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Mitigating The Toxic Effects Of Anticancer Immunotherapy

Tara C. Gangadhar, R. Vonderheide
Published 2014 · Medicine

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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.
This paper references
10.1056/NEJMoa1200694
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
J. Brahmer (2012)
10.1038/nrc3239
The blockade of immune checkpoints in cancer immunotherapy
D. Pardoll (2012)
10.1016/S0140-6736(08)61033-8
Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial
A. Eggermont (2008)
10.1126/scitranslmed.3002842
T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia
M. Kalos (2011)
10.1097/01.CJI.0000178913.41256.06
Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer.
J. Blansfield (2005)
10.1097/CJI.0b013e3182829903
Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy
R. Morgan (2013)
10.1182/blood-2011-10-384388
B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells.
J. Kochenderfer (2012)
10.1016/J.YSUR.2011.09.015
Durable Complete Responses in Heavily Pretreated Patients with metastatic Melanoma Using T-Cell Transfer Immunotherapy
T. Eberlein (2012)
10.1093/jnci/djq009
Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis.
S. Mocellin (2010)
10.1038/mt.2010.31
Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial.
R. Brentjens (2010)
10.1158/1078-0432.CCR-07-0187
Prognostic Factors Related to Clinical Response in Patients with Metastatic Melanoma Treated by CTL-Associated Antigen-4 Blockade
Stephanie G Downey (2007)
10.1182/blood-2011-05-354449
Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma.
C. Louis (2011)
CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans
S. Gende (2011)
E1608 [abstract
Hodi (2013)
Targeted therapy for metastatic melanoma : from bench to bedside
W. J. Hwu (2010)
10.1016/S0084-3873(09)79559-8
Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial
M. S. Gordon (2009)
10.1038/nrc2051
Immunostimulatory monoclonal antibodies for cancer therapy
I. Melero (2007)
10.1200/JCO.2013.31.15_SUPPL.TPS3107
A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell non-Hodgkin’s lymphoma (B-NHL).
I. Melero (2013)
10.1200/JCO.2012.44.6112
Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
A. Ribas (2013)
10.1093/annonc/mdr028
Anti-CTLA-4 antibody-induced Guillain-Barré syndrome in a melanoma patient.
S. Wilgenhof (2011)
exploiting costimulation and target antigens for active and passive T cell immunotherapy
R. H. Vonderheide (2003)
10.1056/NEJMoa1003466
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
10.1056/NEJMoa1104621
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
C. Robert (2011)
10.1210/jc.2012-4075
Endocrine side effects induced by immune checkpoint inhibitors.
S. Corsello (2013)
From Bench To Bedside(第19回)心臓弁膜症と血管新生抑制因子コンドロモデュリン-1
伯野 大彦 (2010)
10.1056/NEJMoa1305133
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
O. Hamid (2013)
10.1056/NEJMe1205943
Tumor immunotherapy directed at PD-1.
A. Ribas (2012)
10.1158/1078-0432.CCR-12-3080
Efficacy and Safety of Retreatment with Ipilimumab in Patients with Pretreated Advanced Melanoma Who Progressed after Initially Achieving Disease Control
C. Robert (2013)
10.1200/JCO.2005.06.205
Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
P. Attia (2005)
10.1038/ni.1679
Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection
S. Blackburn (2009)
10.1245/s10434-008-0104-y
CTLA-4 Blockade with Monoclonal Antibodies in Patients with Metastatic Cancer: Surgical Issues
G. Phan (2008)
surgical issues
G. Q. Phan (2008)
10.1038/mt.2010.24
Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.
R. Morgan (2010)
case report of an unforeseen adverse event in a phase I clinical trial
Brentjens (2010)
10.1056/NEJMoa1215134
Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
S. Grupp (2013)
10.1007/s00262-011-1014-6
The CD40 agonist antibody CP-870,893 enhances dendritic cell and B-cell activity and promotes anti-tumor efficacy in SCID-hu mice
R. Gladue (2011)
10.1371/journal.pone.0060031
Co-Stimulation through 4-1BB/CD137 Improves the Expansion and Function of CD8+ Melanoma Tumor-Infiltrating Lymphocytes for Adoptive T-Cell Therapy
J. Chacon (2013)
10.1093/jnci/djr373
Thyroid dysfunction from antineoplastic agents.
Ole-Petter R Hamnvik (2011)
10.1200/jco.2013.31.18_suppl.cra9007
Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608.
S. Lee (2013)
10.1200/JCO.2008.26.15_SUPPL.3007
Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA)
M. Sznol (2008)
10.1200/jco.2006.24.18_suppl.2507
Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.
R. H. Vonderheide (2006)
10.1056/NEJMoa1200690
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
S. Topalian (2012)
10.1182/BLOOD.V104.11.2657.2657
CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms.
J. Chemnitz (2004)
10.1200/JCO.1999.17.7.2105
High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993.
M. Atkins (1999)
10.1056/NEJMc1302338
Hepatotoxicity with combination of vemurafenib and ipilimumab.
A. Ribas (2013)
10.1158/1078-0432.CCR-1103-3
A Pooled Analysis of Eastern Cooperative Oncology Group and Intergroup Trials of Adjuvant High-Dose Interferon for Melanoma
J. Kirkwood (2004)
10.2214/AJR.12.9751
Ipilimumab-associated colitis: CT findings.
K. Kim (2013)
pilot clinical trial results
Till (2012)
10.1073/pnas.1305394110
Strength of PD-1 signaling differentially affects T-cell effector functions
F. Wei (2013)
10.1158/1078-0432.CCR-12-2064
Agonistic CD40 Antibodies and Cancer Therapy
R. Vonderheide (2013)
10.1016/J.IT.2006.12.001
The road to recovery: translating PD-1 biology into clinical benefit.
J. Riley (2007)
10.1073/pnas.1533209100
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma
G. Phan (2003)
10.1182/BLOOD.V90.7.2541.2541_2541_2548
Effects of Single-Dose Interleukin-12 Exposure on Interleukin-12–Associated Toxicity and Interferon-γ Production
J. Leonard (1997)
10.1053/j.seminoncol.2010.09.007
The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications.
A. M. Di Giacomo (2010)
10.1016/j.immuni.2013.07.002
Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology.
M. Kalos (2013)
10.1200/JCO.2005.04.5716
Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.
Kimberly E. Beck (2006)
10.1200/jco.2013.31.18_suppl.cra9006
Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538).
H. Kluger (2013)
10.1056/NEJMoa1103849
Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
D. Porter (2011)
10.1097/00002371-200411000-00008
Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis.
M. Robinson (2004)
10.1126/scitranslmed.3006034
Identification of a Titin-Derived HLA-A1–Presented Peptide as a Cross-Reactive Target for Engineered MAGE A3–Directed T Cells
Brian J. Cameron (2013)
10.1158/1078-0432.CCR-09-1024
A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma
J. Weber (2009)
CT findings
Kim (2013)
YERVOYTM (ipilimumab): Immune-mediated Adverse Reaction Management Guide [online], https://www.hcp
Bristol-Myers Squibb (2011)
10.1385/IR:27:2-3:341
A translational bridge to cancer immunotherapy
R. Vonderheide (2003)
10.1053/j.seminoncol.2010.09.008
Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies.
P. Ascierto (2010)
10.1056/NEJMOA063842
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.
G. Suntharalingam (2006)
CD 20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD 28 and 4-1 BB domains : pilot clinical trial results
B. Till (2012)
10.1016/S1040-1741(08)79104-8
Enterocolitis in Patients With Cancer After Antibody Blockade of Cytotoxic T-Lymphocyte–Associated Antigen 4
M. Gordon (2008)
10.2214/AJR.12.9567
Reply: To PMID 22623561.
Toshihiro Tanaka (2013)
10.1200/JCO.2013.31.15_SUPPL.9010
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM).
O. Hamid (2013)
10.1200/JCO.2012.41.6750
Management of immune-related adverse events and kinetics of response with ipilimumab.
J. Weber (2012)
10.1126/scitranslmed.3005930
CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia
R. Brentjens (2013)
10.1182/blood-2013-03-490565
Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.
G. Linette (2013)
10.1073/pnas.1221609110
T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy
S. Zhong (2013)
10.1158/1078-0432.CCR-11-2479
Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma
J. Wilmott (2011)
10.1182/blood-2011-10-387969
CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results.
B. Till (2012)
10.1056/NEJMoa1302369
Nivolumab plus ipilimumab in advanced melanoma.
J. Wolchok (2013)
10.1634/theoncologist.13-S4-2
The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation.
J. Wolchok (2008)
Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses.
R. Khattri (1999)
final results of EORTC 18991, a randomised phase III trial
Eggermont (2008)
10.1200/JCO.1989.7.4.486
Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines.
K. Margolin (1989)
a new cause of uveitis
Robinson (2004)
Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials.
J. Wolchok (2010)
10.1200/JCO.2002.03.052
Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy.
J. Kirkwood (2002)
Interferon α adjuvant therapy in patients with high - risk melanoma : a systematic review and meta - analysis
S. Mocellin (2010)
10.4161/onci.23033
Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors
R. Vonderheide (2013)
10.1200/JCO.2005.01.109
Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206.
A. Ribas (2005)
10.1056/NEJMe1305484
Combination checkpoint blockade--taking melanoma immunotherapy to the next level.
James L. Riley (2013)
analysis of toxicity and management guidelines
Margolin (1989)
10.1200/JCO.2013.31.15_SUPPL.3025
Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.
G. Beatty (2013)



This paper is referenced by
Evaluation Of CTLA-4 Blockage Therapy With Metronomic Chemotherapy For The Treatment Of Preclinical Breast Cancer
Karla Parra (2014)
10.1159/000497161
Sorafenib: Experience and Better Management of Side Effects Improve Overall Survival in Hepatocellular Carcinoma Patients: A Real-Life Retrospective Analysis
J. Raoul (2019)
Identification and management of toxicities from immune checkpoint-blocking drugs.
B. Teply (2014)
Targeting immunosuppressive myeloid cells using nanocarriers to improve cancer immunotherapy
M. S. Sasso (2015)
10.1158/2326-6066.CIR-15-0194
Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery
E. Gilboa (2015)
10.1016/j.jgo.2018.07.015
The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population.
J. Sattar (2019)
10.4049/jimmunol.1500281
A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma
Stefano Pierini (2015)
10.1016/j.addr.2020.10.002
Lymph-directed immunotherapy - Harnessing endogenous lymphatic distribution pathways for enhanced therapeutic outcomes in cancer.
O. Feeney (2020)
10.21019/pharmacotherapyfirst.rcc_overview
Renal Cell Carcinoma
Ashley K. Losing (2017)
10.1158/2326-6066.CIR-20-0020
Vaccination against Nonmutated Neoantigens Induced in Recurrent and Future Tumors
G. Garrido (2020)
10.1080/14740338.2020.1736554
The safety and efficacy of pembrolizumab for the treatment of non-small cell lung cancer
José Mª Mazarico Gallego (2020)
10.18632/oncotarget.24277
Semaphorin 4D in human head and neck cancer tissue and peripheral blood: A dense fibrotic peri-tumoral stromal phenotype
Roshanak Derakhshandeh (2018)
10.1177/1721727X15626423
New insights into the anti-PD-L1 and anti-PD-1 reagents in cancer therapy
C. Chen (2016)
10.1097/CJI.0000000000000062
PD-1/PD-L1 Blockade Together With Vaccine Therapy Facilitates Effector T-Cell Infiltration Into Pancreatic Tumors
K. Soares (2015)
10.1007/978-3-319-17807-3_12
Epithelial Mesenchymal Transition Influence on CTL Activity
Wilfried Engl (2015)
10.1016/J.AD.2017.01.016
Nuevos avances de tratamiento inmunobiológico en el melanoma avanzado
M. C. Pérez Gago (2017)
10.1177/1753465816680574
Rapid and partial remission of primary lesion but complicated by secondary fibrosis after treatment with nivolumab in a lung squamous carcinoma
L. Ding (2017)
10.1038/bjc.2016.429
Impact of CTLA-4 blockade in conjunction with metronomic chemotherapy on preclinical breast cancer growth
Karla Parra (2017)
10.1097/CJI.0000000000000121
Severe Psoriasis Flare After Anti-Programmed Death Ligand 1 (PD-L1) Therapy for Metastatic Non-Small Cell Lung Cancer (NSCLC).
P. L. Chia (2016)
10.1080/14712598.2017.1366445
Prospects and progress of immunotherapy for bladder cancer
M. Boegemann (2017)
10.1080/2162402X.2018.1512456
BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways
Peng Yue (2019)
10.1016/j.nano.2017.10.013
Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy.
D. R. Wilson (2018)
10.1038/s41591-019-0374-x
Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy
J. Wang (2019)
10.1007/s10637-017-0524-2
Radiomics to predict immunotherapy-induced pneumonitis: proof of concept
R. Colen (2017)
10.1136/bmj.k4226
Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis
C. Xu (2018)
10.1007/978-1-4939-2727-2_12
Oncolytic Viral Therapy Using Reovirus.
C. Thirukkumaran (2015)
10.1177/1753465815578349
Targeting the immune system to treat lung cancer: rationale and clinical experience
N. Guibert (2015)
This information is current as against Experimental Renal Cell Carcinoma A Tumor Mitochondria Vaccine Protects
Stefano Pierini (2015)
10.4172/2157-2518.1000281
The Mechanism of Checkpoint Inhibitors in Gynecologic Cancer
Karoutsos Petros (2017)
10.1002/wnan.1506
Immunoengineering with biomaterials for enhanced cancer immunotherapy.
Yu-Qing Xie (2018)
10.2217/imt-2016-0022
PD-1 and PD-L1 inhibitors in melanoma treatment: past success, present application and future challenges.
J. Lee (2016)
Applying Deep Learning to Discover Highly Functionalized Nucleic Acid Polymers That Bind to Small Molecules
Michael Wornow (2020)
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