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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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.

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.

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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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.

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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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.

Endocrinopatías por inmunoterapia oncológica / Endocrinopathies by oncological immunotherapy

La relación entre inmunidad y cáncer es compleja. Las células tumorales desarrollan mecanismos de evasión a las respuestas del sistema inmunitario. Esta capacidad permite su supervivencia y crecimiento. La inmunoterapia ha transformado el tratamiento oncológico mejorando la respuesta inmunitaria contra la célula tumoral. Esta se basa en el bloqueo de los puntos de control inmunitario mediante anticuerpos monoclonales contra la molécula inhibidora CTLA-4 (antígeno 4 del linfocito T citotóxico [CTLA-4]) y la proteína 1 de muerte celular programada y su ligando (PD-1/PD-L1). Aunque los inhibidores de los puntos de control inmunitario (ICIs) son fármacos bien tolerados, tienen un perfil de efectos adversos conocido como eventos adversos inmunorrelacionados (EAI). Estos afectan varios sistemas, incluyendo las glándulas endocrinas. Los eventos adversos endocrinos más frecuentes son la disfunción tiroidea, la insuficiencia hipofisaria, la diabetes mellitus autoinmune y la insuficiencia suprarrenal primaria. El creciente conocimiento de estos efectos adversos endocrinos ha llevado a estrategias de tratamiento efectivo con el reemplazo hormonal correspondiente. El objetivo de esta revisión es reconocer la incidencia de estas nuevas endocrinopatías, la fisiopatología, su valoración clínica y el manejo terapéutico. (AU)

The relationship between immunity and cancer is complex. Tumor cells develop evasion mechanisms to the immune system responses. This ability allows their survival and progression. Immunotherapy has transformed cancer treatment by improving the immune response against tumor cells. This is achieved by blocking immune checkpoints with monoclonal antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 and its ligand (PD-1 / PD-L1). Although the immune checkpoint inhibitors (ICIs) are well tolerated drugs, they have a profile of adverse effects known as immune-related adverse events (irAES). These involve diverse systems, including the endocrine glands. The most frequent endocrine immune-related adverse events are thyroid and pituitary dysfunction, autoimmune diabetes mellitus and primary adrenal insufficiency. The increasing knowledge of these irAES has led to effective treatment strategies with the corresponding hormonal replacement. The objective of this review is to recognize the incidence of these new endocrinopathies, the physiopathology, their clinical evaluation, and therapeutic management. (AU)

Predictive Biomarkers of Immune-related Adverse Events Induced by Checkpoint Inhibitors in Malignancies / 中国医学科学院学报

While immune checkpoint inhibitors(ICIs)are effective and promising treatments for a variety of malignancies,they also have safety concerns,especially the immune-related adverse events(irAEs).Unlike the side effects of traditional chemotherapy and targeted therapy,irAEs are adverse events caused by immune activation after ICIs treatment and thus may involve almost every system of the body.Therefore,biomarkers for predicting irAEs after ICIs treatment are urgently needed.Here we review the currently available predictive biomarkers of irAEs.

Type 1 diabetes induced by immune checkpoint inhibitors / 中华医学杂志(英文版)

With the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.

Efectos adversos inmunomediados por inhibidores de PD-1 / PD-1 inhibitors immune-mediated side effects

Los anticuerpos monoclonales que inhiben los puntos de control PD-1 y CTLA-4 se usan actualmente en el tratamiento del melanoma y cáncer metastásico de pulmón de células no pequeñas, entre otros. Se refiere el caso de una paciente con cáncer de pulmón en tratamiento con pembrolizumab. La paciente se presentó con edema facial y parálisis facial periférica. En el laboratorio se observó la hormona tirotrofina (TSH) elevada y se llegó al diagnóstico de hipotiroidismo por pembrolizumab. Inició tratamiento con levotiroxina con mejoría clínica. Se presenta este caso por el importante papel del dermatólogo en el manejo multidisciplinario del paciente oncológico. (AU)

Monoclonal antibodies that inhibit PD-1 and CTLA-4 control points are currently used in the treatment of melanoma and metastatic non-small cell lung cancer, among others. The case of a patient, with lung cancer being treated with Pembrolizumab. The patient was presented with facial edema and peripheral facial paralysis and in the laboratory the elevated hormone Tyrotrophin (TSH) was observed, the diagnosis of pembrolizumab hypothyroidism was reached. She started treatment with levothyroxine with clinical improvement. This case is presented by the important role of the dermatologist in the multidisciplinary management of the cancer patient. (AU)

Inmunotolerancia en un paciente hemofílico pediátrico en Costa Rica / Immunotolerance induction in a pediatric hemophilic patient in Costa Rica

Resumen La hemofilia A es una enfermedad ligada al cromosoma X que predispone al sangrado. Se trata con Factor VIII, ya sea profilaxis o a demanda. La mayoría de países en el resto del mundo utilizan profilaxis, lo cual a la larga es más barato que tratar los pacientes cuando están con un sangrado activo. La producción de inhibidores del factor VIII es la complicación más común y seria del tratamiento. La inmunotolerancia (ITI) es la única opción de tratamiento que ha demostrado satisfactoriamente erradicar esta condición en los pacientes que desarrollan inhibidores, disminuyendo de esta manera no solo los inhibidores sino los costos del tratamiento. Se presenta un caso de inducción satisfactoria de inmunotolerancia con bajas dosis de factor VIII (FVIII) en un paciente pediátrico con hemofilia A severa. A pesar de que la inmunotolerancia se ha practicado antes en Costa Rica, un caso de estos nunca antes había sido publicado.

Abstract Hemophilia A is an X - linked bleeding disorder. It can be treated with Factor VIII prophylaxis or on demand treatment. Most countries in the world use prophylaxis as it is less expensive than treating patients when they are bleeding. The production of factor VIII inhibitors is the most common and serious complication of the treatment. Immune tolerance induction (ITI) is the only option of treatment when patients develop inhibitors proven to be successful to eradicate this condition, therefore decreasing inhibitors and costs. A case of a successful immune tolerance induction with low doses of factor VIII (FVIII) in a pediatric patient with severe hemophilia A and FVIII inhibitors is presented. Even though inmunotolerance has been practice before in our country, a case like this has never been published.

Immunotherapy-induced pneumonitis: cases report / Pneumonite induzida por imunoterapia antineoplásica: relato de casos

ABSTRACT Immunotherapy-induced pneumonitis is a rare complication with incidence estimated around 3%. This disease is difficult to diagnose and has great morbidity. For this reason, it became a challenge for oncologists and emergencists. We reviewed the case of five patients who used anti-PD1 (program cell death receptor antagonist 1) for antineoplastic treatment and developed treatment-induced pneumonitis. All patients had respiratory problems because of immunotherapy and presence of ground-glass radiologic change. Among all patients, only one had grade 5 pneumonitis, and delaying to begin corticosteroid therapy and worsening in clinical picture led to patient death. Other four patients with symptomatic grade 2 pneumonitis underwent corticosteroid therapy and had improvement in clinical and radiologic picture. Two patients were treated after an episode of pneumonitis, and no new pulmonary complications were observed until the end of this study. Immunotherapy-induced pneumonitis, although uncommon, can be potentially fatal. Medical team has the responsibility to pay attention for most common symptoms of the disease such as cough and dyspnea and conduct an early diagnosis and effective early treatment with corticosteroids.

RESUMO A pneumonite secundária à imunoterapia é uma complicação rara, com incidência estimada em cerca de 3%. No entanto, trata-se de uma intercorrência de difícil diagnóstico e com grande morbidade, que tem se tornado um desafio para oncologistas e emergencistas. Foram revisados os casos de cinco pacientes que fizeram uso de anti-PD1 (program cell death receptor antagonist 1) para tratamento antineoplásico e que evoluíram com quadro de pneumonite induzida pelo tratamento. Todos os pacientes apresentaram sintomas respiratórios em vigência de tratamento, com imunoterapia e presença de alteração radiológica em vidro fosco. Dentre estes pacientes, apenas um apresentou pneumonite grau 5, com atraso na introdução de corticoidoterapia, indo a óbito em decorrência do quadro. Os outros quatro pacientes apresentaram pneumonite grau 2, sintomática, sendo tratados com corticoidoterapia e evoluindo com melhora clínica e radiológica. Dois pacientes mantiveram o tratamento após o episódio de pneumonite, sem novas complicações pulmonares posteriores, até o momento. A pneumonite induzida por imunoterapia, apesar de ser um evento pouco frequente, pode acarretar grande morbidade, além de ser potencialmente fatal, cabendo à equipe médica ter atenção aos sintomas mais comuns, como tosse e dispneia, para diagnóstico precoce e tratamento efetivo, com uso precoce de corticoide.

Advances and challenges in therapeutic monoclonal antibodies drug development

The use of serum containing polyclonal antibodies from animals immunized with toxins marked the beginning of the application of antibody-based therapy in late nineteenth century. Advances in basic research led to the development of the hybridoma technology in 1975. Eleven years later, the first therapeutic monoclonal antibody (mAb) was approved, and since then, driven by technological advances, the development of mAbs has played a prominent role in the pharmaceutical industry. In this review, we present the developments to circumvent problems of safety and efficacy arising from the murine origin of the first mAbs and generate structures more similar to human antibodies. As of October 2017, there are 61 mAbs and 11 Fc-fusion proteins in clinical use. An overview of all mAbs currently approved is provided, showing the development of sophisticated mAbs formats that were engineered based on the challenges posed by therapeutic indications, including antibody-drug conjugates (ADC) and glycoengineered mAbs. In the field of immunotherapy, the use of immunomodulators, bispecific mAbs and CAR-T cells are highlighted. As an example of promising therapy to treat infectious diseases, we discuss the generation of neutralizing monoclonal-oligoclonal antibodies obtained from human B cells. Scientific and technological advances represent mAbs successful translation to the clinic