Toxicidad sistémica y pulmonar por inmunoterapia: revisión narrativa a propósito de un caso / Systemic and pulmonary toxicity from immunotherapy: A narrative review and a clinical case report

En el último tiempo, la inmunoterapia se ha convertido en una opción terapéutica para diversos tipos de neoplasias, aumentando la sobrevida en muchos casos, pero también los efectos adversos asociados. Existen tres tipos de inmunoterapia utilizados en cáncer: Terapia de células T con receptor de antígeno quimérico (CAR-T), destacando como reacciones adversas el síndrome liberador de citoquinas (CRS) y el síndrome de neurotoxicidad (ICANS); Anticuerpos monoclonales (AcM), cuyos efectos adversos más comunes están relacionados con reacciones de hipersensibilidad; y los Inhibidores de puntos de control inmunitario (ICI) con toxicidad pulmonar claramente reportada. Para un correcto manejo de estas reacciones adversas se requiere un alto índice de sospecha, un adecuado diagnóstico diferencial y un tratamiento oportuno, basado principalmente en corticoides y guiado por criterios de gravedad. Se presenta el caso de un paciente con reacción granulomatosa sarcoidea posterior al uso de Nivolumab.

In recent times, immunotherapy has emerged as a therapeutic option for various neoplasms, significantly improving survival rates in many cases, albeit with associated adverse effects. There are three types of immunotherapy commonly used in cancer treatment: Chimeric Antigen Receptor T-cell Therapy (CAR-T), notable for adverse reactions such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS); Monoclonal Antibodies (mAbs), with the most common adverse effects being hypersensitivity reactions; and Immune Checkpoint Inhibitors (ICI), with well-documented pulmonary toxicity. Adequate management of these adverse reactions requires a high index of suspicion, accurate differential diagnosis, and timely treatment, primarily based on corticosteroids and guided by severity criteria. We present a case of a patient with granulomatous sarcoid-like reaction following the use of Nivolumab.

Clinical analysis of combined immunotherapy in patients with malignant pleural mesothelioma / 中华肿瘤杂志

Objective: To observe the present situation, efficacy and safety of immunotherapy in patients with malignant pleural mesothelioma (MPM). Methods: The data of 39 patients with MPM in two centers from 2016 to 2021 were collected and the efficacy and safety were evaluated. According to the application of immune checkpoint inhibitors (ICIs), these patients, whose median clinical follow-up amounting to 18.97 months, were divided into immunotherapy group (19 cases) and control group (20 cases). Kaplan-Meier method and Log-rank test were used for the survival analysis. Results: The objective response rate (ORR) and the disease control rate (DCR) in the immunotherapy group is 21.05% and 79.0% respectively, compared with 10.0% and 55.0% in the control group; and the difference was not statistically significant (P>0.05). The median overall survival (OS) in the immunotherapy group was significantly longer than that in the control group (14.53 months vs 7.07 months, P=0.015), but there was no significant difference in the median progression free survival (PFS) between two groups (4.80 months vs 2.03 months, P=0.062). Single factor survival analysis showed that the nature of pleural effusion, pathological subtype and the efficacy of immunotherapy were related to both PFS and OS of the patients with MPM (P<0.05). The incidence of adverse reactions in immunotherapy group was 89.5% (17 out of 19 cases), and the most common adverse event was hematological toxicity (9 cases), followed by nausea and vomiting (7 cases), fatigue (6 cases) and skin damage (6 cases). Five patients had immune checkpoint inhibitors (ICIs) related adverse reactions with grade 1-2. Conclusions: Patients with MPM have begun to receive immunotherapy in more than 2-line mainly combined chemotherapy in the real world, and the median treatment line is 2-line. Either combined with chemotherapy or anti-angiogenesis therapy, ICI inhibitors have significant efficacy, controllable adverse events and good clinical value.

Clinical analysis of immunotherapy rechallenge in advanced gastric cancer / 中华肿瘤杂志

Objective: To evaluate the efficacy and influencing factors of programmed death protein 1 (PD-1) monoclonal antibody rechallenge therapy in advanced gastric cancer (GC). Methods: The clinical data of patients with advanced GC who were treated with anti-PD-1 rechallenge in Henan Cancer Hospital from January 2020 to December 2021 were collected retrospectively. The progression-free survival (PFS) was defined as the time from the first or second used of anti-PD-1 treatment to the date of disease progression or the last follow-up, named PFS(1) and PFS(2), respectively. Kaplan-Meier method and Log rank test were used for survival analysis, Cox proportional hazard model was used to analyze the influencing factors. Results: A total of 60 patients with anti-PD-1 rechallenge therapy were collected, the median follow-up time was 12.2 months. The median progression-free survival (PFS(2)) of anti-PD-1 rechallenge therapy was 2.9 months, the objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.0%. The median PFS(2) of the first and second anti-PD-1 identical and different rechallenge treatment was 3.5 months and 1.9 months (P=0.007) respectively. The median PFS(2) of positive PD-L1 expression in rechallenge therapy was 3.4 months, ORR was 22.7%, and DCR was 63.6%; the median PFS(2) was 4.5 months, ORR was 27.3%, and DCR was 54.5% in patients with median PFS(1)≥6 months. Multivariate analysis showed that peritoneal metastasis was independently associated with anti-PD-1 rechallenge therapy with PFS(2) (HR=2.327, 95% CI, 1.066-5.082, P=0.034). The incidence of adverse reactions in grade 1-2 and grade 3-4 of anti-PD-1 rechallenge therapy was 83.3%, and 35.0%, respectively, and the safety was controllable. Conclusion: Rechallenge therapy with anti-PD-1 is a feasible treatment in advanced GC, but the screening of suitable population for rechallenge therapy still needs prospective data analysis and verification.

Correlation Analysis between Thyroid Function Abnormality and Efficacy in Patients with Advanced Non-small Cell Lung Cancer after Immunotherapy / 中国肺癌杂志

BACKGROUND@#Thyroid function abnormality (TFA) is one of the common adverse reactions in patients with advanced non-small cell lung cancer (NSCLC) treated with immunotherapy, but the risk factors of TFA and its relationship with efficacy are not completely clear. The purpose of this study was to explore the risk factors of TFA and its relationship with efficacy in patients with advanced NSCLC after immunotherapy.@*METHODS@#The general clinical data of 200 patients with advanced NSCLC in The First Affiliated Hospital of Zhengzhou University from July 1, 2019 to June 31, 2021 were collected and analyzed retrospectively. χ² test and multivariate Logistic regression were used to explore the risk factors of TFA. Kaplan-Meier curve was drawn and Log-rank test was used for comparison between groups. Univariate and multivariate Cox analysis was used to explore the efficacy factors.@*RESULTS@#A total of 86 (43.0%) patients developed TFA. Logistic regression analysis showed that Eastern Cooperative Oncology Group Performance Status (ECOG PS), pleural effusion and lactic dehydrogenase (LDH) were factors influencing TFA (P<0.05). Compared with normal thyroid function group, the median progression-free survival (PFS) of patients in the TFA group was significantly longer (19.0 months vs 6.3 months, P<0.001), and the objective response rate (ORR) (65.1% vs 28.9%, P=0.020) and disease control rate (DCR) (100.0% vs 92.1%, P=0.020) of the TFA group were better than those of the normal thyroid function group. Cox regression analysis showed that ECOG PS, LDH, cytokeratin 19 fragment (CYFRA21-1) and TFA were factors influencing prognosis (P<0.05).@*CONCLUSIONS@#ECOG PS, pleural effusion and LDH may be risk factors affecting the occurrence of TFA and TFA may be a predictor of the efficacy of immunotherapy. Patients with advanced NSCLC who have TFA after immunotherapy may obtain better efficacy.

Efficacy and safety evaluation of immunotherapy combined with targeted therapy as second-line treatment in patients with metastatic non-clear cell renal cell carcinoma / 中华肿瘤杂志

Objective: This study aimed to evaluate the efficacy and safety of programmed death-1 (PD-1) inhibitor combined tyrosine kinase inhibitor (TKI) therapy versus TKI monotherapy as the second-line regimen for patients with metastatic non-clear cell renal carcinoma (nccRCC) who failed first-line TKI therapy. Methods: The clinicopathological data of 67 patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020 were retrospectively analyzed, including 22 patients who received TKI monotherapy and 45 patients who received TKI plus PD-1 inhibitor as the second-line therapy. The efficacy was assessed according to Response Evaluation Criteria in Solid Tumors version 1.0/1.1 (RECIST 1.0/1.1), the Kaplan-Meier method was used to plot the survival curves, and the Log rank test was used to analyze the differences in the survival between the two groups. Treatment-related adverse events (AEs) after treatment were observed in both groups. Results: The overall objective response rate (ORR) and disease control rate (DCR) were 37.3% (25/67) and 56.7% (38/67), respectively. The overall second-line progression-free survival (PFS) was 7.7 months and Overall Survival (OS) was 25.2 months. The ORR and DCR of patients in the combination therapy group were 48.9% (22/45) and 71.1% (32/45), respectively, which were significantly improved compared with the TKI monotherapy group [13.6% (3/22) and 27.3% (6/22), respectively] (P=0.007 and P=0.001, respectively). The median PFS of 9.2 months for second-line treatment was longer in patients in the combination therapy group than in the TKI monotherapy group (5.2 months, P=0.001), but the median OS was not statistically different between the two groups (28.2 months vs 20.8 months, P=0.068). Common treatment-related AEs included hypertension, diarrhea, fatigue, stomatitis, hand-foot syndrome, and hypothyroidism. The incidence of hypothyroidism was higher in the combination therapy group [40.0% (18/45)] than in the TKI monotherapy group [22.7% (5/22), P=0.044]; the incidence of other treatment-related AEs between the two groups were not statistically significant (all P>0.05). Conclusion: Immune-targeted combination therapy was more effective than TKI monotherapy alone and was well tolerated in the treatment of metastatic nccRCC patients who failed first-line TKIs.

Efficacy and safety evaluation of immunotherapy combined with targeted therapy as second-line treatment in patients with metastatic non-clear cell renal cell carcinoma / 中华肿瘤杂志

Objective: This study aimed to evaluate the efficacy and safety of programmed death-1 (PD-1) inhibitor combined tyrosine kinase inhibitor (TKI) therapy versus TKI monotherapy as the second-line regimen for patients with metastatic non-clear cell renal carcinoma (nccRCC) who failed first-line TKI therapy. Methods: The clinicopathological data of 67 patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020 were retrospectively analyzed, including 22 patients who received TKI monotherapy and 45 patients who received TKI plus PD-1 inhibitor as the second-line therapy. The efficacy was assessed according to Response Evaluation Criteria in Solid Tumors version 1.0/1.1 (RECIST 1.0/1.1), the Kaplan-Meier method was used to plot the survival curves, and the Log rank test was used to analyze the differences in the survival between the two groups. Treatment-related adverse events (AEs) after treatment were observed in both groups. Results: The overall objective response rate (ORR) and disease control rate (DCR) were 37.3% (25/67) and 56.7% (38/67), respectively. The overall second-line progression-free survival (PFS) was 7.7 months and Overall Survival (OS) was 25.2 months. The ORR and DCR of patients in the combination therapy group were 48.9% (22/45) and 71.1% (32/45), respectively, which were significantly improved compared with the TKI monotherapy group [13.6% (3/22) and 27.3% (6/22), respectively] (P=0.007 and P=0.001, respectively). The median PFS of 9.2 months for second-line treatment was longer in patients in the combination therapy group than in the TKI monotherapy group (5.2 months, P=0.001), but the median OS was not statistically different between the two groups (28.2 months vs 20.8 months, P=0.068). Common treatment-related AEs included hypertension, diarrhea, fatigue, stomatitis, hand-foot syndrome, and hypothyroidism. The incidence of hypothyroidism was higher in the combination therapy group [40.0% (18/45)] than in the TKI monotherapy group [22.7% (5/22), P=0.044]; the incidence of other treatment-related AEs between the two groups were not statistically significant (all P>0.05). Conclusion: Immune-targeted combination therapy was more effective than TKI monotherapy alone and was well tolerated in the treatment of metastatic nccRCC patients who failed first-line TKIs.

Advances in Predictive Research of Immune Checkpoint Inhibitors-related Adverse Events / 中国肺癌杂志

The era of tumor treatment has been revolutionized by the advent of immune checkpoint inhibitors. However, while immunotherapy benefits patients, it can also lead to immune-related adverse events that may affect multiple organs and systems throughout the body, potentially even posing a life-threatening risk. The diverse clinical manifestations and onset times of these adverse events further complicate their prediction and diagnosis. The purpose of this paper is to review the clinical characteristics and predicted biomarkers of adverse events related to inhibitors at immune checkpoints, in order to help clinicians evaluate drug risks and early warn adverse events.
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Cetoacidosis diabética como debut de diabetes mellitus inmunomediada en paciente en tratamiento con inhibidores de checkpoint / Diabetic ketoacidosis as debut of immune-mediated diabetes mellitus in a patient in treatment with immune checkpoint inhibitors

Los inhibidores de checkpoint (ICP) son anticuerpos usados en inmunoterapia contra el cáncer. Uno de sus blancos de acción es el receptor de muerte celular programada-1 (PD-1), el cual es importante para mantener la tolerancia inmunitaria. Sin embargo, este mecanismo se asocia a riesgo de eventos adversos relacionados a la inmunidad que pueden afectar a múltiples órganos incluyendo el sistema endocrino. Se describe el caso inhabitual de un paciente que a los 18 meses de terapia con ICP debutó con cetoacidosis diabética (CAD).

Immune checkpoint inhibitors consist in antibodies used in immunotherapy against cancer. One of their targets is the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, this mechanism is associated with a risk for immune-related adverse events potentially affecting multiple organs, including the endocrine system. We describe the unusual case of a patient who, after 18 months of treatment with an immune checkpoint inhibitor, debuted with diabetic ketoacidosis

Two Case Reports of Type 2 Diabetes Induced by Immune Checkpoint Inhibitors Combined with Chemotherapy / 中国肺癌杂志

Immune checkpoint inhibitors (ICIs) have become an important means of cancer treatment, and their application in the clinic is becoming more and more widespread. The adverse reactions caused by ICIs are gradually recognized. Among them, immunotherapy-related diabetes is a rare adverse reaction and type 1 diabetes mellitusis common. With the wide application of ICIs combined with chemotherapy in lung cancer patients, patients with type 2 diabetes mellitus have gradually been discovered during the treatment. However, the effect of continued use of ICIs maintenance therapy on blood glucose and ICIs treatment process in these patients is still unclear. This article reports two cases of type 2 diabetes mellitus induced by immune checkpoint inhibitor combined with chemotherapy, one of whom converted to type 1 diabetes mellitus, in order to increase the understanding of immunotherapy-related diabetes.
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Current research status on immune-related adverse events / 中华胃肠外科杂志

Immune checkpoint inhibitors have progressed rapidly over the past decade and have become one of the most promising oncology treatments. However, immune checkpoint inhibitors reduce T-cell tolerance and lead to a unique spectrum of immune-related adverse events (IRAE). IRAE can involve multiple systems, including endocrine, gastrointestinal, respiratory and skin systems and there is no predictive marker with high specificity and sensitivity. Mild IRAE can be alleviated by discontinuing immune checkpoint inhibitors while severe IRAEs require active intervention. The first-line treatment is glucocorticoids, and immunosuppressants can be considered in refractory cases. However the optimal choice of immunosuppressants is currently controversial. This review provides an overview of the epidemiology and possible mechanisms of immune-related adverse events, outlines some promising predictive biomarkers, and describes several immunotherapy-related organ toxicity and management.

Analysis of the Efficacy of Immunotherapy in Elderly Patients with Lung Cancer / 中国肺癌杂志

BACKGROUND@#Immunotherapy represented by immune checkpoint inhibitors (ICIs) has become the standard treatment for patients with non-oncogenic advanced non-small cell lung cancer (NSCLC). While lung cancer is most prevalent in elderly patients, these patients are rarely included in pivotal clinical trial studies. We aimed to describe the efficacy and safety of immunotherapy for elderly patients in the "real-world".@*METHODS@#The data of older NSCLC patients and younger patients who received immunotherapy between July 2018 to October 2021 were retrospectively analyzed and the objective response rate (ORR) and progression-free survival (PFS) in different age groups (less than 60 years old was defined as the young group, 60 years-74 years old was the young old group, 75 years old and above was the old old group) were compared. And the impact of different clinical characteristics on treatment response and prognosis were analyzed in each age subgroup.@*RESULTS@#A total of 21 young patients, 70 young old patients and 15 old old patients were included in this study, with ORR of 33.3%, 52.8% and 53.3%, respectively, without statistically significant difference (P=0.284). The median PFS was 9.1 mon, 7.6 mon and 10.9 mon, respectively, without statistically significant difference (P=0.654). Further analysis of the predictors of immunotherapy in each subgroup revealed that patients in the young old group and young group who received immunotherapy in the first line had a longer PFS. The difference of the incidence of adverse events was not statistically significant among the three groups (P>0.05).@*CONCLUSIONS@#The efficacy and safety of immunotherapy in elderly patients were similar to those in younger patients, and PFS was superior in the first-line immunotherapy. Further prospective studies are still needed to explore predictors of immunotherapy in elderly NSCLC patients.

Clinical Value of Autoantibody Prognostic Markers in Tumor Immune Checkpoint Inhibitor Therapy / 中国肺癌杂志

Serum autoantibody markers have the advantages of easy specimen acquisition, simple detection technology and dynamic real-time monitoring. With the wide application of immune checkpoint inhibitors in the treatment of malignant tumors, autoantibody markers in predicting tumor immune checkpoint inhibitors efficacy and forecasting irAEs (immune related adverse events) show good prediction of potential. This review mainly focused on the progress of autoantibody markers in the prediction of therapeutic effect and the monitoring of irAE in tumor immunotherapy.
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Advances on immune-related adverse events associated with immune checkpoint inhibitors / 医学前沿

Immunotherapy has recently led to a paradigm shift in cancer therapy, in which immune checkpoint inhibitors (ICIs) are the most successful agents approved for multiple advanced malignancies. However, given the nature of the non-specific activation of effector T cells, ICIs are remarkably associated with a substantial risk of immune-related adverse events (irAEs) in almost all organs or systems. Up to 90% of patients who received ICIs combination therapy experienced irAEs, of which majority were low-grade toxicity. Cytotoxic lymphocyte antigen-4 and programmed cell death protein-1/programmed cell death ligand 1 inhibitors usually display distinct features of irAEs. In this review, the mechanisms of action of ICIs and how they may cause irAEs are described. Some unsolved challenges, however really engrossing issues, such as the association between irAEs and cancer treatment response, tumor response to irAEs therapy, and ICIs in challenging populations, are comprehensively summarized.

CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies / 医学前沿

The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

Research Progress of Immune Checkpoint Inhibitor-associated Myocarditis / 中国肺癌杂志

Immune checkpoint inhibitors (ICIs) is a negative regulatory factor antibody, which activates T cells to play an anti-tumor effect in immunotherapy, and can also cause immune-related adverse responses, thereby inducing a series of immune related adverse events (irAEs). Among these irAEs, although the incidence of ICIs-related myocarditis is very low, the fatality rate is significantly higher than other adverse reactions, close to 50%. Clinicians should be vigilant when applying ICIs, but the pathogenesis of ICIs-related myocarditis is still unclear. This article combines the recent research results of ICIs to summarize the mechanism and clinical manifestations of ICIs-related myocarditis, so as to improve clinicians' understanding of the adverse reactions.
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Atezolizumab-induced encephalitis in a patient with metastatic breast cancer: a case report and review of neurological adverse events associated with checkpoint inhibitors

Immune-mediated encephalitis as an adverse event due to checkpoint inhibitors is very rare. We describe herein the case of a 38-year-old woman with metastatic triple-negative breast cancer who developed seizures and somnolence twelve days after receiving the first dose of Atezolizumab. Work up ruled out all infectious etiologies, and the patient was eventually diagnosed with immune-mediated meningoencephalitis. Symptoms recovered with a high-dose of steroids, and she was found to have an excellent response on follow-up imaging, which raised the question of whether a relationship exists between the occurrence, and severity of the adverse event and the response to treatment. Only a few other cases of atezolizumab-related encephalitis have been published. Early recognition and treatment are crucial; the reason why we are describing this case along with a review of the literature and a review on all the neurological immune-related adverse events due to the different checkpoint inhibitors.