La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018 / Immune checkpoint inhibitors: a breakthrough in cancer therapy

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.

Analysis of interactions of immune checkpoint inhibitors with antibiotics in cancer therapy / 医学前沿

The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.

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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Clinical Progress in the Immunotherapy of Small Cell Lung Cancer / 中国肺癌杂志

Small cell lung cancer is a kind of malignant tumor with strong invasiveness and poor prognosis, and the classic therapeutic modality of the disease remains multidisciplinary and comprehensive treatment. Treatment options for small cell lung cancer have been stalled for a long time, and new opportunities have emerged in recent years due to the development and initial experience of immunotherapeutic drugs. Clinical trials of some selected immune checkpoint inhibitors have confirmed the efficacy and safety in small cell lung cancer. Based on the results of phase III clinical trials (Impower133 and CASPIAN), Atezolizumab or Durvalumab in combination with chemotherapy has been approved by the U.S. Food and Drug Administration for the first-line treatment of extensive-stage small cell lung cancer. Clinical trials involving immune checkpoint inhibitors are being actively carried out and provide different perspectives for the management of small cell lung cancer. This article aimed to review the clinical progress in immunotherapy of small cell lung cancer.
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Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases / 北京大学学报(医学版)

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 μg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.

Immune checkpoint inhibitors in the treatment of colorectal cancer: a review of clinical trials / 中华胃肠外科杂志

Colorectal cancer is the third most common cancer in the world. The treatments include surgery, chemotherapy, radiotherapy and targeted therapy. The guidelines of many tumor types have been rewritten with the advent of immune checkpoint inhibitors. There are significant differences in the efficacy of immune checkpoint inhibitors in colorectal cancer according to microsatellite status. Microsatellite instability-high (MSI-H) colorectal cancer has made a breakthrough in immunotherapy, whether in the late-line, first-line, adjuvant or neoadjuvant therapy. The success of KEYNOTE-177 study has changed the guidelines with pembrolizumab becoming a standard treatment in the first-line treatment of MSI-H advanced colorectal cancer. The NICHE study, which used immunotherapy as neoadjuvant treatment of colorectal cancer, has made exciting achievements in MSI-H colorectal cancer. For microsatellite stability (MSS) colorectal cancer, many studies are ongoing, and immunotherapy is still unable to challenge the status of traditional treatment. In this paper, we review the clinical trials related to immune checkpoint inhibitors of colorectal cancer, expecting to provide references for the development of colorectal cancer immunotherapy.

Real-world study evaluating the incidence of liver damage conditions in patients with primary liver cancer using immune checkpoint inhibitor-based combination therapy / 中华肝脏病杂志

Objective: To evaluate the incidence of immune checkpoint inhibitor-based combination therapy-induced liver damage in patients with primary liver cancer. Methods: Clinical data of 65 hospitalized cases of primary liver cancer treated with programmed cell death-1 its ligand programmed death-ligand 1 (PD-1/PD-L1) antibody in the Department of Infectious Diseases of the Second Affiliated Hospital of Chongqing Medical University from January 1, 2018 to March 31, 2021 were retrospectively analyzed. The degree of liver injury before and after treatment was assessed according to CTCAE v5.0. Patients were grouped according to gender, age, presence or absence of cirrhosis, baseline Child-Pugh score, BCLC stage, and treatment regimen to compare the incidence of liver injury under different conditions. The χ (2) test or rank-sum test was used for comparison among multiple groups. Results: 46 cases (70.77%) had liver damage of any grade according to the CTCAE V5.0 criteria during the treatment and observation period. All 6 cases who received standardized anti-hepatitis B virus (HBV) treatment developed liver damage. 10 (15.38%), 15 (23.08%), 19 (29.23%), and 2 (3.08%) cases had grade 1, 2, 3, and 4 liver damage respectively. There was no statistically significant difference in the incidence of liver damage between male and female patients (68.33% and 100%, P = 0.180). There was no statistically significant difference in the incidence of liver damage among different age groups (P = 0.245). The incidence of liver damage in cirrhotic and non-cirrhotic group was 72.22%, and 63.64% (P = 0.370), respectively. The incidence of liver damage in patients with baseline Child-Pugh class A, B, and C were 71.43%, 61.11% and 100%, respectively, and the difference was not statistically significant (P = 0.878). The incidence of liver damage was not statistically significantly different under different BCLC stages (P = 1.000). The incidence of liver damage in the PD-1/PD-L1 antibody monotherapy, PD-1/PD-L1 antibody combined with targeted drug therapy, and PD-1/PD-L1 antibody combined with TACE/radiofrequency ablation treatment group were 60.00%, 67.85%, and 86.67%, respectively. There was no statistically significant difference in the incidence of liver damage between the treatment regimen (P = 0.480). Conclusion: Immune checkpoint inhibitor therapy-induced liver damage is common in patients with primary liver cancer; however, it rarely severely endangers the patient's life. Additionally, patient's gender, age, presence or absence of cirrhosis, baseline liver function, BCLC stage and the immunotherapy regimen has no effect on the incidence of immune-related liver damage.

Real-world study on the efficacy and prognostic predictive biomarker of patients with metastatic non-small cell lung cancer treated with programmed death-1/programmed death ligand 1 inhibitors / 中华肿瘤杂志

Objective: To describe the actual efficacy of programmed death-1 (PD-1)/ programmed-death ligand 1 (PD-L1) inhibitors in patients with metastatic non-small cell lung cancer (NSCLC) and explore potential prognostic predictive biomarkers. Methods: Patients with metastatic NSCLC who were treated with PD-1/PD-L1 inhibitors at Cancer Hospital, Chinese Academy of Medical Sciences from January 2016 to December 2019, either as monotherapy or in combination with other agents, were consecutively enrolled into this study. We retrospectively collected the data of demographics, clinical information and pathologic assessment to evaluate the therapeutic efficacy and conduct the survival analysis. Major endpoint of our study is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: The ORR of 174 patients who underwent PD-1/PD-L1 inhibitor was 28.7%, and the DCR was 79.3%. Immune-related adverse events (irAEs) occurred in 23 patients (13.2%). Brain metastasis, line of treatment, and treatment patterns were associated with the ORR of metastatic NSCLC patients who underwent immunotherapy (P<0.05). After a median follow-up duration of 18.8 months, the median PFS was 10.5 months (ranged from 1.5 to 40.8 months) while the median OS was not reached. The 2-year survival rate was estimated to be 63.0%. The pathologic type was related with the PFS of metastatic NSCLC patients who underwent immunotherapy (P=0.028). Sex, age, brain metastasis and autoimmune diseases were associated with OS (P<0.05). Analysis of the receptor characteristic curve (ROC) of neutrophil/lymphocyte ratio (NLR) predicting ORR of immunotherapy in metastatic NSCLC showed that the areas under the curve of NLR before immunotherapy (NLR(C0)), NLR after one cycle of immunotherapy (NLR(C1)) and ΔNLR were 0.600, 0.706 and 0.628, respectively. Multivariate logistic regression analysis showed that NLR(C1) was an independent factor of the ORR of metastatic NSCLC patients who underwent immunotherapy (OR=0.161, 95% CI: 0.062-0.422), and the efficacy of combination therapy was better than that of single agent (OR=0.395, 95% CI: 0.174-0.896). The immunotherapy efficacy in patients without brain metastasis was better than those with metastasis (OR=0.291, 95% CI: 0.095-0.887). Multivariate Cox regression analysis showed that NLR(C1) was an independent influencing factor of PFS of metastatic NSCLC patients after immunotherapy (HR=0.480, 95% CI: 0.303-0.759). Sex (HR=0.399, 95% CI: 0.161-0.991, P=0.048), age (HR=0.356, 95% CI: 0.170-0.745, P=0.006) were independent influencing factors of OS of metastatic NSCLC patients after immunotherapy. Conclusions: PD-1/PD-L1 inhibitors are proved to be efficacious and have tolerable toxicities for patients with metastatic NSCLC. Patients at advanced age could still benefit from immunotherapy. Brain metastasis is related to compromised response. Earlier application of immunotherapy in combination with other modalities enhances the efficacy without elevating risk of irAEs. NLR(C1) is an early predictor of clinical outcome. The OS of patients younger than 75 years may be improved when treated with immunotherapy.

Multi-target combinatory strategy to overcome tumor immune escape / 医学前沿

Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multiimmune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.

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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Biomarkers for Neoadjuvant Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer / 中国肺癌杂志

Surgery is the standard treatment for resectable non-small cell lung cancer (NSCLC). Neoadjuvant and adjuvant therapy have been widely used for preventing recurrence and metastasis. Immune checkpoint inhibitors (ICIs) have brought long-term survival benefits in advanced NSCLC and showed higher downstage rates and pathological remission in the neoadjuvant setting. Predictive biomarkers are of great significance to identify the beneficiaries of neoadjuvant ICIs. At present, the biomarkers are still inconclusive. We summarized the clinical trials of neoadjuvant immune checkpoint inhibitors that have been disclosed so far, and reviewed the progress of the biomarkers associated with those trials.
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Research Progress, Benefit Groups, Treatment Cycle and Efficacy Prediction of Neoadjuvant Immunotherapy for Non-small Cell Lung Cancer / 中国肺癌杂志

The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the therapeutic outlook for patients with non-small cell lung cancer (NSCLC). Preoperative neoadjuvant immunotherapy has been paid more and more attention as an effective and safe treatment. Neoadjuvant immune therapy, however, the relevant research started late, relatively few research results and mainly focused on the small sample size of phase I and II studies, treatment itself exists many places it is not clear, also in benefit population screening, the respect such as the choice of treatment and curative effect prediction has not yet reached broad consensus. This paper reviews the important studies and recent achievements related to neoadjuvant immunotherapy, aiming to comprehensively discuss the procedures and existing problems of this kind of therapy from three aspects of beneficiary groups, treatment cycle and efficacy prediction.
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Immune Checkpoint Inhibitors Related Diabetes Mellitus: A Report of 2 Cases and Literature Review / 中国肺癌杂志

Immune checkpoint inhibitors (ICIs) are widely used in clinic, and the incidence of rare adverse events are increasing. The aim of this paper is to better define the rare adverse effect of diabetes mellitus associated with ICIs. We report 2 cases of diabetes mellitus associated with ICIs. Literature review was conducted and we discussed the clinical presentation, potential mechanisms and suggestions for optimal management. Two patients were both elderly women, case 1 had increased blood glucose after 7 months of using Durvalumab, and cases 2 had diabetic ketoacidosis after 6 weeks of using Pembrolizumab. Both patients were administered exogenous insulin to control blood glucose. Case 1 has been treated with Durvalumab until now and case 2 discontinued using of Pembrolizumab. HLA genotypes and other factors may explain the risk factors of diabetes associated with ICIs in some individuals. Diabetes mellitus associated with ICIs is an uncommon but potentially life-threatening endocrine system adverse event, which requires doctors to be vigilant. The patients who use ICIs need to monitor blood glucose. If they have hyperglycemia, endocrinologists should be asked to assist in diagnosis and treatment.
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Immunotherapy Based on Tumor Microenvironment in Renal Cell Carcinoma / 中国医学科学院学报

Renal cell carcinoma (RCC) is a common lethal urological cancer,the distant metastasis of which is the leading cause of death.Although targeted agents have remarkably improved the overall prognosis of RCC patients,nearly all the patients eventually acquire therapeutic resistance.With the advent of immune checkpoint inhibitors,immunotherapy based on tumor microenvironment (TME) has shown a broad scope in clinical application.The deepening understanding of TME leads to the changes of therapeutic strategies for advanced RCC,and the combination of targeted therapy and immunotherapy is exhibiting a promising prospect.Herein,we reviewed the TME characteristics,candidate predictive biomarkers,and possible targets for future development of drugs against RCC.

Preditores clínicos e laboratoriais da injúria renal aguda dos inibidores do checkpoint imune em neoplasias sólidas / Clinical and laboratory predictors of acute kidney injury from immune checkpoint inhibitors in solid neoplasms

INTRODUÇÃO: Injúria renal aguda é uma complicação importante e comum nos pacientes com câncer, sendo associada a altas taxas de morbidade e mortalidade. Novas classes de quimioterápicos, como os inibidores do checkpoint imune, estão associados a toxicidades imunomediadas, podendo causar nefrites, colites, tireoidites, dermatites e pneumonites. OBJETIVOS: Avaliar a incidência da injúria renal aguda nos pacientes com neoplasias sólidas em uso de inibidores do checkpoint imune, e identificar fatores clínicos, laboratoriais e epidemiológicos associados à injúria MÉTODOS: estudo clínico, observacional, do tipo coorte retrospectiva, em pacientes com neoplasias sólidas usando inibidores do checkpoint imune (nivolumabe, pembrolizumabe, ipilimumabe, durvalumabe, atezolizumabe e avelumabe), realizado no setor de quimioterapia do AC Camargo Cancer Center. Foram incluídos pacientes com eTFG > 60 ml/min e neoplasias sólidas. Injúria renal aguda foi definida pelo Kidney Disease Improve Global Outcomes: pacientes com alterações na creatinina a partir da linha de base (aumento da creatinina sérica de > 0,3mg/dL em 48h ou >1,5 vezes em 7 dias). Foram coletados dados demográficos tais como: sexo, idade, comorbidades (diabetes, hipertensão, doença pulmonar, hepatopatias, doenças cardiovasculares), tipo de neoplasia, presença de metástase, esquemas quimioterápicos prévios, cirurgias, tipo de inibidores do checkpoint imune; dados laboratoriais (creatinina, sódio, função tireoidiana (TSH), proteína C reativa, linfócitos, eosinófilos e amostras de urina (urina tipo 1), em momento anterior à exposição ao medicamento, no ciclo da reação adversa e no último ciclo. Um modelo de regressão de Fine e Gray foi realizado para avaliar o risco de injúria, tendo morte como evento competitivo. RESULTADOS: Um total de 614 foram incluídos, com idade média de 58,4  13,5 anos, sendo 59% do sexo masculino, com eTFG basal 101,4ml/min  33,2 ml/min, creatinina basal 0.8mg/dL (0,18). A injúria renal aguda ocorreu em 36,5% dos pacientes, sendo as etiologias mais frequentes: multifatorial (11,9%), provável imunomediada (9,6%) e infecção (6,8%). Ao fim do seguimento de 12 meses, os pacientes apresentaram creatinina final de 0,9 0,47 mg/dL. Em relação ao status final, 36,9% evoluíram para morte. Na regressão multivariada, o risco de injúria renal aguda geral foi maior naqueles com uso de antibióticos (sHR=2,46; IC 95%, 1,42 ­ 4,26, p<0,01), história de injúria prévia (sHR =2,2; IC 95%, 1,5-3,24, p<0,01) e estratégia Anti-PD1/PD L1 com quimioterapia (sHR=1,54; 1,07 ­ 2,21 IC, p<0,02). Já para lesão imunomediada, foi maior naqueles do sexo masculino (sHR= 2,44; IC 95%, 1,34 ­ 4,44, p < 0,01). A avaliação pelo nefrologista ocorreu em 14,7% dos casos. A mortalidade foi maior naqueles com injúria renal aguda geral (RR=2,04, IC 95%, 1,57 ­ 2,65, p < 0,01), mesmo após ajustado para outras características clínicas. CONCLUSÃO: Neste estudo, os pacientes que receberam os inibidores do checkpoint imune frequentemente desenvolveram injúria renal aguda devido a várias etiologias, sendo a principal etiologia multifatorial. O sexo masculino foi um preditor de risco de lesão renal associada a inibidor do checkpoint imune

INTRODUCTION: Acute kidney injury is a very important and usual complication in patients with cancer. It has been associated to high morbidity and mortality. New chemotherapeutic drugs such as immune checkpoint inhibitors are related to immuno-mediated toxicity and may cause nephritis, colitis, endocrinopathies, skin toxicity and pneumonitis. OBJECTIVES: To evaluate acute kidney injury incidence in patients with solid tumors who are taking immune checkpoint inhibitors and to correlate this data to serum, urinary biomarker and clinical and epidemiological factors of acute kidney injury. METHODS: Retrospective observational cohort designed to identify acute kidney injury's biomarkers in those with solid tumors who are taking immune checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab, durvalumab, atezolizumab and avelumab), at Chemotherapy department of AC Camargo Cancer Center. Patients with eGFR > 60 ml/min and solid neoplasms were included. Acute kidney injury was defined by Kidney Disease Improving Global Outcomes: criteria for changes in creatinine from baseline (increase in serum creatinine of > 0,3mg/dL in 48h or >1,5 times in 7 days). There were used demographic data such as gender, age, morbidities (diabetes mellitus, hypertension, lung, liver, and cardiovascular diseases, tumor characteristics, previous chemotherapeutic schemes, previous surgeries, immune checkpoint inhibitors taken and its dose. Laboratorial data collected were such as renal function (creatinine), electrolytes (sodium), thyroid function (TSH), urine samples (urinalysis), before drug exposure, in adverse events cycle and in last cycle. Statistical analysis was made on SPSS software, 25.0 version, and the results include average, mean, standard deviation and percentages for descriptive data. We assume statistically significant results when p value < 0.05. To assess the risk of injury competing with death, we conducted cumulative incidence curves and used the Fine and Gray model. RESULTS: We included 614 patients in the analysis. Average age was 58,4  13,5 years, with 59% male, and had baseline eGFR 101,4  33,2 ml / min, mean baseline creatinine 0.8  0,18mg / dL. Acute kidney injury occurred in 36,5% of patients, and the most frequent etiologies: multifactorial (11,9%), possible associated with immunotherapy (9,6%) and sepsis (6,8%). At the end of the 12-month follow-up or death, patients had a mean end creatinine of 0,9  0,47mg / dL, 59,7% were alive and 36,9% progressed to death from cancer. In multivariable Fine and Gray model, the risk of overall acute kidney injury was higher in those with antibiotics use (sHR =2,46; 1,42 ­ 4,26 CI, p < 0,02), previous injury history (sHR =2,2; 1,5-3,24 CI, p < 0,01), anti-PD1/PD L1 combined with chemotherapy (sHR =1,54; 1,07 ­ 2,21 95% CI, p < 0,02). Immune checkpoint inhibitor­acute kidney injury risk was higher in males (sHR =2,44; 1,34 ­ 4,44, 95% CI, p < 0,01). The evaluation by the nephrologist occurred in 14,7% of cases. Mortality was higher in those with acute kidney injury (RR =2,04, 1,57 ­ 2,65 95% CI, p < 0,01), even after adjusting other clinical features. CONCLUSIONS: In this study, patients receiving checkpoint inhibitors frequently developed acute kidney injury due various etiologies, with the main etiology being multifactorial. Male was a predictor of immune checkpoint inhibitor ­ associated acute kidney injury.

Endocrine dysfunction induced by immune checkpoint inhibitors / Disfunción endocrina inducida por inhibidores de los puntos de control inmune

Abstract Since their approval in 2011, immune checkpoint inhibitors (ICPis) are increasingly used to treat several advanced cancers. ICPis target certain cellular molecules that regulate immune response resulting in antitumor activity. The use of these new agents needs careful monitoring since they brought a whole new spectrum of adverse events. In this review, we aim to describe different endocrine dysfunctions induced by ICPis and to underline the importance of diagnosing and managing these adverse effects. Immune-related endocrine toxicities include thyroid dysfunction, hypophysitis and, less frequently, type 1 diabetes, primary ad renal insufficiency and hypoparathyroidism. Diagnosis of endocrine adverse events related to ICPis therapy can be challenging due to nonspecific manifestations in an oncological scenario and difficulties in the biochemical evaluation. Despite the fact that these endocrine adverse events could lead to life-threatening consequences, the availability of effective replacement treatment enables continuing therapy and together with an interdisciplinary approach will impact positively on survival.

Resumen Desde su aprobación en 2011, el uso de los inhibidores de los puntos de control inmunes (ICPis) se ha ex tendido para el tratamiento de diversas neoplasias en estadios avanzados. Los ICPis tienen como blanco ciertas moléculas de las células que regulan la respuesta inmune favoreciendo una actividad antitumoral. El uso de estos nuevos agentes requiere un monitoreo específico, ya que se han vinculado con un amplio y nuevo espectro de efectos adversos. El objetivo de esta revisión es describir las diferentes disfunciones endocrinas inducidas por los ICPis y destacar la importancia del diagnóstico y manejo oportuno de estos efectos adversos. Los efectos adversos inmunes endocrinos incluyen disfunción tiroidea, hipofisitis y con menor frecuencia, diabetes tipo 1, insuficiencia suprarrenal primaria e hipoparatiroidismo. El diagnóstico de eventos adversos endocrinos relacionados con la terapia ICPis es un desafío debido a su presentación clínica inespecífica en un escenario oncológico y a las dificultades en la evaluación bioquímica. Estos eventos adversos endocrinos podrían tener consecuencias potencialmente letales, pero la disponibilidad de un tratamiento de reemplazo eficaz permite continuar la terapia y, junto con un enfoque interdisciplinario, generar un impacto positivo en la supervivencia.

Reacciones adversas a medicamentos inhibidores del punto de control inmunitario / Adverse drug reactions associated with immune checkpoint inhibitors

Resumen El manejo de las reacciones adversas inducidas por los inhibidores del punto de control inmunitario (IPCI) en cáncer, demanda un trabajo multidisciplinario. Revisamos las causas y el curso clínico de las consultas e internaciones debidas a reacciones adversas de los IPCI entre septiembre de 2015 y julio de 2019 en el Instituto Alexander Fleming. Se registraron los datos demográficos, diagnóstico oncológico, reacción adversa y su grado, requerimiento de internación, tratamiento, mortalidad y evaluación de la reexposición. Se registraron 124 reacciones adversas por IPCI en 89 pacientes. Sesenta y ocho recibían monoterapia y 21 terapia combinada. Las manifestaciones cutáneas fueron las más frecuentes, seguidas de las generales, endocrinas (con mayor frecuencia hipotiroidismo), colitis, neumonitis, neurológicas y hepatitis. Fueron graves (grado ≥ 3), 26 toxicidades en 25 pacientes. Se internaron 15, y 6 de ellos requirieron terapia intensiva. Un caso fue fatal. Recibieron glucocorticoides 34 (12 de ellos por vía intravenosa). Un paciente recibió micofenolato y uno inmuno globulina endovenosa. En 20 se discontinuó el tratamiento. Ocho se reexpusieron y uno de ellos debió suspender definitivamente. Se presenta en esta serie de casos nuestra experiencia con el diagnóstico y tratamiento de las reacciones adversas de una familia de drogas cuya utilización ha crecido en los últimos años.

Abstract The management of patients with immune-related adverse events (irAEs) frequently demands a multidisciplinary approach. We reviewed the causes and clinical course of medical visits and admissions at the Instituto Alexander Fleming due to irAEs between September 2015 and July 2019. Demographic data, diagnosis, toxicity and its severity, requirement of admission, treatment, mortality, and evaluation of the re-administration of immunotherapy were collected. We found 124 irAEs in 89 patients. Sixty-eight of them received monotherapy (76.4%) and 21 (23.6%) combination of drugs. Cutaneous manifestations were the most frequent cause of irAEs, followed by general manifestations, endocrine dysfunctions (hypothyroidism the most frequent), colitis, pneumonitis, neurologic dis orders, and hepatitis. In 26 adverse events (in 25 patients), severity grade was ≥ 3. Fifteen were admitted and 6 required ICU admission. One patient died. Thirty-four received glucocorticoids, 12 of them by intravenous route. One patient received mycophenolate and one IVIG. In 20, the treatment was discontinued; 8 were re-exposed, with definitive discontinuation in one patient. In this case series we report our experience in the diagnosis and management of adverse reactions related to a family of drugs whose use has grown in recent years.

Incidencia y características clínicas de la enfermedad tiroidea en pacientes con neoplasias malignas tratados con inhibidores de punto de control inmunológico / Incidence and clinical characteristics of thyroid abnormalities in cancer patients treated with immune checkpoint inhibitors

Resumen Introducción: Los inhibidores del punto de control inmunológico (IPCi) son utilizados en los últimos años en el tratamiento de neoplasias malignas avanzadas, con ellos se ha logrado un aumento significativo de la supervivencia; sin embargo, su uso se ha asociado a incremento del riesgo de enfermedades autoinmunes. Objetivo: Describir la incidencia y las características clínicas de los pacientes tratados con IPCi que desarrollaron tiroidopatía. Métodos: Se revisaron retrospectivamente los expedientes de todos los pacientes que recibieron IPCi en los últimos tres años y se identificaron aquellos que desarrollaron anomalías tiroideas. Resultados: La prevalencia de tiroiditis fue de 7 %, con una incidencia de 21.4 % pacientes/mes. La mediana del tiempo para el desarrollo de tiroiditis fue de 63 días. La mayoría de los pacientes presentó síntomas leves o moderados y no requirió hospitalización, si bien todos menos uno desarrollaron hipotiroidismo permanente y requirieron terapia de reemplazo hormonal con levotiroxina. Conclusiones: La disfunción tiroidea secundaria a inmunoterapia es una entidad común en nuestra población. El cuadro clínico suele ser leve y no requiere suspender el tratamiento; sin embargo, debido a la alta incidencia de este evento adverso, los médicos no oncólogos deben estar familiarizados con su diagnóstico y tratamiento, para brindar un manejo multidisciplinario.

Abstract Introduction: Immune checkpoint inhibitors (ICI) are a group of drugs that have been used in recent years for the treatment of advanced malignancies such as melanoma, non-small cell lung cancer and other tumors, significantly increasing survival. However, the use of ICI has been associated with an increased risk of autoimmune diseases, with endocrine organs, specifically the thyroid, being highly susceptible to this phenomenon. Objective: To describe the incidence and clinical characteristics of patients treated with ICI who develop thyroid disease. Methods: The medical records of all patients who received ICI treatment within the last three years were retrospectively reviewed, with those who developed thyroid abnormalities being identified. Results: The prevalence of thyroiditis was 7 %, with an incidence of 21.4 % of patients-month. Median time for the development of thyroiditis was 63 days. Most patients had mild or moderate symptoms and did not require hospitalization, although all but one developed permanent hypothyroidism and required hormone replacement therapy with levothyroxine. Conclusions: Thyroid dysfunction secondary to immunotherapy is a common entity in our population. Clinical presentation is usually mild and does not require treatment discontinuation; however, due to the high incidence of these adverse events, non-oncology specialists must be familiar with the diagnosis and treatment of these alterations in order to provide multidisciplinary management.

Chinese multidisciplinary expert consensus on combined immunotherapy based on immune checkpoint inhibitors for hepatocellular carcinoma(2021 version) / 中华肝脏病杂志

Combined immunotherapy based on immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma has achieved remarkable therapeutic effect in clinical research and practice. However, many problems that need to be resolved have also been recognized in the clinical promotion process. Therefore, the primary effort through the multidisciplinary experts' mutual discussion [Chinese multidisciplinary expert consensus on combined immunotherapy based on immune check point inhibitors for hepatocellular carcinoma (2021 version)] is to implement the principles and methods of clinical application of ICIs treatment, including the selection of indications, prescriptions, treatment methods, monitoring and management of treatment process and adverse reactions, and efficacy evaluation. In addition, the consensus aims to combine the latest research progress, summarize detailed clinical application rules and expert experience, so as to provide reference for health professionals.

Current and future drug combination strategies based on programmed death-1/programmed death-ligand 1 inhibitors in non-small cell lung cancer / 中华医学杂志(英文版)

In recent years, immune checkpoint inhibitors (ICIs) have made breakthroughs in the field of lung cancer and have become a focal point for research. Programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor monotherapy was the first to break the treatment pattern for non-small cell lung cancer (NSCLC). However, owing to the limited benefit of ICI monotherapy at the population level and its hyper-progressive phenomenon, it may not meet clinical needs. To expand the beneficial range of immunotherapy and improve its efficacy, several research strategies have adopted the use of combination immunotherapy. At present, multiple strategies, such as PD-1/PD-L1 inhibitors combined with chemotherapy, anti-angiogenic therapy, cytotoxic T-lymphocyte-associated protein 4 inhibitors, and radiotherapy, as well as combined treatment with new target drugs, have been evaluated for clinical practice. To further understand the current status and future development direction of immunotherapy, herein, we review the recent progress of ICI combination therapies for NSCLC.