An easy to understand, comprehensive review of the key immunotherapy drugs and their benefits, side-effects and issues; and how to get them to work to their maximum potential; the review includes PD-1 and PD-L1 drugs and even alternative immunotherapy options like CAR-T, Dendritic Cell therapy, CIMAvax, and T-VEC.
CANCERactive Immunotherapy Review - the new frontier
Active immunotherapy is a hot topic. Not all drugs are technically immunotherapy drugs and, sadly, it is quite common for patients to be given two drugs in the UK and be told they are immunotherapy drugs!
The immune system
There are basically two parts to your immune system - The Innate System which you have from birth and is made up predominantly of T-cells which will attack any rogue cell found in the body. If they fail, Dendritic cells hand some of the rogue cell to your B-cells, which make antibodies. These are like Jigsaw puzzle pieces that perfectly fit the rogue cell and neutralise it. This is your Adaptive Immune System built over your life time. One of the biggest stimulators of this system is the volume and diversity of your microbiome.
PD-1 and PD-L1 drugs - what's the difference?
* PD-1 drugs - or Programmed Cell Death Protein 1, also called a checkpoint inhibitor. These are drugs that aim to block a protein sent by the cancer cells to block (inhibit) T-cell function, so the rogue cells cannot be attacked effectively. PD-1 drugs inhibit the inhibitors so T-cells are unblocked and their attack effects are restored.
* PD-L1 drugs - or Programmed Cell Death Ligand protein 1 - are also checkpoint inhibitors. They are often correctly termed monoclonal antibodies. PD-L1 helps us in our healthy lives by preventing our immune system attacking healthy cells. PD-L1 is a blocking protein on the surface of cancer cells, making these cells less visible to the T- cells.
PD-1 drugs may be used on their own, or in conjunction with PD-L1 drugs. Because the blocking protein can increase over time - it is called drug resistance - PD-L1 drugs are receiving greater attention now.
Either way, there is much you can do to maximise the full potential of your immunotherapy drugs, and even attempt to duplicate their actions if you have not been given 'immunotherapy drugs'.
Maximising the potential of your immunotherapy drugs
There is a great deal of research on this subject. Oncologists in the USA seem far clearer on the potential of this exciting new breed of drugs. At CANCERactive we have helped patients with lung cancer, colorectal cancer and melanoma be signed off, clear of cancer after the 2-year course.
Rather than repeat it all here, we have a separate review of all the research you will need to get the most from your immunotherapy drugs - How to make your immunotherapy drugs work properly. Just click that link to discover the importance of high soluble fibre diets, good levels of plasma vitamin D, the benefits of gut bacteria such as Akkermansia muciniphila and the family Ruminococcus, and the short chain fatty acid called Butyrate that the latter make. And what colostrum or mother's milk, medicinal mushrooms and even heparin from snails, have to do with cleaning up the surface of cancer cells.
List of PD-1 and PD-L1 drugs
PD-1 drugs prescribed are typically Pembrolizumab (Keytruda) and Nivolumab (Opdivo)
PD-L1, immunotherapy or monoclonal antibody drugs include Tremelimumab, Ipililmumab, Tecentriq (atezolizumab), Cemiplimab (libtayo), Durvalumab (imfinzi), Dostarlimab (jemperli), Sintilimab (tyvyt).
CAR-T immunotherapy and vaccines
The basic idea CAR-T is already being used with some patients as are vaccines to boost the immune system.
We have covered several CAR-T Clinical studies. For example -
* New CAR-T lymphoma immunotherapy drug success
* CAR-T immunotherapy provides potential breakthrough in CLL
Side Effects with immunotherapy
Unfortunately, not all is rosy, with increasing reports of severe side-effects and risks of diabetes and even death, especially with the combination double hit immunotherapy treatments being used. In the UK the Checkmate Trial used Nivolumab and Ipilimumab. Five men came to me all of whom were on Prednisolone for liver damage following just 4 months of the two drugs.
Then a rather embarrassing study showing that PD-1 immunotherapy drugs worked twice as well in men as women.
*****
So, that's the quick summary. Here is some of the background and more detail:
Boosting the immune system to recognise the cancer
The basic idea in Active Immunotherapy is to boost a person's own immune system, not just in quantity, but tailored to fight their specific cancer so it recognises the cancer. Of course, there's nothing particularly new or revolutionary in this idea at all; herbalists believe they have been doing this for years. The excitement is being generated because, for the first time, scientists claim to have developed drugs to do it! Expensive drugs at that; and drugs that can be used Integratively (that is alongside your existing expensive drugs).
The claim is also that these drugs that can increase survival times from a few months currently to a couple of years.
Memorial Sloan Kettering Cancer Center's expert in Immunotherapy, Jedd D. Wolchok MD, PhD, detailed the future in Scientific American in 2014. "While mainstream drugs will attack the tumour, immunotherapy may be used alongside to get the immune system to refocus and help. In this way, melanoma drug ipilimumbab has increased survival times from just seven months to over three years in 20 per cent of patients". (Actually, that's not quite true according to the research data below.)
PD-1 and PD-L1 immunotherapy
This was one major area of excitement. A host of top Pharma companies have rushed to strike deals with biotech company Immunocore.
The common interest was Immunocore's Immune Mobilising Monoclonal T-Cell Receptor against Cancer (ImmTAC).
For example, Merck & Co, which built an anti-PD1 antibody Pembrolizumab (Keytruda) and Bristol-Myers Squibb, which made an anti-PD1 drug Opdivo (Nivolumab).
They all work by blocking a protein on the surface of immune T-cells, called PD1, or PD-1, a Programmed cell Death protein. PD1 is a protective mechanism for the cancer cells and stops the immune system from recognising them. The drugs are humanised antibodies - stopping the blocking protein (the checkpoint).
There is also a binding protein on the surface of tumour cells called PDL1. or PD-L1, or PDL-1. (Someone can't make up their mind!!) There are 'checkpoint inhibitors' for PD-L1 too. Atezolizumab, Avelumab and Durvalumab are the PD-L1 drugs
Immunotherapy removes the checkpoints
A phrase you will hear a lot is that 'cancer hides from your immune system'.
Another is that 'immunotherapy removes the brakes or checkpoints that keep T-cells from recognising and attacking cancer cells'.
'Checkpoints' is the new buzz word. Certainly, at CANCERactive, we have seen patients doing well on Pembrolizumab with cancer and increasing survival times by about 2 years. As if that wasn't enough, now there seems to be even more potential by using HIFU with the drug. At CANCERactive, we have long championed HIFU. Another helping agent seems to be T-VEC, an oncolytic virus which helps with melanoma lesions.
Go To: Pembrolizumab and HIFU
Pembrolizumab (Keytruda) has now been approved by the FDA as a first line drug. You do not have to have taken other drugs first.
The modern History of Immunotherapy
The origins of the current wave of euphoria started in the early 2000s when clinical trials on immunotherapy drugs with melanoma, prostate, renal and ovarian cancers took place. By 2008 there were two CTLA-4 monoclonal antibodies in the game - tremelimumab (Pfizer) and a rival from Bristol-Myers Squibb, both showing a potential to give up to four years of extra life to 20 per cent of patients (it was claimed). By 2010 the BMS rival, ipilimumab, became the first drug ever shown to extend survival for patients with metastatic melanoma in a large phase III trial.
According to the research, Ipilimumab reduced the risk of death by 32% and nearly doubled the likelihood of patients surviving to 1 and 2 years, with some patients experiencing complete and durable clinical regressions.
Based on these results, ipilimumab (Yervoy) was approved by the FDA as first-line therapy for advanced melanoma in 2011 (particularly for melanoma that cannot be surgically removed and is not responding to other drugs.
Immunotherapy for all cancers
Of course, there is little reason to restrict the immunotherapy drugs to any single cancer. Why wouldn't nivolumab work on another difficult-to-treat cancer?
Sure enough, in March 2015 the FDA approved Opdivo (nivolumab) to treat a type of advanced lung cancer squamous non-small cell lung cancer, which has grown after patients used platinum-based drugs.
The euphoria was elevated because the drug performed extremely well. Tested in clinical trials against docetaxel, the immunotherapy group lived on average 3.2 months longer. We will come back to this.
In a second, safety trial, where everybody took nivolumab, 15 per cent of recipients saw their tumours shrink or disappear altogether; a further phase I/II trial by Medarex on prostate cancer patients showed similar results.
In yet another study, this time of 582 patients who were known to produce a certain protein, the immunotherapy treatment showed an average of 17.2 months increased survival versus just 5.6 months for the docetaxel. This is the trial the chap from Sloane Kettering was refering to.
PD-1 inhibitors are now used for a number of cancers including breast cancer, ovarian, melanoma and NSCLC lung cancer. PD-1 has been found on the T-cells of people with Acute Myeloid Leukemia (AML); already ipilimumab is showing promise,
There's a lot of rivalry. The makers of Keytruda claim 'no contest' in the performance of their drug over Opdivo. But, of course, it's all about how you do the research.
CAR-T immunotherapy
Chimeric Antigen Receptor - T-cell therapy. Since 2017, six CAR T-cell therapies have been approved by the Food and Drug Administration (FDA). Despite the excitement around these new tailored treatments, they lead to long-term survival in fewer than half of the patients treated (quote from NCI). They have also come under criticism for their cost, which, in the case of the most recently approved CAR T-cell therapy, is more than $450,000 per year.
At the end of January 2016, two rival research groups rushed to get their Press Releases out first on another line of immunotherapy drugs. Fred Hutchinson Cancer Center in Seattle, and the University of Pennsylvania's Abramson Cancer Center have both been extracting T-cells from patients (cells in the immune system that attack the bad guys) and then genetically modifying them with chimeric antigen receptors (CARs) so that they targeted a protein on the surface of the cancer cell. Result? A CAR-T cell that seeks out cancer cells and destroys them..
Professor Stanley Riddell of Fred Hutchinson and his team developed their CAR-T to attack the CD19 protein on B cells in leukaemia and lymphoma. In patients who were terminal with just five months to live, remission was achieved in 90 per cent with just a single dose of the CAR-T, a result Riddell described as 'Unprecedented'. However, a number of patients had to be hospitalised and two died because the reaction was too strong.
In December 2017, two CAR-T drugs were approved by the FDA; one for children with Acute Lymphoblastic Leukemia (ALL) called Kymriah following excellent clinical trial results; the other CAR-T for adults with non-Hodgkin lymphoma by Kite Pharmaceutical. Two CAR-T drugs are approved for multiple myeloma (1)
Clinical Trials are current - for leukemia, lymphoma and certain children's cancers.
The "double Hit" Immunotherapy treatment
Dr. James Larkin is a medical oncologist at the Institute of Cancer Research and a consultant oncologist at the Royal Marsden. He has been part of a team studying the simultaneous use of two different types of immunotherapy - ipilimumab and nivolumab - in a 945-patient trial. The trial recorded in June 2015, that the cancer (melanoma) failed to advance for more than one year in 58 per cent of patients. In all these cases the tumour shrank, or at least failed to advance.
Where just ipilimumab was used on its own, the figure fell to 19 per cent, and then only for 2.5 months on average.
Dr. John Wagstaff at the University of Swansea Medical School has been getting promising results with the double hit immunotherapy drugs and kidney cancer. Meanwhile, Larkin has now moved on to testing radiotherapy with immunotherapy.
Immunotherapy Risks
There are some serious concerns creeping in about heart problems and even death associated with the new immunotherapy drugs, especially the double hit programme. Check out the drugs you are offered carefully.
However another problem has emerged. It seems that in some clinical trials, people who had a negative reaction to the drugs were removed from the trial. It now appears that about 17-20% of people on immunotherapy have their cancer growth speeded up by the drug!
Go to: Immunotherapy can speed up cancer progression
Improving Immunotherapy results
There is a mystery about immunotherapy. It seems, as we noted above, that large numbers of people get a little benefit out of immunotherapy, with only about 17-20% get long-term benefit. Why doesn't it work on everybody?
One answer may lie in Oncologists' reticent to understand supplements and other aspects of the immune response. For example, no attention is paid to patients' vitamin D levels where levels of 100 ng/ml are essential to activating the T-cells to attack. Boston Medical School say all cancer patients should take 5,000 IUs of vitamin D3 or spend 4 hours in the sunshine. But if you are taking cancer drugs, you may well need a double dose according to research.
The mystery may also lie with the extreme damaging effects immunotherapy has on gut bacteria; Research from Chicago Medical School has shown that taking probiotics may well be essential alongside immunotherapy drugs.
Early clues came from research by Lille Medical School, France where it was noted in research that supplementing with Bifidobacteria helped Ipilimumab work. But - the use of ipilimumab actually destroys these very same gut bacteria!
The Mayo Clinic is now teaming up with Evelo Biosciences to test two gut bacterial formulations. It is thought that an immunotherapy drug PLUS gut bacteria could yield greater success.
Not surprisingly it has been found that increasing fibre intake boosts the effectiveness of immunotherapy drugs. Did I say not surprisingly? Well friendly gut bacteria love soluble fibre so it makes their numbers grow; and the immune system's white cells are produced in greater levels in response to greater numbers of gut bacteria!
Professor Thomas Gajewski of Chicago Medical school has even shown which gut bacteria help immunotherapy work - he found levels of Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium were much higher in patients where the immunotherapy drug worked!
Game, set and match arrived when research from the Georgia Medical School showed that taking antibiotics can damage the effectiveness of certain anti-cancer and cancer immunotherapy drugs as, of course, antibiotics not only damage the T-cells essential to helping these drugs work, but damage the gut microbiome as well.
Embarrassingly, results have been emerging from studies showing that even using ordinary chemotherapy drugs plus taking probiotics deliver a combined result as good as the new immunotherapy drugs. People taking chemotherapy drugs should think very seriously about a daily Probiotic supplement.
It's early days yet.
Immunotherapy vaccines
We have an article elsewhere on this website about the immunotherapy Dendritic Cell vaccine, which is full of potential but so far only seems to work in about 15 per cent of cases. But perhaps the greatest excitement comes from Cuba. There, faced with isolation, the regime built their own thriving drug industry - and in 2015 there was a rush to work with CIMAvax, an immunotherapy vaccine showing great promise with non-small cell lung cancer. Roswell Park Cancer Institute are leading the US clinical trials on the vaccine. The vaccine targets Epidermal Growth Factor (EGF) protein, and thus could be used against any cancer where the development of the cancer were linked to this protein.
Another vaccine has knocked out 100% of lymphoma tumours in mice. Human trials have been fast tracked.
Alternative immunotherapy treatments?
1.Nottingham Trent University in the UK is about to go to clinical trials on a new vaccine that they believe will stop prostate cancer growth (Click here).
2. The first bladder cancer drug for 30 years shank 50 per cent of tumours and made the cancer disappear in 7 per cent (Click here) of cases. One does however wonder for how long are the tumours going to stay shrunk. Despite Cancer Research UK's euphoria, excuse us if we say we've heard it all before.
3. German researchers led by Dr. Ugur Sahin of Johannes Gutenberg University, Mainz have been targeting specific mutations around the DNA in tumours. These changes make the cancer vulnerable, and are absent in healthy cells protecting from attack. The vaccines developed don't just stimulate T cell attack, but the whole immune system. The vaccine has been successful in a variety of hard to treat cancers in mouse models.
4.Nascent Biotech, Inc, is the developer of two immunotherapy drugs: Multipharm and Pritumumab.
Multipharm is a platform technology that makes use of multiple agents, like antibodies and cytokines. It is also being considered as a potential therapy for organ transplantation and various autoimmune disorders.
Pritumumab uses a natural human antibody to treat brain cancer and has already been through Phase I and II clinical trials. It is claimed to increase survival rates by 25 to 30%. As always, I'm not sure whether their survival rate definition is the same as yours or mine.
5. Gc-MAF - this is a naturally occurring protein in the body which kicks macrophages into action. But many cancers and viruses produce Nagalase which blocks this action. Answer? Add lots more Gc-MAF into the body. Its a natural immunotherapy and has Health Authorities extremely hot under the collar because they say it is being used without perfect clinical trials. Fans argue that its a conspiracy to stop a natural cheap compound progressing rather than the expensive drugs (Click here for more info). Gc-MAF originated in Japan where it is legal and they are now using third generation products.
6. Rigvir - This is an oncolytic, non-pathogenic virotherapy which has been used in immunotherapy since 2004. The compound is approved for use by the Latvian, and by the Georgian Government Health Authorities particularly for melanoma, but does seem to have a more general effect. It is also used in some German and Mexican Clinics. A recent Clinical Trial reported in October 2015 was well up to Western standards and reported clear increased survival times.
7. A small aspirin - cancers produce a molecule called PGE2 and this blocks the ability of the immune system to see them. A small aspirin has been shown to stop the production of PEG2 by the Francis Crick Institute in London (Click here to read more). So far, research shows that aspirin seems to improve chemotherapy results.
8. Bifidobacteria - if you want controversy, look no further. It is well accepted that certain probiotics in the gut control the immune system. Feeding them high fibre diets increases their number and research shows this increases immune strength. Now research has shown that taking probiotics (and specifically Bifidobacteria) improves chemotherapy results because they boost immune response. The figures (from the University of Chicago) showed chemotherapy plus probiotics BEAT THE NEW IMMUNOTHERAPY DRUGS (Click here to read more)
Immunotherapy, where next?
1. The dominating PR at the moment is for the PD1 and PDL1 drugs - but there are others rapidly emerging like the CAR-T group and more.
2. Immunocore has developed a core compound for rival Pharma immunotherapy drugs. These all seem therefore to work the same way, but to different levels.
3. This PD1 and PD-L1 attack does seem to work. It extends life for a couple of years in about a fifth of users.
4. It is not necessary to take with other drugs. Of course, a key issue is expense, and so oncologists try more traditional (cheaper) options first.
5. No existing immunotherapy can yet be said to be a 'cure' although it may not be long before developments such as the CAR-T immunotherapy show this potential. Again, for some people.
**********
The history of immunotherapy
Immunotherapy has come down a long road.
The idea of immunotherapy started early in the 1900s. William Coley, MD, a Memorial Sloan Kettering Doctor realised that some patients suddenly beat their cancers after an infection. Although, at the time being unsure whether this was due to the temperature rise during infection (which led to the exploration of hyperthermia as a cancer treatment) or whether it was the fact that an outside pathogen had stimulated the patients immune system (and the invigorated immune system then kicked the cancer out), he decided to experiment. His idea was that he would give cancer patients mild infections using his own pathogens that he called Coleys toxins. This was in 1920.
While having some success, the world moved on and the era of chemo and radiotherapy was born.
Now cancer scientists are beginning to wonder if he was right on both scores. Localised hyperthermia seems full of potential (for example, HIFU,Ablation,NanoKnife), as does re-stimulating a patients immune system.
Then came the drugs. Two examples were Interferon and then Interleukin,dubbed Biological Therapies.
Cancer is a failure of the immune system. Under normal conditions, the immune system acts to fight off rogue cells at early stages, but sometimes a cancer slips through the immune net. There can be a number of ways this happens. Blockages may occur at the outset around the cellular DNA, preventing healthy and normal messages being read. The science of epigenetics is working to reverse these blockages. However, cancer may itself produce proteins to disable the immune systems radar. Or it may slightly alter its own identifying proteins and thus hide. Cancer may also produce proteins to disable the immune systems attack squadron.
There is even an alternative immunotherapy called Gc-Maf that claims to combat low levels of nasalise caused by cancer cells action on the immune system.
Interferon and Interleukin are cytokines. Cytokines are signalling proteins produced by white blood cells, and they command certain white cells to go and do their job. So, the basic idea is that injections of these two compounds will re-stimulate certain areas of the immune system, Interferon is used with a number of cancers from melanoma to kidney cancer. Interleukin seems to be delivering better results and you can find more in our research centre Cancer watch.
Monoclonal Antibodies
The idea here is that you take antigens from cancer cells, inject them into, say, mice and harvest the antibodies. They may then be fused with, for example, melanoma cells, resulting in rapidly diving hybrids. The mice portion is then cleaned, removing as much as possible if not all, through genetic engineering. The result is a drug which usually has a name ending in -mab.
They may stimulate an immune response, others may bind to the cancer cell surface, and others interfere with proteins produced by cancer cells helping them take control of the patients body.
A variety of treatments
Other scientists have looked at areas such as Dendritic Cell therapy. Dendritic cells in a healthy body identify and then carry samples of rogue cells to the lymph nodes for assessment; this prompts the production of T-lymphocytes which come out in large numbers to attack that particular type of rogue cell.
Unfortunately, to date these ideas have met with only limited and varied success. Phase III clinical trials have been inconclusive.
Another area is that of cancer vaccines where vaccines are prepared in the laboratory usually from the antigens on the cancer cell surface. These antigens may be general to cancer cells, or specific to one type. The vaccines are then injected back into the body to cause a strong immune reaction.
All of these areas are covered on our website (www.canceractive.com)
The complex immune system
Saying that the immune system is a complex system is probably one of the worlds biggest understatements. And thinking that just one element (drug, herb, or vitamin) might stimulate the whole is a little nave. For example, apart from dendritic cells, your white cells include platelets, granulocytes, T-lymphocytes, B-lymphocytes, macrophages, Natural Killer cells, and a whole lot more.
Typically a hospital will measure your overall white blood count, but this is being shown to be almost meaningless as even a high count may hide a complete shortage of one type of important cell, as my daughter found to her cost. Fighting a brain tumour with a high white blood cell count, but no NK cells thanks to the chemo, can only have one result.
If you want to stimulate the numbers of white cells the American Vital study showed the best high street compound to be Grape Seed Extract. Its an OPC and Pine Bark Extract (which was not in the research) might be even better. Then there is the powerful curcumin, and herbs such as cats claw and Echinacea shown individually in research to have effects on certain white cells. Vitamin E (the total 8 component version of tocopherols and tocotrienols) is another immune system booster. And sleep is a great aid, as your pineal gland produces melatonin which in turn stimulates the immune system.
But the immune system needs to see the rogue cells. Polysaccharides are important and help communication between cells (Nobel prizes have been won for this discovery). Typically, medicinal mushrooms lead the way, but apples, pears and whole brown rice also contain useful polysaccharides, as do herbs like echinacea and curcumin. One Chinese herb, Astragalus, has a double benefit. It boosts the immune cell numbers and helps light up the bad guys.
But even that's not enough. Carting off some of the rogue cells to the lymph nodes stimulates massive T-cell production. But before they can attack they need activating. So first they pick up a vitamin D molecule thats if you have enough in your blood stream. Harvard Medical School recommends that all cancer patients take 5,000 IUs of vitamin D a day thats half a day on the beach in the sun, if you prefer. Finally, somehow, and it is not yet clear, vitamin K helps in the activation process.
Themicrobiome - controller of the natural immune system
And if that werent enough, massive research studies coming from America and Europe are showing that yourmicrobiome (mainly the 90 trillion bacteria in your gut) direct about 85 per cent of your immune system by prompting a reaction from your white cells. Worryingly, research concludes they become ill first, then you become ill. And you cannot become better until they become better. At all times you should ensure you keep your gut bacteria topped up in terms of volume and diversity. In America there is increasing concern from oncologists that their actions with drugs and antibiotics damage your microbiome further.
People reading this article also read:
Dendritic Cell Therapy CLICK HERE
Gc-MAF CLICK HERE
*****
References
1. NCI - https://www.cancer.gov/about-cancer/treatment/research/car-t-cells