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Author: Holly B.

Third Year Medical Student

Introduction

Immunotherapy (sometimes known as biological therapy) involves manipulating the body’s own immune system to fight disease. It can involve boosting the immune system and helping it identify pathological agents or dampening it when the immune response is inappropriate (1). Immunotherapy has gained particular interest in recent years for its success in treating cancer but is also being used as treatment for other conditions such as allergies and autoimmune diseases (1). It is widely considered a revolutionary development in medicine with the 2018 Nobel Peace Prize in Physiology or Medicine being awarded jointly to two cancer immunotherapy researchers: James P. Allison (The University of Texas) and Dr. Tasuku Honjo (Kyoto University) (2).  Immunotherapy often provides hope for patients with serious conditions and few treatment options. The full potential of immunotherapy, however, is still being explored through countless clinical trials in the hope that further drugs will be discovered in the future.

 

The Development of Immunotherapy

Immunotherapy is often considered a recent advancement in medicine but in fact has been around for centuries in the form of inoculating patients with viruses to develop immunity (3). Variolation is the process of inoculating a patient with smallpox in a way that only gives them a mild form of the disease but allows them to develop immunity against it and has been used in China since the 1500s (3). The famous culmination of inoculation techniques and the foundations of immunotherapy were brought about by Edward Jenner in 1796 (4). He discovered that infecting someone with cow pox, which was relatively safe, later provided immunity to smallpox. It was a breakthrough that allowed for safe vaccinations to be developed, eradicating smallpox, and later bringing other infectious diseases under control (4). In the 1800s William Bradley Coley was one of the first people to use immunotherapy to try and treat cancer. He noted spontaneous tumour regression in some patients following bacterial infection and like vaccines, he began injecting patients with live and inactivated bacteria in the hope of inducing cancer remission (5). This work was followed up in the latter half of the 1900s with the creation of the first ‘cancer vaccine’, the BCG vaccine for early stage bladder cancer (5). This occurred alongside other developments in immunotherapy such as immune suppression in transplant patients (5). In recent years, there has been continued development of immunotherapy, particularly for advanced cancer treatment.

More modern applications of immunotherapy include diseases from cancer to rheumatoid arthritis and asthma. The most well-known use of immunotherapy is in cancer treatment. Cancer immunotherapy is about priming the immune system to recognise cancer cells and to enhance its ability to kill them. Some examples of immunotherapy used in cancer treatment include monoclonal antibodies and CAR T cell therapy (6).

 

Immunotherapy Techniques

Monoclonal antibodies for cancer are antibodies made in a lab that help the immune system to recognise tumour cells as abnormal so it can destroy the tumour cells that otherwise would have remained undetected. They do this by binding to specific antigens on tumour cells and then signalling to the immune system that the tumour cell needs to be destroyed (6). Some monoclonal antibodies act on immune checkpoints. Immune checkpoints are mechanisms secondary to antigen recognition that our immune cells use to recognise healthy cells. They give a negative signal to immune cells, so they are not activated. Cancer cells can exploit these mechanisms to evade destruction by the immune system. Some monoclonal antibodies work by blocking immune checkpoints on immune cells to help them react to tumour cells. Monoclonal antibodies that block immune checkpoints are known as immune checkpoint inhibitors (6). These are one of the most successful examples of immunotherapy in cancer treatment, especially for patients with advanced disease. An example of this is Pembrolizumab, a monoclonal antibody and immune checkpoint inhibitor used in the treatment of advanced non-small cell lung cancer (NSCLC), melanoma, and urothelial tumours (7). T cell immunotherapy is a newer technique that uses modified T cells to identify antigens for example in leukaemia (8).

 

Immunotherapy Treatments

Immunotherapy can be used to treat a wide range of cancers including some that are notoriously difficult to treat and have poor prognoses such as advanced lung cancer. It gives patients hope and the opportunity to prolong survival (9). According to the KEYNOTE-024 trial, the monoclonal antibody pembrolizumab gave 15 months longer median overall survival compared to the standard chemotherapy treatment for advanced NSCLC (10). This evidence is further supported in the KEYNOTE-189 trial (11). Pancreatic cancer which has particularly poor outcomes due to late detection is also undergoing clinical trials with immunotherapy (9). Immunotherapy for cancer treatment acts by enabling the body’s immune system to identify and destroy cancer cells. Enhancing the immune system can cause side effects if the immune cells start to attack normal cells. The side effects will vary depending on the type of immunotherapy being used and the type and stage of cancer it is being used to treat but common side effects include fatigue, diarrhoea, fever, and skin rashes. Severe and life-threatening side effects can occur with immunotherapy but are extremely rare (12).

Immunotherapy can also be used to treat autoimmune conditions by inhibiting the immune response (13). Autoimmune conditions occur when the immune system mistakenly attacks the body’s own normal cells, for example, rheumatoid arthritis and type 1 diabetes (14). A common type of drug is tumour necrosis factor alpha (TNF-α) inhibitors which are routinely used to reduce inflammation in diseases such as rheumatoid arthritis and inflammatory bowel disease (13). Another example of immunotherapy being used to dampen the immune response is anti-rejection drugs such as tacrolimus and cyclosporine used following organ transplant to prevent the patient’s immune system from attacking the transplanted organ (15). The obvious problem with agents that dampen the immune system is the risk of serious infection and so it is important that these patients seek medical attention quickly if they suspect they have an infection (14).

 

Funding for Immunotherapy

The medical breakthrough made by immunotherapy comes at a cost. The financial cost of immune checkpoint inhibitors in cancer treatment, for example, could perhaps make them inaccessible to the NHS. Pembrolizumab is an immune checkpoint inhibitor that has shown significantly prolonged survival times for patients with cancer such as non-small cell lung cancer, melanoma and some kidney tumours (10). According to NICE (National Institute for Health and Care Excellence), Pembrolizumab costs £1,315 per 50mg with patients needing 200mg every 3 weeks. The average cost for one course of treatment for a patient with non-small cell lung cancer is £84,000 (7). NICE found that pembrolizumab proved to be cost-effective for metastatic NSCLC but is only available to patients with advanced cancer who meet certain criteria and is stopped after 2 years of treatment regardless of clinical response (7). The NHS only managed to afford pembrolizumab by reaching a non-disclosed arrangement with MSD pharma that allowed them to acquire it at a reduced price (16).

Immunotherapy really challenges the ethical debates around reasonable costs for medical care. The patients receiving these drugs are often end-of-life or have very limited treatment options and while the drugs are a huge financial burden to the NHS, the symptom relief and extra time with family that it gives patients is invaluable. Questions remain about whether, in the long-term, use of these drugs is sustainable and if there are further breakthroughs with immunotherapy for cancer treatment, how many patients can the NHS afford to treat? The expense of biological agents poses problems in the treatment of other diseases, including asthma (17). Cost effectiveness analysis must be carried out before these drugs become available on the NHS and so often drugs are ruled out or used only for patients who have exhausted other treatment options.

 

Conclusion

Immunotherapy has proven to be an effective and targeted treatment for a range of conditions, especially for cancer. It has a promising future and is the keen focus of many current clinical trials. The immune system can be exploited in countless ways to help to tackle disease and more uses for it will almost certainly be discovered and refined in the future. It gives many patients with advanced and treatment-resistant cancer hope and time which is invaluable. However, the main barrier to the widespread future use of immunotherapy is likely to be the cost. In a system were cost-effectiveness must be considered, the price of immunotherapy on a large-scale is likely to restrict its widespread use. Therefore, it may be retained and used only for those patients with advanced or serious forms of a disease and who have exhausted other treatment options. 

 

References

  1. Sino Biological. www.sinobiological.com/research/immunotherapy
  2. Nobel Prize Awarded to Cancer Immunotherapy Researchers. American Cancer Society. 2018. cancer.org/latest-news/nobel-prize-awarded-to-cancer-immunotherapy-researchers.html
  3. Boylston A. The origins of inoculation. J R Soc Med; 2012. 105(7): 309-313. doi:10.1258/jrsm.2012.12k044
  4. Riedel S. Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent); 2005. 18(1): 21-25. doi:10.1080/08998280.2005.11928028
  5. Dobosz P, Dzieciątkowski T. The Intriguing History of Cancer Immunotherapy. Front Immunol; 2019. 10:2965. 17 Dec 2019. doi:10.3389/fimmu.2019.02965
  6. Types of Cancer Immunotherapy. Cancer Research UK; 2017. www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/immunotherapy/types
  7. Pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer (CDF review of TA447). NICE; 2018. nice.org.uk/guidance/ta531/documents/final-appraisal-determination-document
  8. Miliotou AN, Papadopoulou LC. CAR T-cell Therapy: A New Era in Cancer Immunotherapy. Curr Pharm Biotechnol; 2018. 19(1): 5-18. doi:10.2174/1389201019666180418095526
  9. Immunotherapy by Cancer Type. Cancer Research Institute. www.cancerresearch.org/immunotherapy/cancer-types
  10. Reck M, Rodríguez–Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O´Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza C, and Brahmer JR. Updated Analysis of KEYNOTE-024: Pembrolizumab versus Platinum-based Chemotherapy for Advanced Non-small Cell Lung Cancer with PDL-1 Tumor Proportion Score of 50% or Greater. Journal of Clinical Oncology; 2019. 37:7, 537-546
  11. Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Yee Shan Cheng S, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza C, and Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non–Small-Cell Lung Cancer. Journal of Clinical Oncology; 2020. 38:14, 1505-1517
  12. Immunotherapy side effects. National Cancer Institute. www.cancer.gov/about-cancer/treatment/types/immunotherapy/side-effects
  13. Immunotherapies for autoimmune diseases. Nat Biomed Eng; 2019. 3:247 https://doi.org/10.1038/s41551-019-0394-3
  14. British Society for Immunology; March 2016. www.immunology.org/sites/default/files/autoimmunity-briefing.pdf
  15. Clinical Guidelines for Transplant Medications. BC Transplant; Jan 2019. http://www.transplant.bc.ca/Documents/HealthProfessionals/Clinicalguidelines/ClinicalGuidelineforTransplantMedications.pdf
  16. NHS England strikes deal on new NICE recommended lung cancer immunotherapy drug. NHS England; June 2018. www.england.nhs.uk/2018/06/nhs-england-strikes-deal-on-new-nice-recommended-lung-cancer-immunotherapy-drug/
  17. Anderson WC 3rd, Szefler SJ. Cost-effectiveness and comparative effectiveness of biologic therapy for asthma: To biologic or not to biologic? Ann Allergy Asthma Immunol; 2019. 122(4): 367-372. doi:10.1016/j.anai.2019.01.018

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