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Both Traditional Cancer Therapies and
Immunotherapies Can Lead to Adverse Reactions
Related to Their Respective Mechanisms of Action


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 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 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

Monitoring and vigiliance are important for management of IMARs

Immune Pathways

See where our I-O research into immune pathways is heading

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I-O Biomarkers

Read about I-O biomarkers we're currently investigating

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References–Adverse reactions and I-O

1. Moran P. Cellular effects of cancer chemotherapy administration. J Intraven Nurs. 2000;23(1):44-51. 2. Huang M, Shen A, Ding J, et al. Molecularly targeted cancer therapy: some lessons from the past decade. Trends Pharmacol Sci. 2014;35(1):41-50. 3. Joo WD, Visintin I, Mor G. Targeted cancer therapy—are the days of systemic chemotherapy numbered? Maturitas. 2013;76(4):308-314. 4. Stone HB, Coleman CN, Anscher MS, McBride WH. Effects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol. 2003;4(9):529-536. 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.