Toxicities Associated With PD-1/PD-L1 Blockade

Abstract Immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, produce durable responses in a subset of patients across cancer types. Although often well tolerated, these agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Treatment of these toxicities primarily consists of immune suppression with corticosteroids and other agents. This review briefly discusses the mechanisms of immune-related adverse events, overviews the clinical and pathologic features of major toxicities caused by PD-1/PD-L1 blockade, and reviews their management.

[1]  M. Shah,et al.  Endocrine dysfunction following immune checkpoint inhibitor therapy , 2017, Current opinion in endocrinology, diabetes, and obesity.

[2]  J. Larkin,et al.  Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. , 2017, The oncologist.

[3]  Douglas B. Johnson,et al.  Safety of resuming anti-PD-1 (aPD1) in patients (pts) with immune-related adverse events (irAEs) during combined anti-CTLA-4 (aCTLA4) and aPD1 in metastatic melanoma (MM). , 2017 .

[4]  Douglas B. Johnson,et al.  Clinical presentation of immune-related colitis associated with PD-1 inhibitor monotherapy (MONO) and combination PD-1/CTLA-4 inhibitors (COMBO) in melanoma. , 2017 .

[5]  R. Plummer,et al.  Tremelimumab-Induced Graves Hyperthyroidism
 , 2017, European Thyroid Journal.

[6]  C. Shi,et al.  PD‐1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis’ , 2017, Histopathology.

[7]  C. Rudin,et al.  Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Douglas B. Johnson,et al.  Cardiovascular Toxicities Associated with Cancer Immunotherapies , 2017, Current Cardiology Reports.

[9]  A. Carneiro,et al.  Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis , 2017, Cancer Immunology, Immunotherapy.

[10]  A. Giobbie-Hurder,et al.  Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis. , 2016, JAMA oncology.

[11]  A. Hottinger Neurologic complications of immune checkpoint inhibitors. , 2016, Current opinion in neurology.

[12]  J. Seidman,et al.  Fulminant Myocarditis with Combination Immune Checkpoint Blockade. , 2016, The New England journal of medicine.

[13]  R. Dummer,et al.  Pembrolizumab-triggered Uveitis: An Additional Surrogate Marker for Responders in Melanoma Immunotherapy? , 2016, Journal of immunotherapy.

[14]  F. Hodi,et al.  PD-1 Inhibitor–Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course , 2016, Clinical Cancer Research.

[15]  J. Wolchok,et al.  Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. , 2016, European journal of cancer.

[16]  C. Huttenhower,et al.  Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis , 2016, Nature Communications.

[17]  J. Sosman,et al.  Myasthenia Gravis Induced by Ipilimumab in Patients With Metastatic Melanoma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  A. Daud,et al.  Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression. , 2015, JAMA dermatology.

[19]  J. Sosman,et al.  Melanoma and a Headache. Diagnosis: Hypophysitis. , 2015, JAMA oncology.

[20]  J. Wolchok,et al.  Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  J. Wolchok PD-1 Blockers , 2015, Cell.

[22]  Dirk Schadendorf,et al.  Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. , 2015, The New England journal of medicine.

[23]  J. Larkin,et al.  Pembrolizumab versus Ipilimumab in Advanced Melanoma. , 2015, The New England journal of medicine.

[24]  M. Postow Managing immune checkpoint-blocking antibody side effects. , 2015, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[25]  A. Zwinderman,et al.  Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  J. Wolchok,et al.  Pituitary Expression of CTLA-4 Mediates Hypophysitis Secondary to Administration of CTLA-4 Blocking Antibody , 2014, Science Translational Medicine.

[27]  David C. Smith,et al.  Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  Kisha Mitchell,et al.  Ipilimumab-induced perforating colitis. , 2013, Journal of clinical gastroenterology.

[29]  Antoni Ribas,et al.  Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. , 2013, The New England journal of medicine.

[30]  R. Dummer,et al.  Patterns of onset and resolution of immune‐related adverse events of special interest with ipilimumab , 2013, Cancer.

[31]  A. Shinagare,et al.  Ipilimumab-associated colitis: CT findings. , 2013, AJR. American journal of roentgenology.

[32]  S. Tirumani,et al.  Ipilimumab associated hepatitis: imaging and clinicopathologic findings , 2013, Investigational New Drugs.

[33]  P. Friedlander,et al.  Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma , 2013, Melanoma research.

[34]  A. Hauschild,et al.  Management of immune-related adverse events and kinetics of response with ipilimumab. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  D. Kleiner,et al.  Pathologic Changes in Ipilimumab-Related Hepatitis in Patients with Metastatic Melanoma , 2012, Digestive Diseases and Sciences.

[36]  R. Kefford,et al.  Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[38]  D. Schadendorf,et al.  Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. , 2010, The Lancet. Oncology.

[39]  J. Bluestone,et al.  Control of peripheral T‐cell tolerance and autoimmunity via the CTLA‐4 and PD‐1 pathways , 2008, Immunological reviews.

[40]  Douglas B. Johnson,et al.  Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[41]  J. Larkin,et al.  Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[42]  J. Wolchok,et al.  Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.