Immunotherapy is a relatively new method of fighting cancer and it has become increasingly common in recent times. Unlike many other forms of treatment that can produce unnecessarily unpleasant side effects (such as with chemotherapy), immunotherapy entails using the patient’s own immune system. This is a far milder means of treatment. It uses natural defences and therefore causes less damage. While it is necessary to remove as much of extractable tumours as possible through surgery, it can then be a possibility to use immunotherapies to eradicate the remaining cancer cells, rather than continue with the more abrasive treatments. My research question is therefore ‘how do immunotherapies work as a treatment of cancer and how successful have they been?’.
Normally, the body’s natural defences are capable of detecting and eradicating abnormal cells (cells foreign to the body) that could develop into cancer. Unfortunately, some cancers are capable of avoiding these defences by producing signals that make it harder for the immune system to detect them or by changing themselves so that they are harder to recognise. Immunotherapy seeks to restore or enhance the ability of the immune system in the face of these problems. These therapies either stimulate the activity of certain parts of the immune system or neutralise the signals produced by the cancer cells that inhibit the immune system.
One of the reasons why immunotherapy is not extensively used yet is because each patient is different and therefore their immune systems may be affected by different factors. Some patients may have stronger immune systems than others due to age or diet and therefore different specific therapies will have to be formulated for the individual. There are several main treatments that have been developed with this in mind and I shall be addressing four of them in my article along with corresponding case studies. Each of these therapies works in a different way and has had varying levels of success. A brief explanation of how the immune system battles cancer will first be stated.
How the immune system fights cancer
When abnormal cells are present in the body, they display a specific antigen on their surface. This allows the immune system to have a specific reaction to that antigen and destroy the abnormal cells accordingly. It does this by way of its ability to recognize that the antigens are foreign to the body. When this system fails, it is due to strategies formulated by the tumour cells which allow them to evade detection by the immune system. The cells do this either by failing to display their antigens or by producing signals that affect the immune system’s capabilities. The point, therefore, of immunotherapy, is to boost the immune system so that it will be able to eradicate the cells by bypassing the barriers caused by the tumour cells.
Unfortunately there are factors that can affect the strength of the immune system. One main factor is age. As we age, our immune systems weaken, just as we do. They become more likely to overlook cells foreign to the body, as well as react slower in responding to them. This can not only lead to cancers but make it more difficult to mobilise the immune system to fight developed cancers. It has also been recently discovered that every time the body recovers from an immune attack, a small amount of white blood cells are deactivated.
Another factor is alcohol. Moderate alcohol consumption can be beneficial to the immune system. On the other hand, heavy consumption of alcohol, however, can impair the function of the immune cells, slowing the immune response. On a similar note, immune function is also affected by smoking, both first and second hand. Smokers are more likely to catch nose and throat infections and with immune response diminished, it is harder for the body to fight the infections.
The immune system works in two ways to fight infection: using non-specific cells and specific cells. Non-specific cells are the general response. They have no specific target. Their only aim is to rid the body of foreign cells. Non-specific cells are the first line of defence of the immune system and are designed to engulf or destroy all abnormal cells without prejudice. These include phagocytes and macrophages, both of which engulf foreign matter. Then there is the specific response. This is activated when the non-specific response has not been sufficient. Specific cells include T cells, B cells, helper T cells and cytotoxic T cells. These are present when a specific antigen has been detected and so they have to be fought in a specific way.
The idea of enhancing the immune system to fight cancer was first developed by an American surgeon, William Coley, in the 1890’s. Coley realized that in some patients with cancer who had also contracted bacterial infections at the same time, the cancer would begin to recede. Coley was the pioneer of immunotherapy. In a controversial experiment, Coley injected live bacteria into the patient’s tumour or bloodstream until a fever had developed. The patients were then monitored and the observations recorded. Despite some success, when Coley died in 1936, his ideas died with him. It was not until the 1950’s that his methods were revived once more and the experiments renewed. Using these methods, he realized that the bacterial infections caused the patients’ immune systems to go into overdrive trying to destroy the infection and so cancer cells were caught and destroyed in the process. Thus immunotherapy was born.
One novel immunotherapy in development is the use of therapeutic vaccines. They are extremely promising as they have the capability to produce a strong anti-tumour effect without serious side effects. The main problem with traditional therapies is that the side effects can be extremely debilitating. For example when a patient is treated with chemotherapy, they are essentially filling their body with poison in the hopes of poisoning the tumours. Unfortunately this means that the patient is also being poisoned and can result in fatigue, loss of appetite, hair and nails falling out and damage to nerves and other organs. While this treatment may be very successful, patients tend to try to find other options. Using immunotherapy, most of the side effects will be natural in the body and caused by immune response and therefore mostly milder in nature than those associated with chemotherapy.
Conventional vaccines work by introducing a weakened strain of an illness into the body so that immune system will be able to build up antibodies to the stronger strain. When the immune system is then exposed to the stronger strain, the memory cells will still retain the information of the weaker strains’ antigens and will swiftly and efficiently be able to create the correct antibodies to fight it off. Some cancer vaccines work this way and are preventative. There are cancers that form due to certain infections; for example, some patients who have contracted hepatitis B are at a much higher risk of getting liver cancer. Therefore if they receive the vaccine that prevents hepatitis B they may be able to bypass this potential condition.
Unfortunately there are only some cancers that can be prevented in this way. The main focus of cancer vaccines is to attempt to treat cancers that have already developed. These are therapeutic vaccines. They are different from normal vaccines in that some immune cells must be vaccinated outside of the body in order to mobilise the remaining immune cells in the body to then react with the same response. The first type of therapeutic vaccine is called an allogeneic vaccine. These are vaccines that are developed from cells in a laboratory; not from the patient. While these are easier to develop, they are less effective as they are not specific to the patient. The focus of the case study will be on the second type of therapeutic vaccine.
The second type of therapeutic vaccines is called an autologous vaccine. This means that the vaccines are made from the patient’s own cells. One way this is done is by extracting the patient’s cancer cells and modifying them so that the immune system will be able to recognize and then create antibodies to destroy them. An alternative method is to extract the patient’s immune cells and modify them so that will have a stronger immune response and by exposing them to the antigen of the cancer in question. The cells are then infused back into the patient. The modified cells will be able to signal to other immune cells that they recognize the cancer cells and that they are to be destroyed.
Autologous vaccines can be very difficult to develop as they require a detailed and specific understanding of how the cancer cells and immune cells interact with one another, which varies from patient to patient.
The main autologous vaccine that has been developed is called Provenge (sipileucal-t).
Case study: sipileucal-t
Prostate cancer is an extremely pervasive and deadly cancer in men. When the cancer is local, it can be removed easily enough. Unfortunately sometimes it can reoccur and sometimes it can be metastatic (cancers that are capable of spreading around the body). Men with castration-resistant metastatic cancer do not have a long survival rate, ranging from 12.2 to 21.7 months. While some treatments have been shown to prolong survival rate, some are accompanied by unsavoury side effects.
The approval for sipuleucal-t (Provenge) was achieved in 2010, when the FDA (Food and Drug Administration) allowed it to be used in patients with castation-resistant metastatic prostate cancer. Sipuleucal-t works by targeting ‘prostate acid phosphatase’, the antigen that is expressed by prostate cancer cells. It allows T cells to be able to recognize the antigens of the cancer cells and destroy them. While it is first necessary for the patient to undergo a prostatectomy (an operation to surgically remove the prostate gland and some surrounding tissue), this will usually not eradicate enough of the cancer cells and so further treatment is necessary.
The first data for this treatment was obtained using rats. While the prostate differs from species to species, it was shown that rats that had received the vaccine demonstrated a further destruction of the cancer cells without damage to non-cancer cells and this was a very promising result. The human trials were then conducted between 2003 and 2007.
The trial was controlled and consisted of 512 patients. 171 of these patients received a placebo. The remaining 341 patients received sipuleucal-t. All of the patients had only a life expectancy of about six months but were mostly asymptomatic. The blood of the patients was drawn, the immune cells were extracted and then exposed to a protein that contained the prostate antigen and an immune activator. They were treated three times and the results were evaluated. By the end of the trials 331 of the patients were dead. Sixty-one percent of the sipuleucal-t group were dead and seventy-one percent of the placebo group were dead. However, it was shown that the sipuleucal-t group lived on average 4.1 months longer than the placebo group. Therefore, while the patients were not able to live an inordinate amount of time longer, it appeared as though the sipuleucal-t had extended their life span slightly.
Side effects were present, but they were not severe. The main adverse effects displayed were chills, fever and headache. Compared to the side effects of other treatments that allow the same life span, this treatment was far more favourable. In conclusion, sipileucal-t prolonged the lives of men with asymptomatic metastatic prostate cancer with minimal side effects, but it did not halt disease progression.
The second treatment to be examined uses immune-modifying agents, such as cytokines. Cytokines are chemical messengers that the immune system uses to communicate and regulate itself. They are released by immune cells and signal other immune cells to act in certain ways, producing immune responses necessary to eradicate abnormal cells. Types of cytokines include interferons and interleukins and these have both been used to treat patients with cancer. Interferons are produced as a natural response to abnormal cells. They attach themselves to the cells and slow down the rate of cell division, and break down the barriers that protect them from the immune system. They have been developed into drugs for cancer treatment. Interleukins also occur naturally and work to enhance the immune system. The case study will be focusing on interleukins.
One example of this is in the case of interleukin-2. Interleukin-2 is produced naturally by T cells, when a specific antigen has been alerted. It has also been developed to be used as a drug. It works by counteracting the suppression of the immune system caused by the cancer cells. Interleukin-2 does not directly affect cancer cells; rather it signals a stronger immune response from the immune cells. In some cases, there may not be a high enough production level to have any significant anti-tumour effect, but by increasing the production level it is possible to stimulate a much stronger immune response from B and T cells.
Unfortunately with this treatment there can be a severe side effect of toxicity.
Case study: Interleukin-2
Interleukin-2 has been approved by the FDA starting in 1992 and is often used in high doses to treat metastatic cancers. A trial was conducted to find out what the response and survival rate of patients with metastatic renal cancer and melanoma can be. Both of these cancers can be lethal and are extremely resilient. 500 patients were chosen for this trial. One aspect being highly monitored was the side effects of such high doses of IL-2. The patients were administered the treatment between 1997 and 2012.
The patients with melanoma showed a twenty-eight percent response and the patients with renal cancer showed a twenty-four percent response (either partial or complete). Depending on the severity of the cancer, interleukin-2 was able to extend the lives of the patients from just under a year up to 4 years.
The main issue with interleukin-2 is the fact that there can be extreme adverse side effects. Vascular leakage can occur due to the activity of the cytokines promoting vascular inflammation and toxicity in the form of hypotension and metabolic disruption may also take place.
These drawbacks can sometimes outweigh the benefits of IL-2. Despite this, the study showed that some patients had a significantly increased life expectancy and even showed regression of their tumours. However it is necessary to moderate the dosage per patient in order to avoid the side effects. This way it should be possible to predict the effects of interleukin-2 per patient. However, the percentage of patients that benefited from the treatment is also not as high as was anticipated. It is hopeful that in time the use of IL-2 will be improved upon.
Immune Cell Therapy
The third treatment to be examined is called immune cell therapy. This is an experimental form of therapy that uses a process called ‘adoptive cell therapy’. While there are many approaches to this treatment, this article will be focusing on one. Cytotoxic T cells that have invaded a patient’s tumour, known as tumour-infiltrating lymphocytes, are harvested from the patient through leukapheresis (a procedure to isolate the white blood cells from the rest of the components in a blood sample). While TIL’s have the potential to fight tumours, they may not exert a high enough anti-tumour activity to have any significant effect. They must be separated from the patient and tested to see which of them have the greatest anti-tumour activity. These cells are then grown in large populations in a laboratory and finally activated by cytokines. The cells are then infused back into the patient. The idea behind this process is that, seeing as TIL’s already have the ability to target tumour cells, if they are insufficient to produce an anti-tumour effect, they can simply be reinforced. If the activity of the TIL’s is being suppressed by the tumour cells, it may be possible to overcome this problem and unlock their true potential by exposing the tumour to massive amounts of activated TIL’s.
Case Study: Tumor Infiltrating Lymphocytes in Metastatic Melanoma Patients.
Twenty patients were included in this study. These patients were in the advanced stages of the cancer and most of them had only months to live. This study showed the results of this treatment and the potential side effects. The TIL’s of the patients were extracted and cultivated. The modified immune cells were then infused back into the patients and the results recorded.
It was observed that fifty percent of the patients experienced remission. Regression of the tumours was noted all over the body. Two of the ten patients went into complete remission. The other eight experienced partial remission, and seven of those eight are still responding to the treatment. The side effects were mild and manageable, such as fever, coughing and skin rash. The overall outcome of this treatment is extremely optimistic. Research is being done to explore the means of using this therapy for other types of cancers.
On an opposing note, while the results of this trial have not been moderately successful in adults, a similar study was done on children with advanced acute lymphoblastic leukemia using the same treatment methods. The results were astounding. Thirteen children took part in the trial and eleven of them responded so well that they went into complete remission. At an eighty-five percent success survival rate, this could potentially be a highly successful means curing cancers in children.
Immune Checkpoint Modulation
The fourth and final treatment to be examined uses immune checkpoint modulators. These modulators can help make cancer cells more susceptible to attack by the immune system. Immune checkpoints are restrictive pathways that prevent overly strong immune responses that might damage normal cells as well as abnormal ones. Proteins on the surface of immune cells deactivate them, once it is perceived that they are no longer needed. For example, cytotoxic lymphocyte antigens (or CTLA-4) signal T cells to stop responding when they deem the attack on the immune system to be over. In cancer cells, these checkpoint proteins may be abnormal, and can help tumours evade the immune response. Blocking one of these checkpoints could lift the brakes on the immune system, enabling it to destroy more cancer cells. Immune checkpoint modulators work by preventing the immune system from switching off, like it usually would, using molecules that bind to the surface proteins. This means that the immune response will continue to maintain an active immune attack.
Case study: Anti-CTLA-4
Immune checkpoint modulation was a novel idea to fight cancer with the potential to be incredibly successful. CTLA-4 regulates the immune response of T cells. A drug called Yervoy (or Ipilipumab) has been developed with an antibody that prevents CTLA-4 from restricting the immune system. Clinical trials took place to gauge the success of the drug and to see what the side effects could be. Eighty-eight patients with advanced melanoma took part in the clinical trials. The patients were dosed with the drug but unfortunately, this is when it was discovered that there could be adverse effects. Eighty-six percent of the patients presented with some type of adverse effect and while some had only a rash or fatigue, nineteen percent presented with severe toxicity. Some patients presented with gastrointestinal and hepatic toxicity, accompanied by diarrhea, nausea and colitis. The dosage was experimented with and it was established that if the dose was kept under a maximum amount then the side effects could be minimal.
Some tumour regression was established and was sometimes very successful but varied from patient to patient. The treatment would also sometimes only begin to work long after dosage, so the patient would have to be monitored for an extended period of time. Here is an example of this phenomenon:
Fig 1. (Weber, J.S. and others, (2008))
(A) Response in a 69-year-old male patient who experienced treatment failure with interleukin-2 therapy and biochemotherapy, and was treated with ipilimumab. (B) Response in a 58-year-old male treated with surgery, radiotherapy, adjuvant interferon, chemotherapy, and biochemotherapy who received ipilimumab.
While there are already a number of immunotherapies that are being developed, and used in treatments, there is still a lot to be discovered. Much research is being done to develop other types of it. The problem is that they are both difficult and expensive to develop. Their main goal of immunotherapies is to cure cancer that are metastatic, as they are the most challenging to cure using conventional treatments. A cancer that is local can be removed but a metastatic cancer can sometimes essentially be a death sentence. Immunotherapies would be able to make this problem less challenging as the immune system would be able to seek out the cancer no matter where in the body it travelled to.
One way of improving immunotherapies is to boost the immune system in different ways, prior to treatment. Patients who are hoping to undergo this therapy should make lifestyle changes, such as diet, exercise and giving up smoking and drinking. These factors have shown they can make a huge difference in overall immune response and reaction and can considerably boost the effects of the treatments.
Another method of improving the likely outcome of treatment is through the combination of other conventional treatments or of combining different immunotherapies. Not many trials have yet been done in these cases, but they could potentially be the answer to the limitations of immunotherapy so far. If a patient undergoes chemotherapy and not all of the cancer is eradicated, they may be too weak to continue with another round. If instead immunotherapy was used, this could allow the patient to recover from the chemotherapy and still be treated with minimal side effects at the same time.
Cancer is a condition that has proven to be one of the most vicious and adaptable diseases known to man. While treatments have been found for some and some have shown success in eradicating it, the side effects can make the therapies almost as bad as the illness. With this in mind immunotherapies were developed in order to find a treatment that did not require a foreign poison to enter and degenerate the body in order to cure the cancer. By harnessing and enhancing the immune system it allows the patients body to heal itself with minimal interference.
While the results from these clinical trials are in general well below the level required to replace the more severe conventional therapies to date, it gives hope, that should further research and trials in immunotherapy accelerate, it could lead to higher achievements. Ultimately and ideally, further developments could produce formulas that might perform with the same efficacy as the standard treatments, while offering milder side effects. In the meantime, its’ present contribution of allowing some patients to live an extra year with minimal side effects, is a godsend when compared to the suffering caused by harrowing treatments that would actually not give them any more time than with standard treatments. In that case, it would be possible to hope that cancer might become known in future generations as a disease that plagued our era, but not one that will overly affect that of our descendants.
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