BACKGROUND: The goals of treating patients with cancer are to cure the disease, prolong survival, and improve quality of life. The variation in the rate of irAEs with rechallenge observed in these 2 studies may reflect differences in the initial immunotherapy leading to irAE, because patients in the study by Pollack et al transitioned from combination therapy to anti–PD‐1 monotherapy, which has a lower overall toxicity profile, whereas many of the patients in the study by Simonaggio et al developed the initial irAE on anti–PD‐/1PD‐L1 monotherapy and were later rechallenged with the same class of therapy. CTLA‐4 is expressed on the surface of CD4‐positive and CD8‐positive lymphocytes and competes with the T‐cell–costimulatory receptor CD28 for binding to T‐cell–costimulatory factors, which are expressed on the surface of antigen‐presenting cells in the early phase of the immune response.12 CTLA‐4 binding reduces IL‐2 production and T‐cell proliferation. CRP, ferritin, and other markers of inflammation, including IFN‐γ, IL‐6, and IL‐10, are elevated in patients with CRS.109, 112, 113 Patients with grade 1 CRS should be treated with broad‐spectrum antibiotics along with other workup and supportive care, depending on the end‐organ toxicities observed. Multiple mechanisms have been proposed to account for the development of irAEs, although the exact pathophysiology is not fully understood. Nevertheless, in the last few years, CD40 mAbs have begun to show efficacy, particularly in combination with other therapies, and are now seen as a potentially important and as yet untapped mechanism to extend the effective range of current cancer immunotherapy to include tumors in which baseline T cell activation is insufficient. Cancer Immunotherapy: A Review . Immunotherapy a New Hope for Cancer Treatment: A Review Cancer is a major burden of disease worldwide with considerable impact on society. Thomas Friedrich, Nicholas Henthorn and Marco Durante Review The combination of immune therapy with radiation offers an exciting and promising treatment modality in cancer therapy. In severe cases, this can result in multiorgan failure, which has historically limited the clinical utility of cytokine therapy.6 ICIs, including antibodies against cytotoxic T lymphocyte antigen‐4 (CTLA‐4) and programmed cell death protein 1 (PD‐1) and its ligand PD‐L1, disinhibit T‐cell antitumor function, which can lead to a distinct constellation of organ‐specific inflammatory side effects, or irAEs.5 Another approach to immunotherapy is the ex vivo modification of patient T cells to generate specific antitumor reactivity, a process termed adoptive cell therapy.7 For instance, chimeric antigen receptor (CAR) T cells, which are engineered to recognize a tumor‐associated antigen, are used to treat hematologic malignancies and are being investigated in multiple solid tumor types.7 The most common CAR‐T toxicities in hematologic malignancies are cytokine release syndrome (CRS) and ICANS.8 Because of these toxicity profiles, treatment with cancer immunotherapies requires close monitoring, and toxicity often requires specific management, which can include steroids or immune‐modulating agents.5 As the use of immunotherapy in cancer continues to expand, guidelines addressing the management of ICI and CAR‐T toxicity have also been developed.5, 9-11. If you do not receive an email within 10 minutes, your email address may not be registered, Immunotherapies have transformed the treatment landscape for multiple solid and hematologic malignancies but confer unique toxicity profiles, which vary depending on the type of immunotherapy and are related to the specific mechanism of action. Common irAEs are summarized in Table 1. Another meta‐analysis that included 19 trials of PD‐1 and PD‐L1 therapy for NSCLC found that the incidence of any grade and grade ≥3 pneumonitis was higher with PD‐1 inhibitors compared with PD‐L1 inhibitors (3.6% vs 1.3% and 1.1% vs 0.4%, respectively).77 The incidence of pneumonitis was also higher in treatment‐naive patients compared with previously treated patients (4.3% vs 2.8%). There was a 5‐fold decrease in bone marrow CAR‐T cells in patients who received high‐dose steroids compared with tocilizumab or supportive care alone. Consider HLH/MAS if the following features are present in patients with CRS: Neurologic assessment twice daily, including cognitive and motor function. Here we review the past and present of clinical lung cancer immunotherapy and give a perspective for the future development based on emerging biological insights. Association of sex, age, and eastern cooperative oncology group performance status with survival benefit of cancer immunotherapy in randomized clinical trials: a systematic review and meta-analysis. First published as a Review in Advance on November 7, 2018 Different people have different side effects. We carried out a systematic review of IAD cases induced by cancer immunotherapy published to date using PubMed’s database. 3:55-75 (Volume publication date March 2019) First published as a Review in Advance on November 7, 2018 https://doi.org/10.1146/annurev-cancerbio-030518-055552 The presentation of cardiac irAEs varies and can include dyspnea, chest pain, or acute cardiovascular collapse.11 Cardiac irAEs include myocarditis, pericarditis, cardiac fibrosis, arrhythmias, and new‐onset heart failure.11 Myocarditis can be rapidly fatal; in the multicenter registry of patients with ICI‐induced myocarditis, 16 of 35 patients with myocarditis experienced a major adverse cardiac event at a median follow‐up of 102 days, including 6 cases of cardiovascular death, 3 of cardiogenic shock, 4 of cardiac arrest, and 3 of complete heart block,94 highlighting the potentially life‐threatening nature of this irAE and the importance of vigilant monitoring. Immunotherapy has become a powerful clinical strategy for treating cancer. The first TCR T cell cancer immunotherapy used in the clinic was tested against metastatic melanoma and utilized a TCR that bound a human lymphocyte antigen A2 (HLA-A2)–restricted peptide from a melanocytic differentiation antigen . Zihai Li 1,2, Wenru Song 2, Mark Rubinstein 1 & Delong Liu 2,3 Journal of Hematology & Oncology volume 11, Article number: 142 (2018) Cite this article. Immunotherapy can cause side effects, many of which happen when the immune system that has been revved-up to act against the cancer also acts against healthy cells and tissues in the body. Disinhibition of T‐cell function by ICIs can lead to a spectrum of inflammatory side effects, or irAEs. Because ipilimumab is an immunoglobulin G1 antibody, it can activate the classical complement cascade, leading to a type II hypersensitivity reaction. For example, CHECKMATE 016 (Nivolumab [BMS‐936558; MDX‐1106] in Combination With Suntinib, Pazopanaib, or Ipilimumab in Subjects With Metastatic Renal Cell Carcinoma [RCC]) evaluated the safety and efficacy of different regimens of ipilimumab‐nivolumab, including nivolumab at a dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg (N3I1), nivolumab at a dose of 1 mg/kg and ipilimumab at a dose of 3 mg/kg (N1I3), and nivolumab at a dose of 3 mg/kg and ipilimumab at a dose of 3 mg/kg (N3I3), for metastatic RCC (mRCC).53 In the N1I3 arm, 21% of patients developed grade 3 and 4 elevation in aspartate and alanine aminotransferase (AST/ALT) levels compared with a 4% incidence of grade 3 AST/ALT elevation in the N3I1 arm. A series that included 1479 patients treated with ICI, of whom 179 developed immune‐related enterocolitis, found that patients who received infliximab or vedolizumab ≤10 days after colitis onset had improved clinical outcomes, including decreased hospitalization, a shorter duration of steroid treatment and reduced rates of steroid failure, and shorter symptom duration.47 Prospective studies are needed clarify the optimal timing of infliximab and vedolizumab. https://doi.org/10.1146/annurev-cancerbio-030518-055552, Michael Dougan,1,2 Glenn Dranoff,3 and Stephanie K. Dougan2,4, 1Division of Gastroenterology and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; email: [email protected], 2Harvard Medical School, Harvard University, Boston, Massachusetts 02115, USA; email: [email protected], 3Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA, 4Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. Myasthenia gravis had an earlier onset (median, 29 days) compared with other neurologic toxicities (median, 61‐80 days), and was often associated with myocarditis and myositis. Box 536-20115, Egerton, Kenya. Cancer Treatment Reviews (Incorporating Evidence-based Oncology) is an international review journal that will keep both the clinician and researcher abreast of modern concepts and developments in cancer treatment research through the publication of state of the art, authoritative reviews; evidence-based reviews (using a priori defined selection process to identify key articles from … Five of 8 patients with ocular irAEs had additional extraocular irAEs.93 Because ocular irAEs can be vision‐threatening, patients with new visual symptoms should be referred promptly to ophthalmology. Patients with grade ≥2 CRS should be treated with tocilizumab at a dose of 8 mg/kg intravenously for a maximum of 4 doses; steroids should be added in cases of grade 3 and 4 toxicity and in cases of grade 2 toxicity with persistent hypotension after anti–IL‐6 therapy.5, Tocilizumab is an IL‐6 receptor antagonist that has been shown to lead to rapid resolution of CAR‐T–induced CRS116 and is FDA‐approved for the treatment of severe CRS based on a retrospective analysis of 45 patients (median age, 12 years) who were treated with CD19 CAR‐T cells and received tocilizumab for CRS; the response rate was 69%.117, The ideal timing of tocilizumab, including the benefit of early use in patients at high risk and the effect of steroids and tocilizumab on the durability of remission, are subjects of ongoing study. Furthermore, fatal toxic events most often occurred early after treatment initiation, with a median time to onset of 14.5 days with combination therapy versus 40 days with either anti–PD‐1 or anti–CTLA‐4 monotherapy. Furthermore, patients who developed hypophysitis and were treated with either high‐dose or low‐dose glucocorticoids had improved overall survival compared with patients who received ipilimumab but did not develop hypophysitis.74 Future studies will be needed to clarify the effect of high doses of glucocorticoids on clinical outcomes in hypophysitis. Further studies are needed to develop risk stratification models and to characterize the pathophysiology leading to toxicity, which will improve current preventive and treatment approaches. Translational research suggests that irAEs may develop through a combination of pathways involving autoreactive T cells, autoantibodies, and cytokines.15 For example, T‐cell infiltration of both normal and tumor tissue has been observed.15 T‐cell activation leads to the production of inflammatory cytokines, which can contribute to the development of irAEs. For example, high‐dose interleukin 2 (IL‐2) and interferon (IFN) α‐2b lead to multiple downstream effects4 and have been used to treat advanced melanoma and renal cell carcinoma (RCC).5 Therapeutic approaches to manipulate multiple aspects of the immune system have subsequently been investigated, including immune checkpoint inhibitors (ICIs), adoptive cell therapy, oncolytic viruses, and cancer vaccines. Current clinical use of CAR‐T cells targets CD19, the pan–B‐cell antigen, in the treatment of hematologic malignancies. A team of researchers has found disrupting the interaction between cancer cells and certain immune cells is more effective at killing cancer cells than current immunotherapy treatments. CII is keen to publish broad-ranging ideas and reviews, results which extend or challenge established paradigms, as … Ganoderma is a significant source of natural fungal medicines and has been used for the treatment of various diseases for many years. Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, with an estimated 135 430 new cases and 50 260 cancer-related deaths annually (1). If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. The past few years have seen unprecedented clinical responses, rapid drug development, and first-in-kind approvals from the U.S. Food and Drug Administration. Larger studies are needed to determine risk factors for pneumonitis, including the relationship between smoking history and the risk and role of the PD‐1/PD‐L1 pathway in development of pneumonitis. Natalizumab, an α4‐integrin antibody approved for the treatment of multiple sclerosis, has been used to treat a patient who developed autoimmune encephalitis with anti‐Hu antibodies after treatment with ipilimumab‐nivolumab.88, Renal irAEs are rare, with an estimated incidence of 2% with ICI monotherapy and 5% with combination therapy in a review of published phase 2 and 3 trials that included data on renal outcomes.89 More recent studies have suggested that the incidence of acute kidney injury in patients treated with ICI is higher than that initially reported90; this increased incidence could reflect either checkpoint inhibitor toxicity or other more common causes of acute kidney injury, such dehydration and other nephrotoxic medications. Advances in immunotherapy for colorectal cancer: a review. Cancer Treatment Reviews (Incorporating Evidence-based Oncology) is an international review journal that will keep both the clinician and researcher abreast of modern concepts and developments in cancer treatment research through the publication of state of the art, authoritative reviews; evidence-based reviews (using a priori defined selection process to identify key articles from … Published on 16 March 2021 Potential of Mushroom Compounds as Immunomodulators in Cancer Immunotherapy: A Review. Patients with symptoms of thyrotoxicosis, including tachycardia and tremor, can receive symptom‐directed management with β blockers. Unlike cancer prevention vaccines, cancer treatment vaccines are designed to be used in people who already have cancer—they work against cancer cells, not against something that causes cancer. Eight patients discontinued treatment, and there were no treatment‐related deaths. Immunotherapy. 1 Department of Biological Sciences, Faculty of Science, Egerton University, P.O. However, the use of Ganoderma in cancer immunotherapy is poorly elucidated. Received 25 Oct 2017. Infectious workup: stool culture and ova and parasite, In refractory cases or cases with a contraindication to infliximab, vedolizumab can be used; earlier initiation of biologic therapy may lead to improved outcomes, Consider GI consultation for EGD/colonoscopy with biopsy, CMP at baseline and every 2‐3 wk during ICI, Grade 1: continue ICI with increased frequency of LFT monitoring, Grade 2: hold ICI until recovery to grade ≤1; start systemic steroids if no improvement, ANA, antismooth‐muscle antibodies, and ANCA if autoimmune hepatitis suspected, Grade 3‐4: hold ICI; hepatology consult; start 1‐2 mg/kg/d steroids, CT abdomen/pelvis to evaluate for liver metastases, For steroid‐refractory cases, consider mycophenolate mofetil; infliximab is contraindicated because of concerns about hepatotoxicity, Review medication list for other causes of drug‐induced hepatitis, TSH, free T4 at baseline and every 4‐6 wk on ICI, Asymptomatic hypothyroidism: thyroid hormone replacement if TSH >10 mIU/L, AM cortisol to evaluate for concurrent adrenal insufficiency, Symptomatic hypothyroidism: thyroid hormone replacement, TSH receptor antibodies if Graves disease is suspected, Hyperthyroidism: if symptomatic, consider endocrine consultation and propranolol for symptom control, Physiologic hormone replacement, including levothyroxine and steroid replacement, is typically required for life, Consider baseline ACTH/cortisol in high‐risk patients, Dysfunction of thyroid, adrenal, or gonadal axis, Start steroids before thyroid hormone replacement to avoid adrenal crisis, Endocrinology consult in cases of confirmed hypophysitis, Consider evaluation for other causes of fever, hypotension, and respiratory failure, including infection and progression of malignancy, Grade 2: fever with hypotension not requiring vasopressors or hypoxia requiring up to 6 L/min nasal cannula, CMP, including magnesium and phosphorous, coagulation profile, Grade 3: fever with hypotension requiring one vasopressor or hypoxia requiring high‐flow nasal cannula, facemask, nonrebreather, or venturi mask, CRP and ferritin at baseline and 3 times per wk for 2 wk, Grade 4: fever with hypotension requiring more than one vasopressor, not including vasopressin, and/or hypoxia requiring positive pressure ventilation, Twice‐daily assessment for CRS during the period of highest risk. A meta‐analysis including 38 randomized clinical trials compared the incidence of endocrinopathies resulting from different regimens and found that the incidence of hypophysitis was highest in patients who received ipilimumab and that the incidence of thyroid dysfunction was more common with anti–PD‐1 monotherapy than with anti–CTLA‐4 monotherapy.58 Other endocrinopathies, including primary adrenal insufficiency and insulin‐dependent diabetes mellitus, are rare and were reported in 0.7% and 0.2% of patients, respectively.58 A similar meta‐analysis including 101 clinical trials of patients with multiple solid tumor types reported a pooled 5.6% incidence of hypophysitis in patients treated with ipilimumab.59 The incidence of hypophysitis with tremelimumab, the other CTLA‐4 therapy investigated, was lower (1.8%). Nature. 10 Altmetric. Patients who require hospitalization for neurologic irAEs should be managed in close collaboration with neurology. CRS may be self‐limited and can resolve with supportive care or may become life‐threatening, with capillary leak leading to peripheral and pulmonary edema, hypotension, multiorgan failure, and circulatory collapse.8, 109 The onset of CRS is variable and occurs 1 to 14 days after infusion, with timing dependent on the CAR‐T product and patient population.109 Some patients with severe CRS develop a presentation similar to hemophagocytic lymphohistiocytosis or macrophage‐activation syndrome, characterized by hepatosplenomegaly, hepatic dysfunction, hyperferritinemia, hypofibrinogenemia, and coagulopathy.111 Symptoms of CRS are manifestations of a profound immune response, which could have multiple causes; therefore, patients who have received CAR‐T and develop symptoms consistent with CRS should be evaluated for other causes of fever, hypotension, and respiratory failure, including overwhelming infection and progression of malignancy.111. Another series included 119 patients with melanoma and either preexisting autoimmune disease or a prior significant irAE with ipilimumab who were treated with anti–PD‐1 therapy.102 Among 52 patients with preexisting autoimmune disease, 20 developed a flare requiring immunosuppression. An analysis using a pharmacovigilance database reported an overall incidence of 0.93% of serious neurologic irAEs in patients who had melanoma who were treated with nivolumab with or without ipilimumab.81 The median time to onset was 45 days, and the time to resolution was 32 days. The goal of this Review Series is to concisely review some of the recent developments in cancer immunology and immunotherapy and to detail how new insights into the mechanisms that underlie cancer immune evasion might lead to pathways for identifying novel and efficacious treatments. This past year saw immunotherapy advances in a number of cancer types, expanding its benefits to more patients, both young and old. Melanoma was the tumor most commonly reported (35%) … IrAEs can be variable in their onset, kinetics, and presentation and often require specific management. The differential diagnosis for patients who develop neurologic symptoms on ICI therapy is broad and includes irAE, infection, central nervous system (CNS) metastasis or leptomeningeal spread, paraneoplastic syndromes, vitamin B12 deficiency, and diabetic neuropathy. As neurotoxicity progresses, patients may develop subclinical or clinical seizures and, rarely, diffuse cerebral edema.111 Fatal cerebral edema has been reported.122 Onset has been described from 1 day to 3 or 4 weeks after CAR‐T infusion.8, 115 A single‐center study of CAR‐T neurotoxicity in patients who received CD19 CAR‐T for B‐ALL, non‐Hodgkin lymphoma, or chronic lymphocytic leukemia reported grade ≥1 toxicity in 40% of patients, with a median time to onset of 4 days after CAR‐T infusion and a median duration of reversible neurotoxicity of 5 days.123 Delayed‐onset neurotoxicity occurring 3 to 4 weeks after CAR‐T therapy has been described in up to 10% of patients.8. Adjuvant immunotherapy treatment was associated with a significant survival benefit for patients with stage II melanoma in a study presented at the Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care.