer cells also bind to receptors on the surface of T-cells, generating internal messages that normally keep the immune system from attacking healthy cells.

One of those receptors is called CTLA-4. Allison and his colleagues blocked this receptor on T-cells with an antibody, and discovered that T-cells devoured cancer cells in mice. Since then, other checkpoint inhibitors have been developed and commercialised to block a T-cell receptor called PD-1 or its ligand PD-L1, present on some normal cells as well as cancer cells.

In the US, PD-1 and PD-LI inhibitors have been approved to treat some types of lung cancer, kidney cancer, and Hodgkin’s lymphoma. And the types of potentially treatable cancers are growing: Currently, more than 100 active or recruiting US clinical trials are testing checkpoint inhibitors to treat bladder cancer, liver cancer, and pancreatic cancer, among others.



Another type of cancer immunotherapy, called CAR-T, supercharges the ability of T-cells to target cancer cells circulating in the blood. In August, the first CAR-T treatment was approved in the US for children with aggressive leukaemia, and regulatory approval for a treatment for adults came in October.

To produce CAR T-cells, doctors send a patient’s blood to a lab where technicians isolate T-cells and engineer them to produce chimeric antigen receptors, or CARs. These CARs contain two fused parts: an antibody that protrudes from the surface of a T-cell to recognise a protein on cancerous B-cells (commonly CD-19) in the blood and a receptor inside the T-cell that sends messages to cellular machinery. When the antibody binds to a tumour cell, it activates the internal receptor, triggering the CAR T-cell to attack the attached cancer cell.

In clinical trials, some patients treated with CAR T-cells for aggressive leukaemia went into remission when other treatments had failed. But several high-profile trials had to be suspended because of autoimmune and neurological side effects, some leading to patient deaths.

To improve the safety of CAR-T treatment, researchers are now engineering “suicide switches” into the cells, genetically encoded cell surface receptors that trigger the cell to die when a small molecule drug binds them. If doctors see a patient experiencing side effects, they can prescribe the small molecule drug and induce cell death within 30 minutes.

Other safety strategies include improving the specificity of CAR T-cells for tumour cells because healthy cells also carry CD-19 receptors. To improve CAR-T tumour recognition, some researchers are adding a second CAR, so that the engineered cell has to recognise two antigens before mounting an attack.


As seen with pseudo-coloured scanning electron microscopy, two cell-killing T-cells (red) attack a squamous mouth cancer cell (white) after a patient received a vaccine containing antigens identified on the tumour. Credit: Rita Elena Serda, National Cancer Institute\Duncan Comprehensive Cancer Center at Baylor College of Medicine

As seen with pseudo-coloured scanning electron microscopy, two cell-killing T-cells (red) attack a squamous mouth cancer cell (white) after a patient received a vaccine containing antigens identified on the tumour. Credit: Rita Elena Serda, National Cancer Institute\Duncan Comprehensive Cancer Center at Baylor College of Medicine


 A third type of immunotherapy aims to target mutated proteins that are a hallmark of cancer. Cancer cells display portions of these mutated proteins, called neoantigens, on their surface. Researchers are studying how to use tumour-specific neoantigens in vaccines to help the body mount an immune response targeted at the cancer.

Results from two recent small clinical trials for patients with advanced melanoma suggest that neoantigen vaccines can stop the cancer from growing, or in some cases, shrink the tumours with few reported side effects. But it’s too early in clinical development to know if the vaccines will extend the lives of cancer patients.

There are two steps to making a neoantigen vaccine: first, identify mutated proteins unique to most of a patient’s cancer cells and second, identify portions of those proteins that could most effectively stimulate an immune response.

To identify mutated proteins, researchers sequence the genome of cancer cells and compare it to the sequence in healthy cells. Next, they identify which mutations lead to the production of altered proteins. Finally, they use computer models or cellular tests to identify the portions of proteins that could be the most effective neoantigen.

This last step of predicting neoantigenicity is the most challenging part of developing a new neoantigen vaccine. Lab experiments to confirm the activity of multiple neoantigens are time consuming, and current computer models to predict antigenicity can be inaccurate due to low validation.

A few principles of cancer biology also make developing neoantigens for long-lasting treatment difficult. Some cancers may have too many mutations to test as potential neoantigens. Cancer cells also continue to mutate as tumours grow, and some cells may not display the neoantigens chosen for a vaccine. Finally, cancer cells may naturally stop displaying antigens on their surface, as part of their strategy for evading an immune response.

However, identifying neoantigens can still be useful as cancer biomarkers. Or if used in a vaccine, they may be most effective in combination with other drugs: a few patients in the small clinical trials whose cancer relapsed after the trials responded to treatment with a checkpoint inhibitor.

Cancer has been a common topic in Nobel Laureates’ lectures at many Lindau Meetings. Learn more about these lectures, as well as Nobel Prize winning research related to cancer, in the Mediatheque.

Digging for the Roots: Cancer Stem Cells

Weed is a phenomenon that has annoyed many gardeners. Fortunately, there is a pretty straightforward way to get rid of it: “You can keep cutting the leaves off the weed, but the weed will regrow. But if you cut the tap roots, the leaves will wither away.” This is the ever so perspicuous advice given to us by John Dick, Senior Scientist at the University of Toronto, and one could not be blamed for, at first glance, finding it to be of an apparently trivial nature. But John Dick’s interests do not lie in gardening, and his advice is, in fact, not at all about getting rid of weed. Instead, it is a comment of far greater usefulness: about getting rid of cancer, a disease that we are, in most instances, to this day not able to cure. But what are cancers equivalents of a plant’s roots? They may well be a group of cells termed ‘cancer stem cells’, and great hopes have been set into treating cancer by targeting them. Since hope and hype often lie closely together, let us examine what this is all about…

Schem showing the difference between conventional cancer therapy and cancer stem cell specific therapy Picture: Public Domain

The cancer stem cell hypothesis proposes that not all tumor cells have equal capacities. Rather, each tumor contains a small subset of cells with stem cell-like capacities that are responsible for initiating and sustaining tumor growth, while the bulk of the tumor cells lacks this ability. Importantly, they are also thought of as the culprits for cancer relapse, which can occur many years after the initial tumor has been treated. In fact, it is thought that common chemotherapies, targeting the fast-dividing cells, leave the relatively slow-dividing tumor stem cells unharmed and thus pave the way for an eventual relapse. Moreover, cancer stem cells also have been shown to exhibit a higher resistance to radiation treatment as well as a higher invasiveness correlating with a worse cancer prognosis. In short, if a cancer cell may be considered evil, a cancer stem cell is a lot worse! A common misconception about the research field is that a tumor stem cell is actually a subtype of stem cell and that hence, cancer derives from stem cells. This is not the case. The term “tumor stem cell” only reflects the fact that this is a tumor cell with capacities similar to normal stem cells, such as the capability to maintain itself indefinitely. Tumor stem cells are mistaken for the “cell of origin” of a tumor. The actual cell of origin is different in each type of tumor, and does not have to be atumor stem cell. In some cases, for example with a type of brain tumors called gliomas, it is not even known yet.
Hirntumorstammzellen in einer Petrischale, so genannte

Brain tumor stem cells in a petri dish, so called “speroids”. Picture Minu D. Tizabi

But how did this research field come about ? In the Sixties, it was discovered that not all tumor cells have equal tumor-forming capabilities. 30 years down the road, in 1997, cancer researchers Dominique Bonnet and the above mentioned John Dick published a major report on their recently discovered leukemia stem cells in Nature Medicine, thereby starting off a whole new field in cancer research. The cancer stem cell theory was born, and the following years saw the discovery of such cells in many other cancers like breast, brain or prostate cancer. As with every theory in science, it initially had to face lots of doubt and criticism. A breakthrough was made in 2012, when three independent studies were published, all of which heavily supported the hierarchical organization of cells and hence, the cancer stem cell concept using scientifically powerful and conclusive techniques for tracing single tumor cells and their offspring in vivo. Ever since, there has been no more doubt about the general existence of cancer stem cells. A lot of effort in tumor stem cell research has always been directed to finding a so-called marker, a molecule whose presence on a cell reliably identifies it as a cancer stem cell. To this date, no such reliable molecule has been identified – in one way or another, all proposed and utilized markers are disputed and controversial. In fact, it is unlikely that the marker problem is going to be solved at all, and it may be a better bet to try to define them according to their functional properties rather than their surface molecules, although arguably the latter would make therapeutic targeting easier. Unfortunately, a lot of literature in the field is purely based on assays in the petri dish, often conducted not even with primary cells directly derived from patients (which are more difficult to obtain) but with cells derived from long-grown cell lines instead, which are less representative of real tumors. On the other hand, first clinical trials with drugs designed to target cancer stem cells are now under way, so far yielding moderately positive results. Doubts about the existence of cancer stem cells may have been washed away in 2012, but that has not made things much easier. Indeed, we only gradually begin to realize that things may be a lot more complicated and less clear-cut than they initially appeared to be. A major new insight is the realization that different tumors of the same type may rely on entirely different tumor stem cell populations. As if that had not been complicated enough already, it has been discovered that even the very same tumor can harbor multiple different stem cell populations in its midst! And on another note, it may be possible that some cancers follow the cancer stem cell model while others do not. It is difficult to predict what the future will hold for the cancer stem cell field, but it is likely that the abovementioned insights will eventually transform our approach to the questions at hand. First, cancer stem cells have appeared to be a huge trend, even hype within cancer research throughout the last one and a half decades, but the hope set into them stands on a solid experimental basis and is thus justified. Nevertheless, the field is – also due to the lack of standard conditions for important methods – currently struggling with many issues such as the challenge of developing a clear definition of what tumor stem cells actually are and how they can be identified. As with other potential cancer therapies, no one can tell if these efforts will pay off in terms of clinical results – but there is a good chance that they will and the research area might well be headed for a future Nobel prize. So let us all keep our eyes and ears open to future developments in this exciting field!
Slider image: Steve Garry (CC BY-ND 2.0)