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Immunotherapy – Aiming To Give The Immune System The Upper Hand In The Fight Against Cancer


A T-Cell Attacks a Cancer Cell – Illustration by Viola Schmid

Besides attacking foreign invaders – parasites and pathogenic bacteria and viruses – our immune system also vigilantly patrols the body on the lookout for foreign or altered cells.1 Usually, T-cells will likely induce apoptosis (cell death) in mutant cells before they become a problem.1 However, cancer occurs when mutant cells in neoplasms – abnormally and excessively growing tissue manage to avoid detection.1


How do tumor cells evade the immune system? Early tumor development generally begins with malignant cells that are poor stimulators of the immune response.2 Sometimes, these cells become fully resistant to the innate immune response thanks to a phenomenon called immune editing.2,3 Immune editing occurs because the cells in a tumor are heterogenous.2 As the immune system eliminates the cells in a tumor that it can detect, those cells with mutations that allow them to avoid detection generally remain and multiply.2 The result is a tumor made up of apoptosis-resistant cells that the immune system may not fight.2

At later stages, tumor cells can take a more active role, blocking the maturation of dendritic cells – the cells that enlist lymphocytes (T and B-cells) to attack a specific target.1 They can also alter T-cell signalling.1 T-cells come in several varieties, including cytotoxic and regulatory T-cells.4 Among T-cells, cytotoxic T-cells are the main soldiers, binding and lysing infected or abnormal cells.4 Regulatory T-cells, known as Tregs, make sure cytotoxic T-cells don’t attack unnecessarily, and malfunction of this regulation can result in autoimmune diseases.5 Cancer cells may hijack this system. For instance, their alteration of T-cell signalling could involve upregulation of Treg function, causing cytotoxic T-cells to deactivate when they should be attacking the defective cells.6


A new type of cancer treatment, immunotherapy, might turn the tables in the battle between cancer and the immune system. Immunotherapy may either stimulate the immune system globally or cause the immune system to attack cancer directly. There are several types of immunotherapy, including non-specific immunotherapy, monoclonal antibodies, cancer vaccines, and oncolytic virus therapies.


Non-specific immunotherapy may over-activate the immune system, increasing the probability of it attacking cancer cells.7 One kind of non-specific immunotherapy focuses on stimulation of the immune system through cytokines – proteins that boost the immune system, including interferons and interleukins.7 These proteins encourage cells of the immune system to attack cancer cells and also encourage cancer cells to produce substances attracting immune cells.7


Another type of non-specific immunotherapy involves checkpoint inhibitors. Checkpoint inhibitors are drugs that block checkpoint proteins on T-cells, whose function it is to tell the T-cells to become active or to switch them off.7 Checkpoint proteins exist so that it is possible to control the level of activity of the immune system.3 This is important because underactivity can mean an inadequate response to pathogenic invasion, while overactivity can result in autoimmune diseases.8


Checkpoint inhibitors tend to focus on PD-L1 (programmed cell death ligand 1), PD-1 (programmed cell death protein 1), or CTLA-4 (cytotoxic T lymphocyte associated protein 4).3 PD-L1’s receptor, PD-1, is found on activated T-cells, and the binding of this ligand results in a signal that inhibits T-cell proliferation and activation.3 Some cancers evade the immune system through upregulation of PD-L1 9 and high expression of this protein by tumor cells has been associated with increased tumor aggressiveness and risk of mortality.11,12 Immunotherapies that inhibit PD-L1 are showing some success in clinical trials.13 Similarly to PD-1, CTLA-4 is a receptor found on T-cells that inhibits T-cell activation.3 Giving a patient CTLA-4 inhibitors may prevent cancer cells from inactivating T-cells.13


As aforementioned, overactivity of the immune system can cause harm to the body. For this reason, checkpoint inhibitors can have serious side effects, disrupting normal kidney and liver function, affecting glands, and causing diarrhoea.14,15 However, they can also prolong the lives of cancer patients.16


Adoptive cell transfer involves the transfer of cells into the patient to fight cancer.17 CAR (chimeric antigen receptor) T-cell therapy is one kind of adoptive cell transfer.17,18 This therapy involves the extraction of T-cells from the patient’s bloodstream with the help of an apheresis machine, which separates different parts of blood.19 Once the T-cells are extracted, they are genetically modified to target specific proteins on cancer cells, cultured in vitro, and then these CAR T-cells may be returned to the patient.19


Another kind of immunotherapy involves monoclonal antibodies (MABs). This therapy involves laboratory production of lots of copies of one type of antibody.20 This antibody recognizes specific target proteins either on cancer cells or immune cells.17 If the antibody targets the immune system, it can trigger it to attack cancer cells.16 If the antibody attaches to cancer cells, it may make them more easily detectable by the immune system, and this process is called antibody-dependent cell-mediated cytotoxicity (ADCC).21,16


Vaccines are another promising type of immunotherapy and can aim to either prevent or treat cancer. Vaccines that prevent cancer might target viruses that can cause cancer.3 For instance, human papillomavirus (HPV) can cause cervical and anal cancer and Hepatitis B can cause liver cancer.3,22,23 Hence, vaccination against these viruses may prevent cancer.3,24


Vaccines that treat cancer, called therapeutic vaccines, may teach the immune system to recognize proteins on specific cancer cells, stopping further growth and destroying residual cancer cells.24 Therapeutic vaccines can take many forms, including antigens, which are made up of proteins from cancer cells, whole cancer cells, dendritic cells which were grown next to cancer cells in the laboratory, and DNA from cancer cells.24,25


Oncolytic viruses are viruses either found in nature or modified in the laboratory that reproduce efficiently in cancerous, but not healthy, cells until they lyse (rupture).26 Although these viruses may kill tumor cells directly, they also alert the immune system and antigens released from dying cancer cells may trigger a response against the cancer.24


Emerging immunotherapy tactics are an exciting advancement in the fight against cancer and have many advantages over standard cancer treatments – surgery, chemotherapy, and radiation. These standard treatments have significant rates of relapse because there are sometimes residual malignant cells.24 Surgeons can’t always remove all cancerous cells.10 Radiation and chemotherapy preferentially target dividing cells, so cancer cells that are dividing slowly can sometimes evade them.10 In addition, all these methods can have severe collateral damage on healthy tissue.10


In contrast, since immunotherapy uses the body’s own immune system, it can reach disseminated metastases which surgery cannot target.10 It can also attack all cancer cells, not just those that are dividing.10 Some immunotherapy approaches only target tumour cells, so there is less damage to healthy tissues (one exception is therapy with cytokines).10 As a bonus, memory lymphocytes remember the cancer and prevent its re-emergence.10


Immunotherapy is rapidly being integrated into clinical practice.27 However, there are still challenges to be overcome. It is still not possible to predict the efficacy of immunotherapy treatments in specific patients and there is still a need to develop techniques that are consistently effective in a broader range of cancer types.28 Furthermore, treatment costs are still very high.28


Many of these challenges are likely to be resolved with future research.28 The next step for researchers is to find ways to develop personalized biomarker profiles.28 Furthermore, combining cancer therapies will likely improve efficacy and lower toxicity.28,3




Viola Schmid is the creator of Neural Academy, a YouTube channel focused on biology education. She graduated from the University of Toronto with a BSc in Neuroscience and Geoscience.





Opinions are solely of the author and not Boustead & Company Limited and its affiliates.


Sources:

1. The Immune System in Cancer Pathogenesis: Potential Therapeutic Approaches (Pankita H. Pandya, Mary E. Murray, Karren E. Pollok, Jamie L. Renbarger)

2. New insights into cancer immunoediting and its three component phases – elimination, equilibrium, and escape – Deepak Mittal, Matthew M Gubin, Robert D Schreiber, Mark J Smyth

3. Cancer immunotherapy: the beginning of the end of cancer? Sofia Farkona, Elftherios P. Diamandis, Ivan M. Blasutig

4. T cell responses: naïve to memory and everything in between – Nathan D. Pennock, Jason T. White, Eric W. Cross, Elizabeth E. Cheney, Beth A. Tamburini, Ross M. Kedi

5. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders (Kondĕlková K, Vokurková D, Krejsek J, Borská L, Fiala Z, Ctirad A.)

6. Regulatory T cells: a potential target in cancer immunotherapy – Shitara K., Nishikawa H.

7. http://www.cancer.ca/en/cancer-information/diagnosis-and-treatment/chemotherapy-and-other-drug-therapies/immunotherapy/?region=on

8. Introduction to immunology and autoimmunity – D A Smith and D R Germolec

9. PD-1/PD-L1 immune checkpoint: Potential target for cancer therapy – Dermani FK, Samadi P., Rahmani G, Kohlan AK, Najafi R.

10. Cancer Immunotherapy Takes a Multi-Faceted Approach to Kick the Immune System into Gear – Peniel M. Dimberu, Ralf M. Leonhardt

11. Tumor-Intrinsic PD-L1 Signaling in Cancer Initiation, Development and Treatment: Beyond Immune Evasion – Peixin Dong, Ying Xiong, Junming Yue, Sharon J. B. Hanley, Hidemichi Watari

12. Immune checkpoint regulator PD-L1 expression on tumor cells by contacting CD11b positive bone marrow derived stromal cells – Hyangsoon Noh, Jiemiao Hu, Xiaohong Wang, Xueqing Xia, Arun Satalli, Shulin Li

13. CTLA-4 and PD-1 pathways – Similarities, Differences, and Implications of Their Inhibition – Elizabeth I Buchbinder, Anupam Desai

14. Checkpoint inhibitors: What gastroenterologists need to know – Monjur Ahmed

15. Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience – Omar Mamlouk, Umut Selamet, Shana Machado, Maen Abdelrahim, William F. Glass, Amanda Tchakorov, Lillian Gaber, Amit Lahoti, Biruh Workeneh, Sheldon Chen, Jamie Lin, Noha Abdel-Wahab, Jean Tayar, Huifang Lu, Maria Suarez-Almazor, Nizar Tannir, Cassian Yee, Adi Diab, Ala Abudayyeh

16. Cancer Immunotherapy, Part 1: Current Strategies and Agents – C. Lee Ventola

17. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy

18. CAR T cell immunotherapy for human cancer – Carl H. June, Roddy S. O’Connor, Omkar U. Kawalekar, Saba Ghassemi, Michael C. Milone

19. Autologous Lymphapheresis for the Production of Chimeric Antigen Receptor (CAR) T Cells – Elizabeth S. Allen, David F. Stroncek, Jiaqiang Ren, Anne F. Eder, Kamille A. West, Terry J. Fry, Daniel W. Lee, Crystal L. Mackall, Cathy Conry-Cantilena

20. Monoclonal Versus Polyclonal Antibodies: Distinguishing Characteristics, Applications, and Information Resources – Neil S. Lipman, Lynn R. Jackson, Laura J. Trudel, Frances Weis-Garcia

21. Role of antibody-dependent cell-mediated cytotoxicity in the efficacy of therapeutic anti-cancer monoclonal antibodies – Alexandre Iannello, Ali Ahmad

22. HBV and liver cancer – Leung N

23. https://www.who.int/news-room/fact-sheets/detail/human-papillomavirus-(hpv)-and-cervical-cancer

24. Current status and future directions of cancer immunotherapy – Hongming Zhang, Jibei Chen

25. Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time – Wouter W. van Willigen, Martine Bloemendal, Winald R. Gerritsen, Gerty Schreibelt, I. Jolanda M. de Vries, Kalijn F. Bol

26. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/understanding-immunotherapy

27. Cancer Immunotherapy, Part 2: Efficacy, Safety, and Other Clinical Considerations – C. Lee Ventola

28. Cancer Immunotherapy, Part 3: Challenges and Future Trends – C. Lee Ventola


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