. 2014 Jan; 11(2):91-9.
doi: 10.1038/nrclinonc.2013.245.

Mitigating the toxic effects of anticancer immunotherapy

Tara C Gangadhar 1 Robert H Vonderheide 1 
  • PMID: 24445516
  •     67 References
  •     91 citations


Advances in our understanding of the regulatory mechanisms of the immune system have led to the development of novel approaches for cancer therapy, including inhibition of immune checkpoints with anti-CTLA-4 and anti-PD-1 antibodies. An increasing number of immunomodulatory treatments are under investigation, and are beginning to show promise in clinical trials. As more-effective therapies become available based on modulation of the immune system in order to trigger or enhance antitumour immune responses, clinicians will need to become familiar with recognizing and controlling the adverse effects arising from immune therapy. This Review describes the toxicity profiles for various anticancer therapies based on the use of agents that block immune checkpoints, immunostimulatory agents, and adoptive T-cell therapy (that is, infusion of modified autologous T cells). The management of patients receiving these treatments presents unique challenges for clinicians. Nevertheless, many of the adverse effects associated with these treatments are reversible and can be managed with supportive care either with or without cessation of therapy. This final point is extremely important given the continued development of new cancer immunotherapies, and the importance of safe and effective use of existing effective FDA-approved agents.

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Invest New Drugs, 2017 Oct 28; 36(4). PMID: 29075985    Free PMC article.
Cardiotoxicity of immune checkpoint inhibitors.
Gilda Varricchi, Maria Rosaria Galdiero, +5 authors, Carlo Gabriele Tocchetti.
ESMO Open, 2017 Nov 07; 2(4). PMID: 29104763    Free PMC article.
Highly Cited. Review.
Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy.
David R Wilson, Rupashree Sen, +3 authors, Young J Kim.
Nanomedicine, 2017 Nov 12; 14(2). PMID: 29127039    Free PMC article.
Highly Cited.
Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers.
Claire Lhuillier, Claire Vanpouille-Box, +2 authors, Sandra Demaria.
Semin Cancer Biol, 2017 Dec 21; 52(Pt 2). PMID: 29258856    Free PMC article.
How Checkpoint Inhibitors Are Changing the Treatment Paradigm in Solid Tumors: What Advanced Practitioners in Oncology Need to Know.
Marianne Davies.
J Adv Pract Oncol, 2016 Jul 01; 7(5). PMID: 29282426    Free PMC article.
Immune Checkpoints in Leprosy: Immunotherapy As a Feasible Approach to Control Disease Progression.
Hayana Ramos Lima, Thaís Helena Gasparoto, +10 authors, Ana Paula Campanelli.
Front Immunol, 2018 Jan 10; 8. PMID: 29312289    Free PMC article.
Semaphorin 4D in human head and neck cancer tissue and peripheral blood: A dense fibrotic peri-tumoral stromal phenotype.
Roshanak Derakhshandeh, Sonia Sanadhya, +4 authors, Rania H Younis.
Oncotarget, 2018 Mar 16; 9(13). PMID: 29541402    Free PMC article.
Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation.
Matthew G K Benesch, Iain T K MacIntyre, Todd P W McMullen, David N Brindley.
Cancers (Basel), 2018 Mar 16; 10(3). PMID: 29543710    Free PMC article.
Highly Cited. Review.
Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer.
Maarten Versteven, Johan M J Van den Bergh, +4 authors, Eva Lion.
Front Immunol, 2018 Mar 31; 9. PMID: 29599770    Free PMC article.
Highly Cited. Review.
Deciphering mechanisms of brain metastasis in melanoma - the gist of the matter.
Torben Redmer.
Mol Cancer, 2018 Jul 29; 17(1). PMID: 30053879    Free PMC article.
Management of the cutaneous adverse effects of antimelanoma therapy.
Rose Congwei Liu, Germana Consuegra, Pablo Fernández-Peñas.
Melanoma Manag, 2018 Sep 08; 4(4). PMID: 30190925    Free PMC article.
Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor.
Sang-Soo Kim, Joe B Harford, +2 authors, Esther H Chang.
Oncoimmunology, 2018 Oct 06; 7(10). PMID: 30288347    Free PMC article.
Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis.
Cheng Xu, Yu-Pei Chen, +12 authors, Jun Ma.
BMJ, 2018 Nov 10; 363. PMID: 30409774    Free PMC article.
Highly Cited. Systematic Review.
BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways.
Peng Yue, Taylor Harper, +6 authors, Gerald M Feldman.
Oncoimmunology, 2018 Dec 14; 8(1). PMID: 30546949    Free PMC article.
Synergistic cancer immunotherapy combines MVA-CD40L induced innate and adaptive immunity with tumor targeting antibodies.
José Medina-Echeverz, Maria Hinterberger, +11 authors, Henning Lauterbach.
Nat Commun, 2019 Nov 07; 10(1). PMID: 31695037    Free PMC article.
Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity.
Greta Garrido, Brett Schrand, +10 authors, Eli Gilboa.
Nat Commun, 2019 Aug 23; 10(1). PMID: 31434881    Free PMC article.
Sorafenib: Experience and Better Manage-ment of Side Effects Improve Overall Survival in Hepatocellular Carcinoma Patients: A Real-Life Retrospective Analysis.
Jean-Luc Raoul, Xavier Adhoute, +4 authors, Marc Bourlière.
Liver Cancer, 2019 Dec 05; 8(6). PMID: 31799203    Free PMC article.
Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy.
Jun Wang, Jingwei Sun, +16 authors, Lieping Chen.
Nat Med, 2019 Mar 06; 25(4). PMID: 30833750    Free PMC article.
Highly Cited.
STING modulators: Predictive significance in drug discovery.
Xiangling Cui, Rongyu Zhang, Shan Cen, Jinming Zhou.
Eur J Med Chem, 2019 Aug 17; 182. PMID: 31419779    Free PMC article.
Combination therapy targeting both innate and adaptive immunity improves survival in a pre-clinical model of ovarian cancer.
Christina A Hartl, Adrian Bertschi, +5 authors, Michael S Goldberg.
J Immunother Cancer, 2019 Aug 01; 7(1). PMID: 31362778    Free PMC article.
From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview.
Carlo Gabriele Tocchetti, Christian Cadeddu, +12 authors, Giuseppe Mercuro.
Antioxid Redox Signal, 2017 Apr 12; 30(18). PMID: 28398124    Free PMC article.
Vaccination against Nonmutated Neoantigens Induced in Recurrent and Future Tumors.
Greta Garrido, Brett Schrand, +12 authors, Eli Gilboa.
Cancer Immunol Res, 2020 Apr 17; 8(7). PMID: 32295785    Free PMC article.
Nanomedicine and macroscale materials in immuno-oncology.
Qingxue Sun, Matthias Barz, +5 authors, Yang Shi.
Chem Soc Rev, 2018 Nov 23; 48(1). PMID: 30465669    Free PMC article.
The rationale for including immune checkpoint inhibition into multimodal primary treatment concepts of head and neck cancer.
Ingeborg Tinhofer, Volker Budach, Korinna Jöhrens, Ulrich Keilholz.
Cancers Head Neck, 2016 Aug 10; 1. PMID: 31093338    Free PMC article.
Immunosuppressive checkpoint Siglec-15: a vital new piece of the cancer immunotherapy jigsaw puzzle.
Xiubao Ren.
Cancer Biol Med, 2019 Sep 14; 16(2). PMID: 31516742    Free PMC article.
Enhancing cancer immunotherapy with nanomedicine.
Darrell J Irvine, Eric L Dane.
Nat Rev Immunol, 2020 Feb 02; 20(5). PMID: 32005979    Free PMC article.
Radiation-Induced Enhancement of Antitumor T-cell Immunity by VEGF-Targeted 4-1BB Costimulation.
Brett Schrand, Bhavna Verma, +8 authors, Adrian Ishkanian.
Cancer Res, 2017 Jan 14; 77(6). PMID: 28082399    Free PMC article.
Immune Checkpoint Inhibitor-Induced Thyroiditis Is Associated with Increased Intrathyroidal T Lymphocyte Subpopulations.
Anupam Kotwal, Michael P Gustafson, +5 authors, Mabel Ryder.
Thyroid, 2020 Apr 24; 30(10). PMID: 32323619    Free PMC article.
Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.
Lindsey M Kuehm, Niloufar Khojandi, +13 authors, Ryan M Teague.
Cancer Immunol Res, 2020 Oct 08; 9(2). PMID: 33023966    Free PMC article.
Healthy cells functionally present TAP-independent SSR1 peptides: implications for selection of clinically relevant antigens.
Antonius A de Waard, Tamara Verkerk, +10 authors, Robbert M Spaapen.
iScience, 2021 Feb 09; 24(2). PMID: 33554062    Free PMC article.
Treatment- and immune-related adverse events of immune checkpoint inhibitors in advanced lung cancer.
Jun Shao, Chengdi Wang, +3 authors, Weimin Li.
Biosci Rep, 2020 Apr 22; 40(5). PMID: 32315071    Free PMC article.
Systematic Review.
Knowledge gap about immune checkpoint inhibitors among rheumatologists and medical students: a survey.
Guilherme Ferreira Maciel da Silva, Joaquim Ivo Vasques Dantas Landim, +4 authors, Francisco Airton Castro Rocha.
Rheumatol Int, 2020 Aug 09; 41(5). PMID: 32767082
A Review of Cancer Immunotherapy Toxicity II: Adoptive Cellular Therapies, Kinase Inhibitors, Monoclonal Antibodies, and Oncolytic Viruses.
Neeraj Chhabra, Joseph Kennedy.
J Med Toxicol, 2021 Apr 07; 18(1). PMID: 33821435    Free PMC article.
Stoichiometry of multi-specific immune checkpoint RNA Abs for T cell activation and tumor inhibition using ultra-stable RNA nanoparticles.
Dan Shu, Long Zhang, +2 authors, Peixuan Guo.
Mol Ther Nucleic Acids, 2021 Apr 20; 24. PMID: 33868786    Free PMC article.
SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions.
S Srinivasan, N A Yee, +4 authors, J M Mejia Oneto.
Adv Ther (Weinh), 2021 Apr 20; 4(3). PMID: 33869738    Free PMC article.
Efficacy and side effects of immune checkpoint inhibitors in the treatment of colorectal cancer.
Salomon M Manz, Marco Losa, Ralph Fritsch, Michael Scharl.
Therap Adv Gastroenterol, 2021 May 06; 14. PMID: 33948110    Free PMC article.
The Cytosolic DNA-Sensing cGAS-STING Pathway in Liver Diseases.
Zhilei Wang, Nian Chen, +5 authors, Zhaofang Bai.
Front Cell Dev Biol, 2021 Aug 14; 9. PMID: 34386500    Free PMC article.
Adrenaline fuels a cytokine storm during immunotherapy.
Stanley R RIddell.
Nature, 2018 Dec 14; 564(7735). PMID: 30542198
High Granulocyte-Macrophage Colony Stimulating Factor to Interleukin 10 Ratio and Marked Antioxidant Enzyme Activities Predominate in Symptomatic Cattle Naturally Infected with Candidatus Mycoplasma haemobos, Theileria orientalis, Theileria sinensis and Trypanosoma evansi.
Onyinyechukwu Ada Agina, Kim Tho Cheah, +6 authors, Hazilawati Hamzah.
Animals (Basel), 2021 Aug 28; 11(8). PMID: 34438696    Free PMC article.
TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.
Meredith L Stone, Jesse Lee, +11 authors, Gregory L Beatty.
JCI Insight, 2021 Jun 09; 6(14). PMID: 34101617    Free PMC article.
Safety profile of poly (ADP-ribose) polymerase (PARP) inhibitors in cancer: a network meta-analysis of randomized controlled trials.
Shengnan Bao, Yuanping Yue, +13 authors, Yongmei Yin.
Ann Transl Med, 2021 Sep 18; 9(15). PMID: 34532366    Free PMC article.
Prolonged survival in patients with hand-foot skin reaction secondary to cooperative sorafenib treatment.
Masanori Ochi, Toshiro Kamoshida, Masahiro Araki, Tadashi Ikegami.
World J Gastroenterol, 2021 Sep 21; 27(32). PMID: 34539142    Free PMC article.
PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy.
Jinhua Liu, Zichao Chen, +3 authors, Zhen Zhang.
Front Pharmacol, 2021 Sep 21; 12. PMID: 34539412    Free PMC article.
PD-L1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer in PD-L1 Positive Patients: A Safety Data Network Meta-Analysis.
María Rosario García Campelo, Edurne Arriola, +8 authors, Delvys Rodríguez-Abreu.
J Clin Med, 2021 Oct 14; 10(19). PMID: 34640601    Free PMC article.
Immune Checkpoint Inhibitors and the Heart.
Diana Larisa Mocan-Hognogi, Sebastian Trancǎ, +3 authors, Anca Simona Bojan.
Front Cardiovasc Med, 2021 Oct 19; 8. PMID: 34660728    Free PMC article.
Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints.
Yaolin Xu, Lijie He, Qiang Fu, Junzhe Hu.
Front Oncol, 2021 Dec 04; 11. PMID: 34858835    Free PMC article.
A Network Comparison on Safety Profiling of Immune Checkpoint Inhibitors in Advanced Lung Cancer.
Yi-Dan Yan, Jiu-Jie Cui, +4 authors, Hou-Wen Lin.
Front Immunol, 2021 Dec 21; 12. PMID: 34925331    Free PMC article.
Systematic Review.
The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy.
Patrick Kwabena Oduro, Xianxian Zheng, +7 authors, Qilong Wang.
Acta Pharm Sin B, 2022 Feb 08; 12(1). PMID: 35127372    Free PMC article.
Safety of Immune Checkpoint Inhibitor Resumption after Interruption for Immune-Related Adverse Events, a Narrative Review.
Marion Allouchery, Clément Beuvon, +3 authors, Mickaël Martin.
Cancers (Basel), 2022 Feb 26; 14(4). PMID: 35205703    Free PMC article.
Enhanced Cancer Therapy Using an Engineered Designer Cytokine Alone and in Combination With an Immune Checkpoint Inhibitor.
Anjan K Pradhan, Praveen Bhoopathi, +9 authors, Paul B Fisher.
Front Oncol, 2022 Apr 12; 12. PMID: 35402258    Free PMC article.