An overview of immunotherapy
Immunotherapy is a type of cancer treatment that boosts the body’s natural defences to fight cancer cells. It uses substances made by our body or in a laboratory to improve how our immune system works to find and destroy cancer cells (Understanding Immunotherapy, 2020). The immune system is a complex network of cells and proteins that helps our body defend infections. The immune system will keep a record of every germ or microbe it has ever defeated, so that it can recognise and destroy similar microbes quickly if they enter the body again. Abnormalities of the immune system can lead to problems such as immunodeficiencies (a state when the immune system's ability to fight against infectious diseases and cancer is compromised or entirely absent) (Immune system explained, 2017).
Different immunotherapies serve different functions. Some of the treatments may help the immune system to slow down the growth of cancer cells, while others help to destroy the cancer cells or stop them from spreading to other parts of the body. For example, the T-cell therapy will fight cancer by altering T cells present in part of the immune system. T cells are one of the most important white blood cells of the immune system, which are responsible for killing the infected host cells or activating other immune cells; the oncolytic virus therapy will use viruses to infect and destroy cancer cells. Immunotherapy treatments can both be used alone or combined with other cancer treatments (Understanding Immunotherapy, 2020).1
Types of cancers immunotherapy benefits
Immunotherapy treats different types of cancers , including but not limited to brain cancer, breast cancer, kidney cancer and lung cancer. While some cancers are more immunogenic than others, in general, immunotherapy is effective across a wide variety of cancers. Immunotherapy can produce durable responses, unlike chemotherapy or radiation, however, these occur only in around 25% patients (Immunotherapy: Cancer Treatment, CAR T-Cell Therapy, Types, Risks, 2020).
Recently, encouraging results were discovered by scientists among the use of immunotherapy drug pembrolizumab (Keytruda®) together with chemotherapy, a drug treatment that uses powerful chemicals to kill fast-growing cancer cells, for treating metastatic nonsquamous non-small cell lung cancer (describing the situation when lung cancer has spread from the lungs to other parts of the body). According to a study published in The New England Journal of Medicine, the dual approach was more effective than chemotherapy alone for metastatic nonsquamous non-small cell lung cancer. Patients who received dual therapy lived longer than those who received only chemotherapy. The findings suggest that earlier introduction of immunotherapy for certain patients might one day become the standard treatment (Gerber M.D., 2018).
However, immunotherapy does not entirely cure late-stage lung cancer, it can only give some patients more precious time with family and friends (Gerber M.D., 2018).4 These limitations have pushed immunotherapy researchers towards the use of several drugs in combination. Researchers hope to enhance and broaden the benefits by combining immunotherapies, or pairing them with other types of cancer treatment such as chemotherapy or radiation (The benefits of immunotherapy combinations, 2017).
Researchers were drawn to the combination of PD-1 and CTLA-4 inhibition because drugs with these targets are well established. Ipilimumab was the first checkpoint immunotherapy to reach the market (in 2011) and the first two PD-1 inhibitors, pembrolizumab and nivolumab, won regulatory approval in 2014. The combination of PD-1 and CTLA-4 inhibitors has since moved into clinical trials for other malignancies, including stomach, breast, bladder, pancreatic, renal, lung and ovarian cancers. The pairing still makes up the lion’s share of immunotherapy combination trials. That tally includes two-way trials combining inhibitors of the PD-1 pathway and CTLA-4, as well as three-way trials combining both of those checkpoint inhibitors with other treatments, such as chemotherapy and radiotherapy (The benefits of immunotherapy combinations, 2017).5
Before and now of immunotherapy
William Bradley Coley, MD., borned in 1862, is the pioneer of cancer immunotherapy and developed a treatment based on provoking an immune response to bacteria. From 1925 to 1933, Coley developed the theory that post-surgical infections had helped patients to recover better from their cancer by provoking an immune response. In 1891 he began to experiment by deliberately causing this phenomenon. Later, he invented a treatment named Coley's toxins, which is a mixture consisting of killed bacteria and he claimed that it could effectively treat cancer (Pioneer of Immunotherapy, 2017).
After Coley’s death in 1936, his daughter, Helen Coley Nauts, started looking through her father’s files of patients he had treated with Coley’s toxins. Hence she saw that he had extraordinary rates of success in regressing some cancerous tumors. In 1953 Helen Coley Nauts started the Cancer Research Institute, dedicated to understanding the immune system and its relationship to cancer. In the more than 60 years since, researchers have expanded their understanding of the immune system dramatically and today, that understanding is paying off. Treatments that harness the power of the immune system are now available for a range of cancers such as stomach, lung, leukemia, melanoma and kidney (Pioneer of Immunotherapy, 2017).6
Expectations and Challenges
Although immunotherapy is nearly the biggest breakthrough in medical lung cancer treatment in the past decade, it is not yet as advanced as some patients would hope. Doctors and patients need to have frank conversations about the capabilities of immunotherapy and understand that while it allows us to extend the lives of patients with metastatic lung cancer, it’s not usually curative. As for doctors and researchers, curing this difficult disease is a long-term goal (Gerber M.D., 2018).4 These technical difficulties somehow prevent the field of immunotherapy from achieving large-scale success. Examples of the obstacles faced by immunotherapy are listed below:
1. Cost: cancer Immunotherapy drugs are expensive
Stated in a study, the cost of pembrolizumab (a type of immunotherapy known as a checkpoint inhibitor that makes cancer cells more vulnerable to attack by our body's own immune system) incurred one-year per patient is $145,010. The high cost of applying these medicines could limit patient’s access hence exerts strains on patient’s finance. Thus, it may hinder the economic sustainability of health care systems (Ventola C. L., 2017).
2. Efficacy: only effective in subsets of patients with select cancers
A major challenge for cancer immunotherapies is the need to develop agents that are consistently effective in a majority of patients and cancer types. Even though encouraging results have been observed in a small portion of patients treated with cancer immunotherapies, many immunotherapy treatments have demonstrated efficacy in only a select group of cancers hence in a minority of patients with those cancers. Reasons for the variability in patient response to cancer immunotherapies have been proposed. This includes tumor heterogeneity (the quality of being diverse and not comparable in kind), variability in cancer type and stage as well as treatment history. (Ventola C. L., 2017).7
3. Usage: immunotherapies are not given as first-line treatments
Because immunotherapies have worked in only a minority of patients, conventional chemotherapies but not cancer immunotherapies are widely used as a first-line cancer treatment. Hence, immunotherapy is only given to patients whose immune systems are already compromised due to advanced disease and/or previous therapies. The ability of cancer immunotherapies to restore anti-tumour immune function (referring to the innate and adaptive immune responses which lead to tumour control) under these conditions is challenging. It may further decrease its efficacy (Ventola C. L., 2017).7
4. Side effects
The side effects of immunotherapy include fatigue, nausea, vomiting, body aches, high or low blood pressure and others. They are especially common in therapies like oncolytic virus therapy. Although many side effects will go away on their own, others can grow to be more serious and require further treatments (Side Effects of Immunotherapy, 2020).
Side effects of immunotherapy can be mild, moderate, or even life-threatening. Doctors may pause the treatment or prescribe a type of medication called a corticosteroid (a class of drug that lowers inflammation in the body, and reduces immune system activity. ), depending on how severe the side effects are. If side effects worsen or do not improve, doctors may even stop immunotherapy (Side Effects of Immunotherapy, 2020).8
An example of severe side effects caused by immunotherapies is the case of Mr. Cara, an apparel industry executive from Bridgewater, N.J.. He had non-small-cell lung cancer, and every two weeks, he had intravenous infusions of Yervoy and Opdivo. He only had a bit of fatigue the day after the infusion in the beginning. But turning the wrath of the immune system against cancer can be a risky endeavor: Sometimes the patient’s own body gets caught in the crossfire. About two months into the treatment, Mr. Cara broke out in a rash all over his arms, back and chest. It became so severe that he had to go off the drugs. A steroid cream cleared it up and he was able to resume treatment — but with only one drug, Opdivo. Doctors stopped the other in hopes of minimizing the side effects (Harnessing the Immune System to Fight Cancer, 2016).
Future trends
Despite the fact that many obstacles still impede the success of cancer immunotherapies, these obstacles will likely be surmounted through the implementation of available and potential solutions, including the development of more targeted cancer immunotherapies, personalized treatment with cancer immunotherapy drug combinations, and additional important innovations.
Primarily, work must be done to establish immunotherapy as a standard of care for immune-sensitive tumours. This can help to broaden the applicability of immunotherapy across a variety of cancers, and enhance its efficacy for a wider range of patients (Ventola C. L., 2017).7
Besides, the field of cancer immunotherapy is expected to advance rapidly in the coming years. Researchers believe that it will move away from cancer immunotherapies that broadly activate the immune system, and toward more targeted approaches that enhance efficacy and reduce toxicity. To achieve this, additional tumour antigens need to be defined as targets for cancer immunotherapies. The identification of additional prognostic and predictive biomarkers will also provide benefits in predicting and improving patient survival (Ventola C. L., 2017).7
Furthermore, personalized drug combinations based on the specific biomarkers (a measurable indicator of the severity or presence of some disease state) or pathways that drive the biology of each patient’s tumour, are expected to be one of the most promising strategies of immunotherapy in the future. As the current approach of targeting single molecular abnormalities or cancer pathways, is described by some experts as “reductionist” which is unlikely to lead to a cancer cure, drug combinations that target several molecular alterations or cancer pathways might enhance the efficacy of cancer treatments. Recent insights regarding the immune regulation of cancer are expected to provide the basis for the development of more potent cancer immunotherapy combinations. However, toxicity would be expected to be a limiting factor with drug combination strategies, so the recognition and management of adverse events will be critical for treatment success (Ventola C. L., 2017).7
Conclusion
During recent decades, the understanding of cancer immunology has advanced dramatically, hence, the rapid progress that has led to the present era of cancer immunotherapy is expected to continue. (Ventola C. L., 2017).7 However, there are still obstacles awaiting to be overcomed in the pathway of immunotherapy, such as we need to further improve our immunotherapeutic modalities to maximize efficacy and minimize toxicity (Tsiatas, M., Mountzios, G., & Curigliano, G., 2016).
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