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Both Traditional Cancer Therapies and
Immunotherapies Can Lead to Adverse Reactions
Related to Their Respective Mechanisms of Action
Radiation
Radiation induces DNA damage by directing high-energy particles to cells.15,16 Adverse reactions observed with radiation exposure arise due to damage of normal cells in the irradiated sites.4,15
Chemotherapy
Chemotherapy can cause damage to rapidly dividing cells, including tumor cells and healthy cells such as hematopoietic stem cells and gastrointestinal mucosal epithlium cells, leading to adverse reactions.1,17,18
Targeted Therapy
Targeted therapies interfere with signaling pathways that promote cell proliferation.19 While targeted therapies have a high affinity for the molecule of interest, they can often bind to other molecules, resulting in both on-and off-target effects.20-22
Immunotherapy
Immunotherapy promotes the antitumor response of activated cytotoxic T cells by targeting the immune system, enabling
T cells to attack the tumor. However, this can sometimes cause T cells to target healthy tissue, leading to adverse events known as immune-mediated adverse reactions.23
- Most cancer therapies will have some effect on normal cells, leading to adverse reactions
- Chemotherapeutic drugs target various stages of the cell cycle, inhibiting cell division and leading to cell death
- Fast-dividing cells, such as tumor cells, are preferentially affected by these therapies1
- However, fast-dividing healthy cells, such as cells in hair, skin, and the digestive tract, can also be affected1
- Targeted therapies bind to receptors that block crucial tumor survival pathways
- These agents can bind to the same or analogous receptors on healthy cells as well2,3
- Radiation therapy is directed toward the tumor; however, healthy cells in close proximity to tumors may also be adversely affected4
- During any immune response (eg, against pathogens, tumors, or any foreign threat) healthy cells may also be attacked5-7
- Immunotherapies activate the immune response to counter tumor survival and growth strategies, and may lead to immune-mediated adverse reactions (IMARs)8,9
- When normal cells are impacted during immunotherapy treatment, this can lead to a specific type of adverse reaction referred to as an IMAR8
- The link between immune activation and IMARs is an area of ongoing research
- The activation of certain immune cells, such as T cells and natural (NK) cells
, has been associated with IMARs9,10
- Activating and inhibitory pathways modulate immune-cell activation and the stimulation of an immune response25,26
- These pathways can vary in the intensity of their effect on immune activity, and thereby self-tolerance27
- The dynamic expression of a receptor and its ligand can dictate the strength of a particular pathway in the immune response27
- The activation or inhibition of certain pathways has been associated with IMARs27,28
- IMARs can develop in various organ systems and may occur in a distinctive temporal pattern28-31
- IMARs can occur during treatment and after treatment discontinuation29
- Exploring the relationship between immune activation and autoimmunity may provide a better understanding of IMARs25
- Early identification and management are essential, as IMARs can occur at any point during treatment continuum and beyond30-34
- Therefore, patients, caregivers, and healthcare providers should remain vigilant during and after immunotherapy treatment to potentially minimize the complications associated with IMARs, some of which may be life threatening8,30
- It is important to educate patients about identifying IMARs and contacting HCPs to help manage them30,31
- With early detection and intervention, IMARs can be addressed28,33,35
- Symptoms and signs (eg, clinical chemistries, physical manifestations) of underlying IMARs should be monitored closely30,31
- In addition, when appropriate, specialists may also be consulted36
- There are treatment algorithms available to assist healthcare providers (HCPs) in managing IMARs35,37
- In addition, recent guidelines provide consensus recommendations for the management of IMARs31,37,38
- Management principles can include delaying or discontinuing therapy and administration of immunosuppressive agents and organ-specific reversal agents29,31,32,34,39
- Specific and more detailed guidance for managing IMARs associated with individual products can be found in their accompanying prescribing information
- As research in immunotherapy advances and more data are made available, effective management of IMARs will evolve39
References–Adverse reactions and I-O
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5. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol. 2010;125(2 suppl 2):S3-23. 6. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6(3):173-182. 7. Thangavelu G, Gill RG, Boon L, Ellestad KK, Anderson CC. Control of in vivo collateral damage generated by T cell immunity. J Immunol. 2013;191(4):1686-1691. 8. Amos SM, Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118(3):499-509. 9. Chen TT. Statistical issues and challenges in immuno-oncology. J Immunother Cancer. 2013;1(1):18. 10. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 11. Winer A, Bodor JN, Borghaei H, et al. Identifying and managing the adverse effects of immune checkpoint blockade. J Thorac Dis. 2018;10(suppl 3):S480-S489. 12. Aramaki T, Ida H, Izumi Y, et al. A significantly impaired natural killer cell activity due to a low activity on a per-cell basis in rheumatoid arthritis. Mod Rheumatol. 2009;19(3):245-252. 13. Fort MM, Leach MW, Rennick DM. A role for NK cells as regulators of CD4+ T cells in a transfer model of colitis. J Immunol. 1998;161(7):3256-3261. 14. Park Y-W, Kee S-J, Cho Y-N, et al. Impaired differentiation and cytotoxicity of natural killer cells in systemic lupus erythematosus. Arthritis Rheum. 2009;60(6):1753-1763.
15. Zhang B, Yamamura T, Kondo T, Fujiwara M, Tabira T. Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells. J Exp Med. 1997;186(10):1677-1687. 16. Baskar R, Dai J, Wenlong N, Yeo R, Yeoh K-W. Biological response of cancer cells to radiation treatment. Front Mol Biosci. 2014;1:24. doi:10.3389/fmolb.2014.00024. 17. Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: a review. Plast Reconstr Surg. 2014;133(1):49e-56e. 18. Jansman FGA, Sleijfer DT, de Graaf JC, Coenen JLLM, Brouwers JRBJ. Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer. Drug Saf. 2001;24(5):353-367. 19. Nicolson GL, Conklin KA. Reversing mitochondrial dysfunction, fatigue and the adverse effects of chemotherapy of metastatic disease by molecular replacement therapy. Clin Exp Metastasis. 2008;25(2):161-169. 20. Wujcik D. Science and mechanism of action of targeted therapies in cancer treatment. Semin Oncol Nurs. 2014;30(3):139-146. 21. Widakowich C, de Castro G JR, de Azambuja E, Dinh P, Awada A. Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist. 2007;12(12):1443-1455.
22. Liu S, Kurzrock R. Toxicity of targeted therapy: implications for response and impact of genetic polymorphisms. Cancer Treat Rev. 2014;40(7):883-891. 23. Bumbaca D, Wong A, Drake E, et al. Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4. mAbs. 2011;3(4):376-386. 24. Disis ML. Mechanism of action of immunotherapy. Semin Oncol. 2014;41(suppl 5):S3-S13. 25. Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol. 2015;15(4):243-254. 26. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 27. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989-1004. 28. Liu J, Blake SJ, Harjunpää H, et al. Assessing immune-related adverse events of efficacious combination immunotherapies in preclinical models of cancer. Cancer Res. 2016;76(18):5288-5301. 29. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. 30. Davies M, Duffield EA. Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events. Immunotargets Ther. 2017;6:51-71. 31. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559-574. 32. Kumar V, Chaudhary N, Garg M, et al. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol. 2017;8:49. doi:10.3389/fphar.2017.00049. 33. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148. 34. Martins F, Sykiotis GP, Maillard M, et al. New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol. 2019;20(1):e54-e64. 35. Gelao L, Criscitiello C, Esposito A, Goldhirsch A, Curigliano G. Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an “innocent bystander.” Toxins (Basel). 2014;6(3):914-933. 36. Sznol M, Postow MA, Davies MJ, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70-76. 37. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768. 38. Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5:95.doi:10.1186/s40425-017-0300-z. 39. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv119-iv142. 40. Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015;13:211. doi:10.1186/s12916-015-0455-8.