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  • Immunotherapy drugs heralded as game changing cancer treatment

  • MD Anderson Professor Allison stripped cancer’s ability to evade attack

  • Nivolumab focuses on the environment around a cancer

  • Immunotherapy drugs are too expensive as sustainable treatments

  • The future is personalized medicine says cancer expert Karol Sikora

A new drug class that neither directly treats nor kills cancer is heralded as a game changer in cancer treatment. 
 

New hope for late stage cancer patients

In March 2015, the American Food and Drug Administration (FDA) awarded an expanded approval for Opdivo (nivolumab), to treat non-small-cell lung cancer, which is the most common type of lung cancer, and means lung cancer patients who have failed other therapies and have no other treatment options, have another shot at containing their tumors. In June 2015, the European Commission approved the same Bristol-Myers Squibb drug in a fast track assessment for previously treated advanced melanoma patients.

Accelerated assessment was given in Europe because Opdivo (nivolumab) qualified as a “Medicinal product of major interest from the point of view of public health, and in particular from the viewpoint of therapeutic innovation.” 

FDA and EU approvals of the drug Opdivo, opens the door for other, next-generation immunotherapies to treat advanced cancers. These are heralded as a new class of game changing drugs. But are they? 
 

The genesis

Because cancer is a result of your body’s own cells growing abnormally, your immune system is held back from recognising cancer as foreign and potentially harmful. This is important because without such checks your immune system would kill you.  

Professor James Allison, director of MD Anderson’s immunotherapy platform, which cultivates, supports and tests new developments of immunology-based drugs and combinations, is credited with ground-breaking research that stripped away cancer’s ability to evade attack by the immune system. Allison’s discoveries led to nivolumab to improve the survival rate of patients with metastatic melanoma, and his insights into the basic biology of immune system T cells is broadly applicable to a variety of cancers. 
 

How it works

These new drugs release the body’s own weapons: killer white blood cells called T cells, and have been likened to taking the brakes off the immune system so that it is able to recognise tumors it wasn't previously recognising, and react to destroy them.

Unlike traditional cancer therapies such as surgery, chemotherapy, radiation or the anti-cancer drugs, immunotherapy does not target the tumor itself. Instead, it focuses on the environment around the cancer, and releases a check on the immune system’s appetite for anything that it does not recognize, so the body’s own defences can recognize tumor cells as targets. Allison says, “This drug doesn’t treat cancer; it doesn’t kill cancer cells so you can’t inject it and expect cancer to melt away immediately because it won’t.” 

However, when nivolumab is combined with tumor-targeted treatments, it lowers the risk of recurrent cancers. It does this by training the body’s T cells to recognize specific features of tumors, just as they do for viruses and bacteria. Thus, the immune system itself is programmed to destroy any returning or remaining cancer.
 

Too costly

Although immunotherapies are generating excitement among cancer clinicians and researchers, clinical studies on melanoma patients show relatively modest prolongations of life, compared with historical norms, at significant costs. For example, the cost of Opdivo (nivolumab) for one patient is about £100,000 per year.

Speaking at the 2015 American Society of Clinical Oncology (ASCO) conference in Chicago, Dr Leonard Saltz from Memorial Sloan Kettering Cancer Center, New York City, suggested that new immunotherapies would cost more than US$1 million per patient per year at the higher dose currently being studied in many different cancer types, and warned, "This is unsustainable.... We must acknowledge that there must be some upper limit to how much we can, as a society, afford to pay to treat each patient with cancer . . As someone who worries about making cancer care available to everyone and minimizing disparities, I have a major problem with this: these drugs cost too much."
      

Takeaway

According to cancer expert Professor Karol Sikora the future of cancer treatment is personalized medicine rather than new immunotherapy products. Personalized cancer care takes into account the individual’s disease, and their personal circumstances. According to Sikora, “The extent to which treatment can be tailored to an individual has been limited by crude descriptions of their disease, and generic treatment options. Advances in genomics and drug responsiveness are leading to more detailed descriptions of a patient’s cancer and better-targeted treatments, which offer significant advantages over blunderbuss chemotherapies. Personalised medicine is the real future for all our patients. Forget the drug hype; this is where the real hope lies”

Here Mike Birrer, Professor of Medicine at the Harvard University Medical School, and Director of the Cancer Center at Massachusetts General Hospital describes personalised medicine:  

         
               

 
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  • Leading cancer scientist says we should abandon looking for a cancer cure
  • Another leading cancer scientist discovers key to killing all cancers
  • Cancer is an inevitable consequence of our multicellular make-up
  • Each person's cancer is unique
  • One in three people will develop cancer in their lifetime
  • Every day 1,500 Americans, and more non-Americans, die of cancer
Most cancers cannot be cured and scientists should devote their efforts to preventing and managing the disease instead of trying to find a cure. That’s the view of Melvyn Greaves Professor of Cell Biology at the Institute of Cancer Research, UK.

 

Game changing cure for all cancers

Greaves’ suggestion comes at a time when Professor Philip Ashton-Rickardt, from Imperial College London discovered a previously unknown protean, which boosts the body’s ability to fight off any cancer or virus. “This is a completely unknown protein. Nobody had ever seen it before or was even aware that it existed. It looks and acts like no other protein . . . . It could be a game-changer for treating a number of different cancers and viruses,” says Ashton-Rickardt.
 

Unanswered questions about cancer

Cancer is an uncontrolled cell proliferation, propelled by mutant genes that invade our tissues and hijack essential body functions.  Some regard this process as a ‘disease of the genome’. Around one in three of us will, at some time in our lives, be diagnosed with cancer; every day 1,500 Americans and vastly more non-Americans die of the disease. Missing from the narrative about cancer has been a coherent framework that makes sense of all its complexities and uncertainties: why are we so vulnerable to cancer, why is there so much diversity between different cancers, and even within single cancer types?  And why does treatment so often fail or only temporarily succeed?

Mike Birrer, Professor of Medicine, Harvard University Medical School and Director of Medical Oncology, Massachusetts General Hospital describes the Cancer Genome Atlas, a landmark cancer research program, which begins to address some of these questions: 


        

                                      

Previously undiscovered protein

The protein discovered by Ashton-Rickardt, named lymphocyte expansion molecule, or LEM, promotes the spread of cancer killing T cells by generating large amounts of energy. Normally when the immune system detects cancer it goes into overdrive trying to fight the disease, flooding the body with T cells. But it quickly runs out of steam.

The new protein discovered by Ashton-Rickardt causes a massive energy boost, which generates T cells in such great numbers that the cancer cannot fight them off. It also causes a boost of immune memory cells, which are able to recognise tumors and viruses they have encountered previously so there is less chance that they will return. Ashton-Rickardt, whose studies to-date have been in mice, is hoping to produce a gene therapy whereby T cells of cancer patients could be enhanced with the protein, and then injected back into the body. In three years he expects to begin human studies. If successful, Ashton-Rickardt’s discovery could end the need for chemotherapies, as the body itself would fight the disease, rather than toxic drugs.

Alex Walther, consultant medical oncologist and Director of Research in Oncology at University Hospitals, Bristol describes the challenges of clinical trails in personalised molecular medicine: 

        
                                                 

Need for smarter cancer strategies

Although sceptical about a cancer cure, Greaves has spent years unravelling the causes of childhood leukaemia by examining the genetic influences and biological pathways that lead to the disease. In 2008, breakthrough research led by Greaves and Professor Tariq Enver, achieved a world-first by confirming the existence of stem cells responsible for childhood acute lymphoblastic leukaemia.

Greaves insists that, “We need to get smarter. Very intelligent people who aren't scientifically minded think there must be a cause, there must be a cure, and it’s just not right. It’s fundamentally wrong . . . Talking about a cure for cancer in terms of elimination is just not realistic. . . . There are a few cancers that are curable, but most are probably not, including the common carcinomas in adults . . . . We should therefore not try to eliminate the cancer, we should try to hold it in check,” says Greaves. 
 

Experts disagree

Leading cancer expert Professor Karol Sikora, is confident cancer cures could still be found, and finds Greaves’ pessimism, “Strange, given that Professor Greaves has done so much to help find a cure for leukaemia. I absolutely think we will find new cures in the future, and the closer we get to understanding the mechanism of the disease, the quicker this will happen.

Professor Peter Johnson, chief clinician at Cancer Research UK agrees with Sikora, “We already have cures for many types of cancer. For example, millions of people who have had breast cancer, prostate cancer or bowel cancer are alive years after their surgery to remove the tumour, if it was caught early enough.” 
 

Molecular Darwinism 

Cancer researchers throughout the world are attempting to find cures for individual cancers using increasingly advanced methods. These include ramping up the body's own immune system to fight the disease; personalized treatments based on the DNA of the tumors, and gene therapies. But Greaves believes no therapy will work in the long term because tumors continue to evolve like all life forms. "Isn't it odd that when you read reports about new cancer therapies they work dramatically, but three months later, cancer is back with a bang. It's almost always the story" says Greaves. 

In his book, Cancer: The Evolutionary Legacy, Greaves describes the Darwinian process by which cancer cells mutate, and diversify by natural selection within our tissue ecosystems. According to Greaves cancer is an inevitable consequence of our make-up as a multicellular reproductive animal. Since multicellular organisms have been around for 700 million years there has been a long time for cancer to evolve; and, without DNA mutation, we ourselves would not have evolved, and adapted into what we are. According to Greaves, "Cancer becomes a statistical inevitability of nature; a matter of chance and necessity." 
 

Takeaways

Evolutionary principles derived from ecology, and the study of human evolution can change the way we think about the big question in cancer research. Will this provide new avenues for more effective cancer control or a cure? 

 
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In July 2014 the European Translational Research Network in Ovarian Cancer (EUTROC), held its annual conference in London. High on its agenda was cancer's resistance to established drugs.

Cancer is a complex disease. It arises from random "errors" in our genes, which regulate the growth of cells that make-up our bodies. Error-laden cells either die or survive, and multiply as a result of complex changes that scientists don't fully understood.
 
Translational medicine
Translational medicine is a rapidly growing discipline in biomedical research, which benefits from a recent technological revolution that allows scientists to monitor the behaviour of everyone of our 25,000 genes, identify almost every protein in an individual cell, and work to improve cancer therapies.
 
Ovarian cancer is the forth most common form of cancer in women, after breast, lung and bowel cancer. Each year, in the UK some 7,000 people are diagnosed with ovarian cancer, in the US it's 240,000. Most women are diagnosed once the cancer has spread beyond the ovaries, which makes treatment challenging, and mortality rates high. Only 10% of women diagnosed with ovarian cancer at the latest stage survive more that five years. 
 
 
Molecular profiling
EUTROC employs a multi-disciplinary, collaborative, "bench-to-bedside" approach in order to expeditiously discover new therapies, which tailor medical treatment to the specific characteristics of specific cancers: personalised medicine.
 
Cancers are like people: not all are alike, and when examined at a molecular level they show that their genetic makeup is very different. Clinicians use molecular profiling to examine the genetic characteristics of a person's cancer as well as any unique biomarkers, which enables them to identify and create targeted therapies designed to work better for a specific cancer profile.
 
Combatting cancer resistance
Personalising treatment to target errors in specific cancers at the point of diagnosis fails to address the fact that cancers mutate in response to treatment. Even drugs that are initially effective may become ineffective as the cancer returns and re-establishes its ability to grow and spread. Cancer often behaves like a taxi navigating a way round a localised traffic jam

 

An approach to combat this is to treat a cancer with one target drug, and if the cancer returns with newly developed resistance, identify how that resistance occurred and target that with another drug, and so on, until the cancer and its resistances are beaten.  This is similar to accepting that a local traffic jam may be bypassed, and finding and blocking all the ways around the jam.
 
Another approach is to target and block something critical for the survival of a specific cancer. This is similar to blocking a strategic point that controls all the traffic coming in and leaving a city. For example, taxi drivers clogging up Trafalgar Square and bringing London to a standstill. But scientists are a long way from achieving this because researchers don't know whether such targets in relations to cancers exists, and even if they did, they don't know whether they can be blocked effectively. And, even if such targets were discovered and were blocked, scientists still don't know what would be the side effects of doing so. 
 
Takeaways
For personalised medicine to be successful, clinicians and scientists need to track the evolutionary trajectories of cancers in patients through sequential episodes of treatment and relapse. Besides being a major clinical and scientific challenge, this is also a significant informational and communication challenge, which networks such as EUTROC are addressing.
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