During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

Summary Objectives Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID‐19) associated invasive aspergillosis at a single centre in Cologne, Germany. Methods A retrospective chart review of all patients with COVID‐19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. Results COVID‐19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. Conclusion Clinicians caring for patients with ARDS due to COVID‐19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co‐infection.

Highlights d Low avidity and broad cross-reactivities of pre-existing SARS-CoV-2 memory T cells d Strong CCCoV-specific memory CD4 + T cell responses in all analyzed individuals d SARS-CoV-2-specific CD4 + T cells in COVID-19 patients lack cross-reactivity to CCCoVs d Low avidity and clonality of SARS-CoV-2-specific T cell responses in severe COVID-19

Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4 ؉ CD25 hi regulatory T cells (T reg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia ( IntroductionHuman and murine CD4 ϩ CD25 ϩ T cells contain cells that suppress antigen-specific T-cell immune responses. [1][2][3][4][5] These naturally occurring regulatory CD4 ϩ CD25 ϩ T cells originate from the thymus and play a central role in the maintenance of peripheral tolerance by suppression of autoreactive T-cell populations. In murine models, regulatory T cells (T reg cells) prevent autoimmune and inflammatory diseases 1,6,7 and inhibit antitumor immune responses. [8][9][10][11][12] Although a truly unique marker for T reg cells is still not available, several molecules have been associated with these cells including cytotoxic T lymphocyte-associated protein 4 (CTLA4), [13][14][15][16] glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR, TNFRSF18), 17,18 Forkhead box P3 (FOXP3), [19][20][21] Lselectin (CD62L, SELL), 22,23 and OX40 antigen (CD134, TNFRSF4). 23,24 In humans, T reg cells are enriched within the CD4 ϩ CD25 hi population, whereas CD4 ϩ CD25 lo T cells represent mainly previously activated T helper cells. 25 These CD4 ϩ CD25 hi T reg cells inhibit proliferation and cytokine release by conventional CD4 ϩ CD25 Ϫ T cells. 26 Decrease of these cells was found in patients with autoimmune diseases, 27-31 whereas an increase of T reg cells in patients after allogeneic bone marrow transplantation was associated with a reduced graft-versus-host disease. [32][33][34][35] In patients with malignant melanoma, 36 Hodgkin lymphoma, 37 or ovarian, 38,39 gastric, 40,41 lung, 39,42 breast, 43,44 and pancreatic cancer 43 inhibitory CD4 ϩ CD25 ϩ T cells are also increased. In an elegant study, Curiel et al 38 demonstrated that functional T reg cells were enriched in ascites from women with ovarian cancer, migrated toward CCL22 expressed by tumor cells and tumor-associated macrophages, and specifically inhibited antitumor immunity. Moreover, within this setting, the increase of T reg cells predicted poor survival. 38 Only recently, studies assessing a potential influence of chemotherapy on T reg cells have been initiated. In mice, low-dose cyclophosphamide decreased the number of T reg cells. 45 Based on these observations we were interested in understanding whether CD4 ϩ CD25 hi T cells are also increased and possess inhibitory capacities in B-cell chronic lymphocytic leukemia (CLL) and, if so, to assess the frequency and function in the context of stage of disease and prior therapy. CLL, the most common type of leukemia in the Western hemisphere, 46 is characterized by clonal proliferat...

IntroductionThe lack of clinically sufficient antitumor immune responses has been attributed to soluble inhibitory factors such as TGF␤1 1,2 or PGE 2 3-5 as well as the induction and expansion of regulatory cells. 6,7 CD4 ϩ CD25 high regulatory T cells (T reg cells) were shown to be expanded in murine tumor models. 8 Moreover, their deletion reinstated an efficient antitumor immune response leading to complete tumor regression. [9][10][11] We and others have demonstrated that CD4 ϩ CD25 high FoxP3 ϩ T reg cells are also expanded in patients with solid tumors, [12][13][14][15][16][17][18][19] Hodgkin lymphoma, 20,21 or B-cell chronic lymphocytic leukemia (CLL). 22 Both in humans and in animal models, T reg cells have been described as anergic cells exerting strong suppression after T-cell receptor (TCR) stimulation. [23][24][25] As demonstrated in murine models, natural T reg cells usually originate from the thymus, 26,27 although cells with similar characteristics can also be generated in the periphery under appropriate conditions. 28 More recently, the diversity and developmental stage of thymic emigrants with a T reg -cell phenotype as well as CD4 ϩ CD25 ϩ T reg cells within peripheral blood were examined. 29,30 In healthy individuals, the levels of T-cell receptor excision circles (TRECs) were comparable in both conventional CD4 ϩ CD25 Ϫ and regulatory CD4 ϩ CD25 ϩ thymic populations. However, the number of TRECs was significantly higher in thymic emigrants than in peripheral blood-derived T cells, which strongly suggests thymic development of human CD4 ϩ CD25 high T reg cells. 30 Nevertheless, conventional CD4 ϩ CD25 Ϫ T cells from peripheral blood of healthy donors contained higher TREC numbers than their CD4 ϩ CD25 ϩ counterparts, which is in line with the possibility of extrathymic expansion particularly within the T reg -cell subset. 29 Until recently, CD4 ϩ CD25 high T reg cells have been described to belong to the memory T-cell compartment. 24,[31][32][33] Valmori et al, 34 however, identified a T reg -cell population with a naive phenotype (CCR7 ϩ CD45RA ϩ ), which they termed natural naive T reg cells (NnTregs). As expected, the frequency of these NnTregs was relatively low in healthy individuals. NnTregs were shown to vigorously proliferate in response to contact with autologous antigen-presenting cells, suggesting that particularly this subpopulation is enriched in T cells bearing self-reactive T-cell receptors. 34 Most recently, Seddiki et al 35 described the persistence of a population of naive CD45RA ϩ T reg cells in adult life.Little is known about the differentiation, origin, and mechanisms of expansion of T reg cells in cancer patients. We and others have observed that increase of T reg -cell frequency correlates with disease state, 13,22 which might be explained by an antigendependent mechanism of peripheral expansion in response to tumor progression. However, it is unknown if these T reg cells are also more differentiated toward a central or even effector memory phenotype. M.B. designed res...

Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.

Objectives Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. The objectives of this multinational study were to determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as outcome. Methods The European Confederation of Medical Mycology (ECMM) conducted a multinational study including 20 centers from nine different countries to assess epidemiology, risk factors, and outcome of CAPA. CAPA was defined according to the 2020 ECMM/ISHAM consensus definitions. Results A total of 592 patients were included in this study, including 11 (1.9%) patients with histologically proven CAPA, 80 (13.5%) patients with probable CAPA, 18 (3%) with possible CAPA and 483 (81.6%) without CAPA. CAPA was diagnosed a median of 8 days (range 0-31) after ICU admission predominantly in older patients [adjusted hazard ratio (aHR) 1.04 per year; 95%CI 1.02-1.06] with any form of invasive respiratory support (HR 3.4; 95%CI 1.84-6.25) and receiving tocilizumab (HR 2.45; 95%CI 1.41-4.25). Median prevalence of CAPA per center was 10.7% (range 1.7%-26.8%). CAPA was associated with significantly lower 90-day ICU survival rate (29% in patients with CAPA versus 57% in patients without CAPA; Mantel-Byar p<0.001 ) and remained an independent negative prognostic variable after adjusting for other predictors of survival (HR=2.14; 95%CI: 1.59-2.87, p<=0.001 ). Conclusion Prevalence of CAPA varied between centers. CAPA was significantly more prevalent among older patients, patients receiving invasive ventilation and patients receiving tocilizumab, and was an independent strong predictor of ICU mortality.

Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov , NCT04327388 ; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 1...