In his novel, War of the Worlds, the author H.G. Wells tells about the dystopian future in which aliens would invade Earth and kill humans by the millions owing to their advanced weapons and technology, only to be defeated by bacteria to which they had no immunity. Our immunity is arguably the most complex part of our bodies. It is so adaptive that it can fight anything from bacteria to viruses to even cancer cells. The employment of immunotherapy is indeed one of the breakthroughs in modern medicine, and its benefits still surprise us to this day.
What is immunotherapy?
Immunotherapy in the broader sense refers to the treatment of medical conditions by either stimulating or suppressing the immune system. It is used in a wide variety of conditions related directly or indirectly to the immune system. Although the term can encompass the use of immunizations, they are not considered as a “therapy” but prophylaxis against infection. Nonetheless, some vaccines can be used in the treatment of cancer as will be highlighted later in the article. In its use in autoimmune diseases, it is commonly referred to as “biological therapy”.
The spectrum of immunotherapy encompasses the following:
- Immunosuppressive drugs like those used after organ transplantation and in immune disorders like systemic lupus, rheumatoid arthritis, and systemic sclerosis. Drugs like glucocorticoids act by several mechanisms to suppress inflammation and autoimmunity.
- Immune tolerance: This includes many therapies that aim at resetting your immune system so it will not react inadequately to antigens. They are used following organ transplantation, in autoimmune conditions and allergies. They include the injection of autoregulatory cells which aim at resetting the sensitivity of your cells towards your antigens, or the use of allergens in small doses in cases of seasonal allergy. Small doses of allergens allow for the immune system to become accommodated to the allergen without triggering an allergic response.
- Immune enhancement therapies: This subtype of immunotherapy is the one under much research in recent years. It includes the use of vaccines, cells, or antibodies to stimulate the immune system against specific cells, bacteria, or viruses. From the previous mechanisms, monoclonal antibodies are the most used in cancer.
The first use of monoclonal antibodies dates to 1975, and the first monoclonal antibody was Muromonab which targeted a specific cellular receptor called CD3 and was used following organ transplantation. The “CD” here is an abbreviation for cluster of differentiation which is a man-made system of using cellular receptors to differentiate different types of cells. If a cellular receptor is unique, it is assigned a different number.
Sublingual immunotherapy
One of the recent advances in managing allergies is immunotherapy. Building an immune tolerance can spare the patient a life-long need for antiallergic medications and their side effects, especially in mild allergic conditions like allergic rhinitis and sinusitis.
In the past and following allergic testing, the specific allergen that triggers symptoms was injected under the skin in small doses intermittently over a period of time to build a tolerance against that specific allergen. This modality has recently been replaced for some allergens including dust mites -one of the commonest allergens for allergic rhinitis and asthma- and pollen and has shown high efficacy in controlling the symptoms of hay fever.
Tablets containing the allergen are placed under the tongue for extended periods without the need for injections.
Immunotherapy for cancer
When we talk about cancer, we tend to imagine this once-per-life occurrence that ends in death or severe morbidity, and this perception is partly due to the grim outcome of many cancers. However, the reality is quite different, and cancer is far from being a rare occurrence on the microscopic level. Our cells are in a constant state of division and genetic errors are common. What prevents these errors from progressing to full blown cancer are many mechanisms including those responsible for repairing any errors of genetic division or the self-destruction of cells whose errors are beyond repair. The destruction of such cells can be either auto where the cell digests itself, a process called apoptosis, or by the immune system.
Cancers escape such mechanisms by both causing a mutation in the genes that are responsible for repair or self-destruction -also called tumor suppressor genes- and by deceiving the immune system into thinking that they are normal. The concept of immunotherapy is to help the immune system identify an invading organism or cancer or to damage it.
Regarding monoclonal antibodies, it was thought that this binding alone can selectively kill all cancer cells and spare all normal ones, but the reality is far more complex. For immunotherapy to work properly, a monoclonal antibody has to target a vital cellular structure that is only present in cancer cells. Cellular receptors work by sending and receiving signals and then giving orders that control cellular division and survival. Mutations sometimes manifest as abnormal receptors making targeting cancer cells feasible.
Immunotherapy for leukemia
Leukemia was traditionally treated by aggressive chemotherapy causing severe side effects and an overall bad outcome for most patients. Chemotherapy is still the main therapy in most acute leukemias with stem cell transplantation a viable option especially in young patients. The role of immunotherapy in leukemia is stimulating the immune system to attack and destroy abnormal white blood cells circulating in the blood, and in this sense, stem cell transplantation is considered an immunotherapy. When bone marrow is transplanted, it produces new, healthy white blood cells that can target cancer cells and destroy them. There are four main types of leukemia which are: acute lymphoblastic, acute myeloid, chronic lymphocytic and chronic myelocytic leukemias.
Several other monoclonal antibodies and antibody-drug complexes are now employed in cases of leukemia. They target specific CD markers on the surface of cancer cells like CD20, CD53, CD33 and CD22. These markers are identified by doing a bone marrow biopsy then running histochemical investigations on the specimen to make sure that those markers are present before initiating therapy.
Common monoclonal antibodies in use include:
- Rituximab (Rituxan): A monoclonal antibody that targets CD20.
- Ofatumumab (Arzerra): A monoclonal antibody that targets CD20 and is mainly used in Chronic lymphocytic leukemia. Chronic lymphocytic leukemia is considered resistant to chemotherapy making Ofatumumab its first-line drug.
- Inotuzumab (Besponsa): An antibody-drug complex targeting CD22 and used in patients with acute lymphoblastic leukemia.
- Alemtuzumab (Campath): Which is a monoclonal antibody that targets CD53 in chronic lymphocytic leukemia.
- Gemtuzumab (MyloTarg): An antibody-drug complex in use in cases of CD33 acute lymphoblastic leukemia, especially in children.
Interferons are one of the most critical chemical mediators secreted by our bodies in inflammation, viral infections, and cancer. They are used as medications in many conditions including viral infections such as hepatitis. In leukemia, they were used especially in CD20 positive chronic myeloid leukemia. Its use has, however, greatly decreased following the introduction of Imatinib, which is a potent anti-leukemia drug that targets the main genetic abnormality in chronic myeloid leukemia (The Philadelphia chromosome).
Immunotherapy for melanoma
Melanoma is the most aggressive skin cancer and one of the most aggressive cancers that can affect humans, and the reason behind that is its early spread. Unlike squamous cell carcinoma of the skin, melanoma can spread to the blood or lymphatics early making its surgical treatment impossible. Fortunately, if there is a cancer in which the role of immunotherapy shines, it has to be melanoma. Ever since immunotherapy was used for this malignancy, the survival of cases with stage III melanoma improved dramatically.
The main type of immunotherapy used in melanoma are checkpoint inhibitors, and they work by activating T-cells of the blood and letting them attack the cancer cells. Three main checkpoint inhibitors are available for cases of surgically unresectable melanoma: Ipilimumab, Pembrolizumab and Nivolumab. Pembrolizumab and Nivolumab act on a specific receptor on T-lymphocytes called PD-1, and when they bind to it, the inhibition of T-lymphocytes is removed, and they are allowed to attack cancer cells at will. They can be used alone or a combination of the two drugs Ipilimumab and Nivolumab may be used for better results. They can also be used in select resectable cases after surgery (neoadjuvant therapy). The reason as to why the combination of the two drugs is not a standard regimen is that it comes with more severe side effects and a higher risk of developing an autoimmune reaction.
Interleukin 2 is one of the key cytokines secreted by white blood cells in response to viral infections and cancer. It is produced as a medicine and can be given as an intravenous infusion in some cases of advanced melanoma where it stimulates the immune system to attack cancer cells, but it has mostly fallen out of favor and replaced by immune checkpoint inhibitors owing to its higher risk of inflammatory side effects.
Local injection has been in use for a while in treating advanced melanoma. It relies on inducing an immune reaction that destroys cancer cells locally. Among the options is the BCG injection into the melanoma. BCG is the tuberculosis vaccine which can stimulate an immune reaction locally to destroy cancer cells. Another example is the T-VEC therapy which is the local injection of a virus into the melanoma cells to kill them. The virus commonly injected is herpes simplex.
Advanced melanoma with multiple distant metastases still has a bad outcome and a high risk of mortality despite advances in immunotherapy. New clinical trials are needed to develop new drugs or test the effectiveness of existing ones for advanced cases of melanoma.
Immunotherapy for breast cancer
Breast cancer is the commonest cancer affecting women and a major concern for women after menopause. Screening programs have led to a dramatic decrease in breast cancer mortality rates since most cancers discovered are surgically resectable with breast conservative surgery, but advanced cases are still present in developing countries and in some cases who don’t undergo regular screening.
The main modalities of breast cancer therapy are surgery, chemotherapy, radiotherapy, and hormonal therapy. In the recent past, breast cancer was considered a bad candidate for immunotherapy since it was thought to be immunologically “cold” which means that its cells do not have enough targetable receptors by immunotherapy. This claim has been refuted by recent clinical trials that explored the effectiveness of immunotherapy in advanced breast cancer especially triple-negative breast cancer -which is considered immune to hormonal therapy- and HER2 neu breast cancer.
When your doctor orders a breast biopsy following suspicion of breast cancer, it is done for 2 main reasons: the first is to confirm the diagnosis, and the second is to detect the “biological behavior” of the cancer. The biological behavior of cancer is the number and type of receptors on the surface of its cells. The main receptors found in cancer cells are estrogen receptors, progesterone receptors, HER2/neu, and ki-67. Breast cancer which proves to be rich in estrogen or progesterone receptors is ideal for hormonal therapy. Cancers with neither estrogen, progesterone nor her2 receptors are considered triple negative.
Monoclonal antibodies have been developed to target the her2 in her2-rich cancers. Available medications include Trastuzumab which is sold as a monoclonal antibody under the name Herceptin or as an antibody-drug complex under the names Enhertu and Kadcyla. It is only effective in breast cancers rich in her2 neu receptors and mostly ineffective in others. Other immunomodulatory therapies are also available including the checkpoint inhibitors Pembrolizumab and Atezolizumab. They are mainly used for advanced triple-negative breast cancer and breast cancer with certain mutations in genes called mismatch repair genes (MMRs).
Immunotherapy in lung cancer
Lung cancer is not only the most common cancer to affect humans in general, but also the leading cause of cancer mortalities worldwide, and the reason behind its fatality lies in part in its late presentation. By the time patients present by symptoms, they are already late, and the cancer is unresectable. There are two main types of lung cancer: Small cell and non-small cell lung cancer with the non-small cell variant forming more than 80% of cases.
Traditional therapies of lung cancer include surgery, chemotherapy, and radiotherapy and all three of them are minimally effective in late stages -stage III and above-. Immunotherapy has been developed for lung cancer and has increased the survival of many patients with unresectable lung cancers.
Different classes of immunotherapies are used including:
- Checkpoint inhibitors like Atezolizumab, Durvalumab, and Nivolumab: They are used for advanced and metastatic small cell and non-small cell lung cancers.
- Anti-VEGF targeted monoclonal antibodies like Bevacizumab, and Ramucirumab: They are mostly used in advanced cases of non-small cell lung cancers.
Immunotherapy is one of the most promising modalities of treatment in advanced lung cancer, and drugs like checkpoint inhibitors have shown very promising results in increasing survival rates of cases with unresectable lung cancer.
How effective is immunotherapy in cancer?
Ever since immunotherapy was developed for cancer, it has been wrongly believed to be the last treatment in humanity’s struggle with cancer. Results, however, are far from expectations. As mentioned above, many monoclonal antibodies were found to not target vital receptors on cancer cells. Another hurdle was the immunogenicity of such treatment. Monoclonal antibodies are manufactured outside the human body -mostly in rats- and are proteins, making them ideal for developing immune reactions and rejection. This had been the problem for more than 20 years following the initial conception of monoclonal antibodies in the 70s.
Several techniques were employed since then that overcame these problems including the use of humanized antibodies that are less animal and more human, causing a significant drop in the incidence of allergic reactions. Antibodies were also developed to target more specific cellular structures, making them more specific and lethal to cancer cells. These changes, along with the fact that immunotherapy, in general, has fewer side effects than chemotherapy and radiotherapy made it a standard of care in many cancers. It is still not the killing bullet for all cancer, but we have come a long way.
Side effects of immunotherapy
Immunotherapy is indeed less toxic than chemotherapy owing to its mechanism of action which, unlike chemotherapy, doesn’t directly destroy cancer cells, but stimulates the immune system to target and attack them either by activating T-cells or by labeling cancer cells. Chemotherapy also has a much higher chance of destroying normal cells than immunotherapy. However, like all medicines, side effects always have a chance of happening in immunotherapy.
The most severe side effects of immunotherapy especially checkpoint inhibitors -which are one of the most promising immunotherapies- stem from their mechanism of action. Immune checkpoint inhibitors activate dormant T-cells so that they can target and destroy cancer cells. This activation must be kept in balance to avoid the development of autoimmune disorders which occur when T-cells target the body’s antigens and cells. Several organs may be damaged by this overactivation including the gastrointestinal tract causing severe intractable diarrhea, the liver causing autoimmune hepatitis which can be severe enough to cause liver failure, the heart causing myocarditis, or the thyroid gland causing decreased thyroid hormone (hypothyroidism). Most commonly, however, are skin rashes and flu-like symptoms.
Other immunotherapies like monoclonal antibodies can cause allergic reactions owing to their non-human components. Immunosuppressive immunotherapy can also cause an increased risk of infection especially upper respiratory tract and gastrointestinal tract infections.
Some patients who underwent immunotherapy were also found to develop arthritis at a younger age. The relationship between immune activation and the development of future cancers is unevidenced and remains a subject of many clinical trials. What is important to understand is that immunotherapy may be a kinder method of treatment than traditional cancer therapies, but it is far from being free of side effects.
Is immunotherapy painful?
One of the main concerns of patients undergoing immunotherapy is whether the treatment is painful. This stems from their experience with some chemotherapeutic drugs which tend to be irritant to the skin and veins causing painful thrombosis ulceration at their site of injection. Immunotherapy, on the other hand, is not irritant to blood vessels and tends to not leave scars at its site of injection. However, the risk of skin reactions can be high in some types of immunotherapy especially in checkpoint inhibitors.
Activation of the immune system can occur at the site of injection causing skin rash, redness, itching, and mild edema. It tends to be self-limited and your doctor will prescribe creams and topical applications to alleviate any pain or itch you might have.