Immunotherapy: new hope in the battle against cancer

Immunotherapy is a burgeoning sector that heralds a breakthrough against the world’s second-most deadly disease. Dr Mike Tubbs explains how investors can benefit too.

Cancer is the world’s second-biggest killer. The disease is responsible for around one in six deaths globally; 9.6 million people succumbed to it in 2018, while 18.1 million new cases were diagnosed. In 2025 there will be more than 20 million new cases, according to the World Health Organisation’s International Agency for Research on Cancer, and 29.5 million in 2040. To reduce cancer deaths we need new treatments beyond the conventional options of surgery, radiotherapy, chemotherapy and drugs discovered years ago. Fortunately, the last few years have seen a breakthrough in cancer treatments as a new field of research has developed: immunotherapy.

A new approach

Cancer immunotherapy is a new method of fighting cancer that uses the body’s own immune system to kill cancer cells where they are growing. This doesn’t happen naturally. The immune system is wired to conduct safety checks that prevent it attacking normal body cells. Cancer cells cleverly use these checks to fool the immune system into thinking tumour cells are just like normal cells – in other words, the cancer cells make themselves invisible to the body’s T-cells (white cells tasked to deal with disease carriers). That means T-cells cannot recognise cancer cells and therefore cannot attack them. The techniques of immunotherapy are all based on various ways of removing this cloak of invisibility from cancer cells and helping the immune system work better at destroying them.

The first immunotherapy drug to consistently improve survival, Yervoy (from Bristol-Myers Squibb), was approved in 2010 for treating metastatic melanoma (one that has spread to other parts of the body) and there are now at least ten immunotherapies approved for treating cancer with several approved for many different cancers. The fast pace of research is clear from the 2,000 or so ongoing clinical trials of new immunotherapy drugs. That will drive growth of the global cancer immunotherapy market from $40bn in 2017 to $170bn by 2028.

Miraculous results with some cancers

Immunotherapy can have miraculous results for particular kinds of cancer. One famous case is Philadelphia’s Stefanie Joho. Her colon cancer was raging out of control, with a massive tumour appearing in her abdomen despite surgery and chemotherapy. Her oncologist said there were no more treatment options left. However, Stefanie’s sister Jess discovered a clinical trial at Johns Hopkins University and Stefanie joined it. It was a trial of Keytruda, a drug not then approved for colon cancer, but which had helped treat former president Jimmy Carter’s brain and liver cancer. The results on Stefanie were remarkable: her tumour shrank and then disappeared, leaving her free from all signs of cancer. Further investigation showed that Stefanie had a genetic glitch called MMR deficiency; her cancer had many more mutations than usual and it was therefore more likely her immune system would recognise it and attack it with the assistance of Keytruda. In 2017, America’s Food and Drug Administration (FDA) approved Keytruda to treat colon cancers of Stefanie’s type. There are many similar stories of patients with advanced cancer whose lives have been saved by immunotherapy drugs.

Three key types of immunotherapy

There are three important types of immunotherapy. The first is antibody checkpoint inhibitor therapy (ACIT). ACIT uses monoclonal antibodies (a type of protein produced in a laboratory) to target immune checkpoints, which regulate pathways in the immune system that stimulate or inhibit its action. Checkpoint therapy blocks checkpoints that tumours use to protect themselves from the immune system. This blocking flags up tumour cells so that the immune system can recognise and attack them. The second sort of immunotherapy is known as T-cell therapy, of which CAR-T cell TCR are the best known examples. T-cells are taken from the patient and genetically modified to add a chimeric antigen receptor (CAR), which specifically recognises cancer cells. The resulting modified CAR-T cells are multiplied outside the body and then reintroduced into the patient to attack tumours. CAR-T therapy in the US famously treated the leukaemia contracted by Zac Oliver, a young man from Shropshire, after a Daily Mail fund-raising campaign. He was declared cancer-free last month.

Mixing and matching

One of the frustrations of many early immuno-oncology drugs is that they work very well on only some patients and with only some types of cancer. This is why a lot of effort is now being put into the third approach: combination therapies (CT). They aim to enhance the immuno-stimulatory response by combining two different antibody therapies, or an antibody therapy with a conventional pharmaceutical one. Bristol-Myers Squibb’s mix of Opdivo and Yervoy, for instance, combines two ACIT antibody therapies, each targeting one of the body’s two main proteins critical to the immune system’s ability to control cancer growth. The Opdivo+Yervoy combination is the first treatment for metastatic melanoma with a better-than-50/50 chance of patients responding. Another example is the combination of Keytruda with chemotherapy for lung cancer, which is more effective than either alone.

New lines of enquiry

Two further categories of immunotherapy exist, but here drugs are only just beginning to emerge. Oncolytic virus therapies (OVT) are being pioneered by Amgen. A virus is injected into the tumour, enters the cancer cells (but not healthy ones) and makes copies of itself so the cancer cells burst and die. Amgen’s Imlygic uses modified herpes viruses to do this. Cancer vaccines, meanwhile, expose the immune system to an antigen that the immune system then recognises and destroys – in this case, cancer cells.

With more and more immuno-oncology drugs and other treatments for cancer being approved, doctors need to find out which drug is most suitable for a particular cancer in any specific patient. This is particularly important for certain cancers, such as Stephanie Joho’s, where immunotherapy can produce a miraculous cure. The answer lies in genomic testing, an area covering people’s genetic predispositions to certain types of cancer as well as the genetic make-up of tumours, which can help discern how they might develop.

There are now several genetic tests for tumours on the market that can indicate the most effective treatment. This helps to make targeted precision cancer treatment a reality. Examples of such tests are Oncofocus® from Oncologica® and FoundationOne from Roche. Given the range of cancers treatable with the checkpoint inhibitors Opdivo, Keytruda and Opdivo+Yervoy, a test called the Tumour Inflammation Signature (TIS) has been developed to help predict whether patients will respond to these drugs.

Since the first effective cancer immunotherapy was approved in 2010, many other single and combination immunotherapies from major biopharma companies have been approved for various types of cancer. Their 2018 sales vary from less than $100m to $7bn.

Opdivo: another miracle cure

The only two super-blockbusters – boasting sales of over $5bn – are Opdivo and Keytruda, which both have sales of around $7bn and have at least nine approvals each for different types of cancer. Stefanie Joho’s colon cancer was cured with Keytruda, and Opdivo has had similarly miraculous effects. The US Cancer Research Institute cites Maureen O’Grady, 62, who in 2009 was diagnosed with stage-four (the final stage) lung cancer that had spread to her liver and heart. She was given a year to live by her doctors. She tried chemotherapy, which had horrendous side effects and merely slowed the growth of the cancer, and also Tarceva, a conventional lung-cancer drug.

She stopped both chemotherapy and Tarceva after discovering a clinical trial of Opdivo at Yale. She joined the trial in early 2010 and found she had almost no side effects from Opdivo. Her first scan after eight weeks on Opdivo showed she was responding dramatically to treatment. The tumours shrank to almost nothing after two years and Maureen was alive and well six years after original diagnosis. Dr Herbst, chief of medical oncology at Yale, said: “In 25 years I’ve never seen anything like it.” The FDA approved Opdivo for lung cancer in 2015. The potential of these drugs, then, is enormous – and small biotechs as well as giant pharmaceuticals are getting in on the act. Below, we look at how investors can profit.

The stocks and funds to consider now

There are four main ways for investors to participate in the success of immunotherapies. The first is to back large biopharma companies that make a substantial proportion of sales from immunotherapies and have promising new ones in the pipeline. Two of these companies – Bristol-Myers Squibb (NYSE: BMY) and Merck (NYSE: MRK) – stand out, with super-blockbusters Opdivo and Keytruda. No other firms at present have even a blockbuster (sales more than $1bn a year) to their name.

The FDA approval history of Opdivo shows how its range of application has expanded following first approval for advanced melanoma in 2014. Approvals for lung cancer and kidney cancer followed in 2015, hepatocellular cancer in 2017 and expanded kidney and colorectal cancer indications in 2018. Opdivo/Yervoy combinations have been approved for melanoma (2015 and 2016) and for kidney and colorectal cancer in 2018. Keytruda has a comparable approval history to Opdivo.

Bristol-Myers Squibb had immunotherapy sales of more than $8bn in 2018, or 35.5% of total 2018 sales, making cancer immunotherapy a substantial proportion of revenue. It is taking over Celgene, a blood-cancer specialist, which in turn has bought Juno Therapeutics, a firm with a pipeline of CAR-T therapies. The combined companies would have had 2018 revenues of $37.9bn.

For Merck, Keytruda’s $7.2bn of 2018 sales made up 17% of total revenue (of $42.3bn). A small immunotherapy portfolio should therefore contain Bristol-Myers Squibb and Merck.

Many smaller firms have pipeline immunotherapies, but no approved drugs on the market; only a few, such as Tocagen (Nasdaq: TOCA) have Phase-III trials (the final stage of clinical tests) in progress. Most are based in the US, which has 30 of the top 46 immunotherapy start-ups; four are from the UK. Investment success depends on the smaller company either being acquired or partnering its key drug with a large biopharma. Brave investors willing to do a great deal of research may wish to explore this sub-sector.

Another approach to the immunotherapy boom is to invest in the industry’s suppliers: companies making things needed to diagnose or develop immunotherapies. Enter Illumina (Nasdaq: ILMN), a world leader in genomic testing used for deciding which drug is likely to be most effective for any particular combination of tumour and patient.

Grail, a company spun out of Illumina and soon to be floated, is developing a DNA-based blood test for the very early detection of cancer. Consider also MorphoSys (Frankfurt: MOR), a supplier of antibodies, many of which are used for cancer drugs.

A fourth way to gain exposure is through funds, although the main biotech and healthcare-orientated trusts do not have especially large proportions of their top-ten portfolio holdings in cancer immunotherapy companies. The Biotech Growth Trust (LSE: BIOG) has Celgene, Illumina, Gilead Sciences and Amgen accounting for 26.1% of its portfolio, while the BB Healthcare trust (LSE: BBH) contains Illumina, Celgene and Bristol-Myers Squibb, jointly contributing 32.6% of the overall portfolio’s value.

Given that most cancer immunotherapy companies are in the US, another option is to track the Nasdaq Biotech index directly. This can be done with the iShares Nasdaq US Biotech ETF (LSE: BTEC), which charges 0.35%. Illumina and immunotherapy groups Gilead Sciences, Amgen, Incyte and Celgene jointly comprise 30% of the index.

Source: moneyweek.com

Dr David Fenelly

MD FRCPI ESMO

Former: Consultant Medical Oncologyst St Vincent’s University Hospital (SVUH); St Luke’s Hospital, National Maternity Hospital; St. Vincent’s Private Hospital; and Blackrock Clinic, Dublin; Member of International Advisory Board of Oneview Ltd. and Oneview Healthcare PLC; Member Director Centre for Colorectal Disease of SVUH;

Member of American Society of Clinical Oncology, European Society of Medical Oncology and Irish Society of Medical Oncology; Fellow of Royal College of Physicians; Formerly: Member of Breast and Gynaecological Cancer; Post Graduate Training from Memorial Sloan Kettering Cancer Centre.

Prof Umberto Tirelli

MD

Former: Consultant Medical Oncologyst National Cancer Institute Aviano; Specialist in Oncology, Hematology and Infectious Diseases; “Commendatore” of the Italian Republic, awarded by the President of the Republic for scientific merit; co-founder and VP of the Associazione Scientifica Galileo 2001; Member of the Technical Scientific Board (CTS) at Centro di Riferimento Oncologico (CRO) in Aviano, Istituto Nazionale Tumori; Assigned to the Scientific Council of AIN (Associazione Italiana Nucleare) on nuclear power; Former President of AIMAC (Cancer Patients Italian Association) and now part of the Scientific Council;

Formerly appointed by the Italian Minister of Health as member of the National Oncology Commission; Member of the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the American Society of Hematology (ASH),and the International Immune-compromised Host Society (IHS); Member of the Scientific Committee of the AIOTE (Italian Association of oncology of the elderly);

Task Force Member (EORTC – European Org for Research and Treatment of Cancer) – Cancer in the elderly; Member of National Academy of Medicine for medical oncology (AIOM);  Environmental Comm. Committee mmber appointed by the Minister of the Environment.

Prof Daniele Generali

MD

Former: Consultant Medical Oncologyst, Azienda Istituti Ospitalieri, Cremona and Prof of Medical Oncology, Trieste Univ; Former Prof of Molecular Oncology, Institute of Molecular Medicine, Oxford Univ. Member of the Board of European Commission for initiative on Breast Cancer; Director of the Unit of Molecular Therapy and Pharmacogenomics, Azienda Istituti Ospitalieri, Cremona; Clinical Director of the Italian Red Cross, Cremona Section; Scientific Director of the Association of Research in Oncology Onlus, Cremona.

I would just like to thank you all for your help, support and professionalism this year, I contacted you after my recurrence of breast cancer, everything was explained to me in detail and I decided to go ahead with the test, I am so glad I did, every one I dealt with was so kind and encouraging, I was very scared about the journey ahead of me. The promptness of all the team was amazing my biopsy was collected quickly and I was contacted by Sarah constantly with updates on what was happening. As soon as the tests were completed I was sent the report with a follow up telephone call from the Doctor who talked me through it, he said he would be available to answer any further questions.

I showed the report to my hospital. Doctors and they were impressed with the information gathered and I am on the drugs recommended in my report and I have been really well with no side effects. Thank you all again.

I would like to pass not only my, but my father’s, gran’s and entire family and friends appreciation to not only Oncologica® but to you directly. Sarah, you went above and beyond what was expected, you took a personal interest and gave huge support. Your tone was always polite and you helped to listen to myself during the emotional moments when speaking. The hope you as a person gave and the encouragement, helped when I had to mount the challenge on behalf of my mother and father. Myself and my father agreed before taking to Oncologica® that as long as we tried all avenues and did everything we could for my late mother, this would be the only way we could coped.

Without yourself and Oncologica® we would not have been able to achieve the goal. My late mother took hope, encouragement and huge amounts of mental positively from the work but more importantly the personal touch you gave. As a person your indirect support helped my late mother. A person who didn’t praise health professionals easily due to career in the NHS and private sector. She praised you from the information, hope and personal feel you gave. You helped to give her peace of mind and know all options were looked into. I can’t sum up our, my feelings as they hold you in the highest regard. Perhaps, to say you have our eternal gratitude summons it all.

I just wanted to get in touch to thank you and the whole team at Oncologica® for the reports you did for my Dad. Despite a very poor prognosis, following the advice in the Oncologica® reports he has been receiving an immunotherapy drug under Dr Fennelly in St Vincent’s Hospital, Dublin, since the early spring and is now in much better health. The latest scans show a significant reduction in the size of the main tumour and a stagnation in the growth of secondary tumours. He is no longer in significant pain and is able to enjoy day to day life again. Thank you all for your hard work, we really appreciate it.

After being diagnosed with stage 4 lung cancer my mothers only treatment option on the NHS was chemo therapy. The doctors gave her 6 months without treatment and only 9 with treatment but her quality of life would have been awful if undergoing chemo therapy.

After finding Oncologica® their help, advice and support have been second to none. Their ground breaking analysis and treatment options enabled my mother to undergo immunotherapy which has successfully reduced the size of her tumour and thankfully she is still with us over 2 years later. This would have not been possible without Oncologica®!

Without Oncologica® we do believe that my mother would no longer be with us but through them and their continued support she is still hear and enjoying her life with us and able to watch her grand children grow and play. We cannot thank Oncologica® enough for everything they have done and their continued support and cannot recommend them highly enough.” Many, many thanks from the whole family.

Karan Jensen was diagnosed in 2017, aged 48 with cervical cancer. Karan ordered the Oncofocus® Test to identify additional treatment options and shares her story here in the following Q&A.

How did your diagnosis come about?

I had been having regular smear tests, but then one came back with irregular cells and the doctor asked to see me in 6 months time. We were moving, so I delayed going back, but when I did get to the doctors, they ended up doing a biopsy. Within 2 weeks I was diagnosed with Stage 2B cervical cancer with lymph node involvement.

What happened after you were diagnosed?

Treatment was started to cure my cancer. I had four cycles of chemotherapy plus 32 sessions of radiotherapy.

Did this treatment work?

Unfortunately, the tumour did not change with this type of chemotherapy, so I then started on alternative therapies.

Did the second round of treatment work?

I was meant to have six sessions of this chemotherapy, but after three, I had a scan and found out that the tumour had grown. I was told that there was no point continuing treatment as my cancer was incurable, and to go home and get things in order.

Did you experience any side effects of chemotherapy?

During chemotherapy, I was hospitalised four times with infections and neutropenic sepsis. The chemotherapy also caused swelling of my legs (lymphoedema), and my kidneys had been damaged so that I had to have a nephrostomy bag attached to collect urine.

How did you feel when they told you that you cancer was incurable?

I have an 11-year-old son, so I was not going to give up and did some research online on the best treatments for my cancer.

What did you find searching online?

I found out about the Oncofocus®® cancer test by Oncologica® on their website and got in touch.

Was it easy getting the Oncofocus® test done?

It cost £2000 but it was an easy decision to make. I just had to fill in a few forms and Oncologica® did all the work to get the biopsy from my hospital.

What were the results of the Oncofocus® test?

The test quickly came back that my tumour was exceptionally high in a protein called PD-L1, so it would respond really well to immunotherapy, which works by boosting a person’s immune system to help it recognise and fight cancer cells.

What happened when you knew the results of the test?

The treatment that the test recommended was not available on the NHS so my oncologist contacted Christie Hospital in Manchester, which was part of the PROCLAIM-CX-072 clinical trial that is investigating an experimental drug that targets PD-L1.
I was very sick at this stage, and the doctors were not sure that I would be well enough to get into the trial. As my levels of PD-L1 were so high, however, they thought they had to give me the opportunity.

Was this new treatment successful?

I was meant to have four sessions of CX-072 plus ipilumumab every 3 weeks, plus CX-072 maintenance therapy for a year. Although the treatment was not as bad as chemotherapy and I did not lose any hair, it still made me feel very poorly. After the third session, I developed a bad reaction and the level of some of my white blood cells that fight infection, neutrophils, plummeted and could not be restored to normal. It was therefore too risky to continue the treatment.
The good news was that a scan in March this year showed that the new therapy had reduced the tumour by 50%.

Are you still receiving treatment?

Even though the treatment has stopped, my immune system has taken over and is fighting the tumour. I am scanned every 2 months, and every time my tumour reduces by a further 0.5% to 1%. Last week I had another scan, and it had reduced by 3% and I feel better today than I have over the past 3 years.

What are your thoughts on the Oncofocus® test?

If I had had the test before receiving chemotherapy, this would have saved the NHS a load of money giving me a treatment that did not work and putting me through so much. I continue to need a nephrostomy bag due to the damage done by chemotherapy, which needs changing once a week and the tubes replaced in hospital every 3 months.

What is happening now?

We are now at the ‘watch and wait’ stage. However, as I have had such a good response to the immunotherapy and feel so much better, I can have more treatment if needed in the future. The swelling in my leg has gone down and I can now wear my shoes and move around normally again. I was so sick that I did not think that I would see last Christmas. Now I will get to experience Christmas again this year.

I was diagnosed with terminal bowel cancer in March 2018. I started radiotherapy, which worked well. The tumour then started to cause a build up of fluid in my abdomen, which chemotherapy helped to reduce. However, when the first line chemotherapy stopped working after 5 months and then the second line chemotherapy failed to work at all, the fluid returned and I had two stays in hospital to help drain it.

Having exhausted standard therapy and become bedbound, I found out about the Oncofocus® Test from an online search. The overall process from submitting the form to Test results was easy and rapid. The company called to talk me through the process and to explain the results of the Test, and also took care of the logistics of collecting the sample from the hospital. It turned out that I have a rare cancer mutation and was lucky to have had a response at all to the initial chemotherapy.

I had a remarkably effective and rapid response to the drugs that the Test recommended for my cancer mutation. After just 2 weeks of treatment, my abdomen returned to normal size. After 4 weeks of treatment, I was swimming, walking and fully enjoying all that life has to offer again. I am truly grateful for the significant improvement in quality of life I experienced, especially as I had no side effects from the new drugs. The extra months that this gave me meant that I had further quality time with my family and could prepare them better for life without me.

A father of two with terminal cancer has been given new hope after being offered a free pioneering test to help find alternative treatments.

Mick Weldon, 38, from Cambourne, has a rare form of stomach cancer which is resistant to conventional forms of treatment.

In April, the News reported on Mick’s efforts to crowdfund enough money to cover the cost of analysis of new treatments.

After reading his story, Cambridge-based research company Oncologica® approached Mick to offer a ground-breaking test for free.

Mick was first admitted to hospital in December 2015 with a suspected ruptured ulcer, only to be later diagnosed with a cancer that had spread to his abdomen, liver, and surrounding organs.

Doctors found that Mick had a rare subset of Stage 4 GIST stomach cancer called wild type SDH deficient, which is incurable, but could be held at bay by new drugs.

Normally costing around £1,500, Mick under went an Oncofocus® test, which has been developed to detect every mutation linked to every drug and applicable to all tumour types.

Oncologica® claim that the test can identify specific treatment options in 85 to 90 per cent of patients.

Mick’s results show that a certain protein, PDL-1, expressed by his tumours, was acting as a ‘cloaking agent’ and effectively hiding the tumour from his immune system.

He now hopes his crowdfunding efforts will help to finance three cycles of anti-PDL-1 drugs.

“I’ve gone from having no options to a lot of options,” he said. “I’m amazingly positive. I’ve gone from a place where I had no hope to where I have a viable option. We’re all really upbeat.”

Mick hopes new treatments will give him more time to spend with his wife Emma and daughters Charlie, 17, and Rebecca, 15.

He previously said: “No one prepares for their own death, no wife wants to stand by and watch her once proud strong husband slowly degrade, and I can’t even begin to imagine how hard it must be for two beautiful young ladies to watch the father they have looked up to for as long as they have known slowly slip away.”

If Mick is able to secure the funding for his three cycles of drugs he hopes the evidence gathered will benefit other cancer patients.

“The NHS needs evidence,” he said. “We have to prove these drugs are viable.”

“I’d like to be in a position to start up a database where people can find this information where people can look up their options.”

He also remains realistic about how any new drugs will help his condition, but very thankful to the support of Oncologica®.

“Even if this fails, at least something is being done and I’m not just waiting to die,” Mick said.

“[Oncologica®] are absolutely amazing people. It buoyed me up. Until that point I was coming to the end of conventional treatment.”

Dr Marco Loddo, co-founder and scientific director at Oncologica®, said: “We saw the article and learnt about Mick’s story and in particular that his tumour type was quite rare and found out that he had exhausted all treatment options on the NHS.

“We hoped that we might be able to help with our tests. We’re happy to help.”

Oncologica® is a precision oncology services laboratory and contract research organisation founded in 2014.

Its Oncofocus® test aims to help encourage a move away from toxic non-specific cancer treatments to the use of the new generation of biological anti-cancer agents called targeted therapies.

Targeted therapies specifically hit cancer cells and not the normal cells of the body. They are said to be more effective than chemotherapy because patients are spared severe toxic side effects such as hair loss, infections, anaemia, gut toxicity and fatigue.

Professor Gareth Williams, co-founder and medical director, said: “What we are doing is to optimise the treatment pathway to provide a roadmap and that can have huge benefits for patients. You can avoid all the toxicity issues.”