fig15_killertSometimes it pays to think differently about a problem. Who would think that treating a cancer without actually targeting the cancer could be a viable strategy? But this is exactly what the latest major breakthrough in cancer therapy has shown.

The breakthrough is in a group of drugs called “Immune checkpoint blockers”. They have already provided remarkable results in the treatment of two of the most common and dangerous cancer types (melanoma skin cancer and lung cancer), and they are being tested in other tumour types with promising results so far. Interestingly, these efficient and powerful chemotherapies do not kill tumour cells directly. Instead, they are cleverly designed to boost the body’s own defences against the tumours.

In order to understand how they operate, it is important to note that the immune system protects our body by recognizing, attacking and remembering potential harmful elements like tumours, viruses, or other invaders. These elements are generally called antigens.

The key players in an efficient immune response are a subtype of white blood cells called T-cells, which are normally in a resting state. T-cells need to get activated in order to start attacking the bad guys. To do so, they need to interact with another type of blood cells, the presenting cells. These search the body for antigens. If they encounter one, they present it to the T-cells, which get activated and start proliferating, moving to the site of the antigen and mobilizing other immune cells to the same site in order to orchestrate an efficient attack.

This outright response is necessary to confront most threats. However, an excessive T-cell activity results in damage to the own tissues or autoimmunity (have a look at this article about autoimmunity in our blog). Hence, the activation of T-cells needs to be counteracted and tightly regulated.

This control is mediated by immune checkpoints, a group of mechanisms which modulate the interaction between T-cells and presenting cells or between T-cells and the target tissue and attenuate the activation of the T-cells and the immune response.

However, these crucial immune checkpoints are often co-opted by tumours in order to escape from the immune system. This leads to the hypothesis that by blocking the immune checkpoint we could reactivate the immune system against the tumour.

This hypothesis was tested in 1996 by injecting tumour cells into mice treated with an immune checkpoint blocker or with a control treatment. All of the blocker treated-mice rejected the tumour. These promising results on animal models prompted the scientific community to explore this hypothesis in human patients. After years of exploratory studies to ensure the safety of the drugs, finally in 2011 the drug was ready to be tested in advanced melanoma patients.

The clinical trial showed a discrete increase in survival of the patients. It is important to keep in mind that even a small increase of survival is a great success when dealing with advanced cancers. Moreover, the toxicity was as expected related with autoimmune problems (mainly in skin and gastrointestinal system) but it was mostly tolerable and controllable. The most striking result was that 20% of the blocker-treated patients seemed to respond to the treatment long term, entering into complete remission. These results open the door to the exciting possibility that these drugs could actually cure the tumours of a subset of patients.

The second generation of immune checkpoint blockers, called PD-1 inhibitors, were described as “Drugs of the year 2013” by some scientific journals. They proved to increase survival not only in metastatic melanoma, but also in a subtype of advanced lung cancer, and in 2014 two molecules were approved for the treatment of those patients. Their toxicity is lower and the percentage of responders is higher. They are also being tested with promising results in other tumours such as renal cell carcinoma and bladder cancer.

The field is now working against the clock to understand which patients are more likely to benefit from the remarkable effects of these compounds and to develop tests to identify them. In the meanwhile, the investment in these molecules is increasing exponentially, trying to quickly develop them and get them into the clinic. And while it is still early days to fully comprehend the long- term benefits of these drugs, it is undeniable that new strategy is a powerful tool to fight cancer.


  1. The key issue that seems to be ignored by medical scientists in looking to use the immune system against cancer is that the immune system is working in conjunction with cancer. You keep rejecting this idea. Let’s suppose that you are right and I am wrong. Explain to me how the following is possible WITHOUT the immune system’s help.

    Cells need to get through epithelium tissues and other tissues, through the walls of blood and lymphatic vessels and other epithelium tissues etc in leaving the primary site and in the destination site which is typically another organ. They can’t do that on their own, they need help, they need for the tissues to become permeable.

    So I ask you, if not the immune system, then by what other means can tissues become permeable as to allow other cells, like cancer cells to exit one area into the blood stream and then leave the bloodstream and enter other areas? My knowledge maybe limited but all I know is that immune cells, which release histamine or whatever else, enable cancer stem cells and other cancer related cells to get through tissues and membranes, by making them permeable. I don’t think the cancer stem cells themselves released anything to make this happen but I could be wrong. There is nothing in the literature to suggest that cancer cells release histamine.

    This is not the only evidence but it is the glaring evidence of cancer and the immune system working hand in hand.

    BTW using the immune system to fight cancer may cause a tumor to go away for a time BUT at a cost.. That cost is AUTOIMMUNITY and it is well enough documented. The bargain is “live another few years while the cancer mass regrows but having to now also suffer autoimmune disease of some sort”. Bah!.


    • Dear Kyrani99

      Thank you very much for your interesting comment. Let’s see if I can answer to some of your concerns.

      Regarding your comments about the immune system working in conjunction with cancer, most of the scientific field- including myself- agree with you. Actually, that is the whole point of the article!! Cancer cells “kidnap” many of the defence mechanisms to avoid the immune system’s surveillance. Moreover, inflammation- which should defend us from threats- is often a risk factor for suffering different sorts of cancer.

      Furthermore, as you are pointing out in your comment, inflammation can influence the capacity of the cells to move from their primary site to their metastatic site. The signalling involved is quite complicated, and includes many substances (“cytokines”) apart from histamine, which is not particularly involved in this process.

      Let me point out, however, that cancer cells do express many genes that are involved in interacting with the immune system to facilitate their survival and their migration. Have a look here (http://www.nature.com/nature/journal/v454/n7203/full/nature07205.html) for more information on this interesting subject.

      Also, cancer cells do acquire the capacity of moving regardless of the immune system. Again, the mechanisms involved are quite complicated. A nice way of picturing it is thinking about how much cells have to move in the embryonic state to form all our body from one single cell. Well, it has been shown that cancer cells re-acquire some of those embryonic features, which allow them to move much easily.

      So the take home message is that the interaction of cancer cells and the immune system is very complicated. This new generation of drugs try to make the immune system recognize the tumour cell as “bad” and attack it, instead of creating an unspecific inflammation which not only is in the long term unable to eliminate the tumour, but it can even help it grow and invade.

      Finally, regarding your concerns about autoimmunity: You’re right; autoimmunity is the most frequent secondary effect, in keeping with the mechanism of the drugs. Nobody is trying to hide it! It is, however, as I specified in the article, mostly tolerable and controllable with steroid therapy. Everything is a matter of risk versus benefit. In the cases we’re discussing, patients often have a life expectancy of months, and so autoimmune problems are understandably considered an acceptable risk.


  2. Hello myriamsolar,

    I don’t see that we are in agreement.
    It may appear that in the cases where there is inflammation that cancer cells could possibly “use the situation” so as to leave the site and enter the bloodstream. But this is insufficient to explain all that happens in metastasis.

    Firstly there is metastasis from sites where there is no inflammation.
    And in many cases the destination site has no inflammation. So we have to explain a number of manouvers that the cells need to do, especially to be able to move outside the epithelium membrane and enter the blood stream.

    Secondly we need to be able to explain how it is that cells can exit the bloodstream when they need assistance from the immune cells. As you mentioned cytokines are an important aspect.

    The cancer cells need to exit the blood capillary walls. To do this they need a number of things but two important ones are that the cells of the epithelium tissue in the required area become detached so that there is space enough for the cancer cells to exit. However before that can happen the cancer cells need to get out of the bloodstream, which is traveling very fast (someone told me at about 70mph), slow down and stick or roll along the vessel wall at the right place to make an exit. This requires resident macrophages to release cytokines in order for the endothelial cells of the blood vessels to express cellular adhesion molecules including selectin. Thus the cancer cells and other stromal cells that travel with them in a group ( which has been seen I’ll try to find the scientific article) can adhere to the endothelial and hence have a chance to get through the tissue. I don’t think it is correct to say “cancer cells do acquire the capacity of moving regardless of the immune system”. Cancer cells need immune cells co-operation in metastasis.

    I agree there are parallels with cells moving in the embryo but here we are talking about stem cells. And you say they “re-acquire some of those embryonic features” but they don’t do this out of damage and then Darwinian micro evolution and natural selection processes as is being proposed in the official cancer story. The truth of the matter is that cancer cells are stem cells and they have up-regulated through epigenetics and other deliberate changes such as mosaic deletions or inclusions. This was discovered by Barbara McClintock (her career span from about 1930s to 1980s).

    She discovered “transposable elements, genes that change position among the chromosomes”, which are now talked about as “frame shifts” and attributed to miscopying or damage from so-called carcinogens. She also discovered what she called breakage-fusion-bridge (BFB) cycles. BFB occurs at a predictable site on a given chromosome, thus providing a means of producing directed mutations i.e., changes. These are also pointed to as an aberration these days and claimed to be caused by damage or miscopying.

    The reality is that the genome is very dynamic but it is being interpreted as genomic instability. This then sells the rogue cell story of cancer and thus as cancer cells being “bad” so there is a case made to justify immunotherapy for cancer. This means the immune system is trained to attack “self” cells and thus the autoimmunity.

    What I am saying is that cancer is stem-cell mediated immunity, which is erroneously ignited in the body much like inflammation that attacks normal body cells giving rise to dermatitis and other autoimmune diseases. Why does this happen?

    While scientists adhere to “the body is a machine” paradigm, they can justify physical causes as being the cause of disease and hence make drugs to treat but none can cure the cancer and they poison the body in the process. However if one is data driven then one has to accept that the body is purpose-driven, which means the whole picture changes. Ideas that are taken to be real or true, i.e., they have become belief begin to play a huge role.

    The scientific evidence.
    In clinical trials that test for chemotherapy drugs, the people in the control arm who are given a blank, i.e., sugar pills and saline solutions or even distilled water, suffer the same side effects as those in the intervention arm who have been given the toxic drug BUT for different reasons.

    Those with the toxic drug suffer damage to rapidly dividing cells such as at the root of their hair so their hair falls out. Those in the control arm have only taken sugar or water, so there is no damage to these cells. HOWEVER those among them, who believe that they have taken the toxic drug (in fact they choose to believe it because they are desperate for a cure), they will then believe that the root of their hair will be damaged by the toxic drug. This belief ignites an inflammatory response. So the cells at the roots of their hair become damaged due to inflammation. A belief leads to inflammation, which causes damage so their hair falls out.

    Along these lines…
    i.e., if there is the perception of damage and it is believed, then the body ignites an inflammatory response, whether there is damage there or not.

    we can say that if there is the perception of possible damage then the body will move to build a protective barrier to minimize or avoid damage to the organ tissues. Of course the only barrier the body can build is with cells. Stem cells modify their genomic expression, to up-regulate genes, make many copies, create deletions and frame shifts in order to generate the type of cells that it is perceived are needed, eg dormant, dense cells whose purpose is to ward off or fence off some region or regions as is believed require protection.

    When a person can appreciate that the action taken is mistaken and unnecessary the body will move to clear away the mass. It will revert the cells back to fully-specialized cells of what ever tissue they belong to, to revert some back to stem cells needed for tissue integrity and repair and to clear away the excesses by apoptosis.

    One can either by:
    1. addressing the beliefs, realizing that they are false ideas not based on sound evidence, or
    2. by simply understanding the foul game play or cheat that is behind cancer,

    effect deliberate cancer remission. I have done it on a number of occasions.

    The body will store cancer stem cells for future use, just as it stores any and all immune products, eg antibodies. Having had cancer I have cancer cells in my body. These cancer stem cells remain dormant just as antibodies are dormant until it is perceived that they are needed. On understanding the problem well one can go further to “stage-manage” one’s biology as to never develop cancer. You can bullet proof yourself against cancer.


  3. melanoma skin cancer and lung cancer are very common among our society. If this new strategy can work well in this field. I do believe that it will not be so long for researching other treatment to other types of cancer.


    • Thanks for your comment, coimminoprecipitation. You are very right. Actually, in November 2015, some weeks after my post,a drug of this group was approved for some types of renaercancer.


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