RESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) are widely used in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC); however, the toxicity profiles are inconclusive. METHODS: Clinical trials evaluating ICIs for R/M HNSCC were searched from online databases. The characteristics of the studies and the results of incidences of any grade treatment-related adverse events (trAEs), grade three or more trAEs, treatment-related deaths, trAEs leading to discontinuation of treatment, and specific trAEs were extracted. RESULTS: Twenty studies with 3756 patients were included. The pooled incidences of any grade trAEs, grade three or more trAEs, treatment-related deaths, trAEs leading to discontinuation of treatment for overall population were 62.07% (95% CI, 59.07%-65.02%), 13.82% (95% CI, 11.23%-16.62%), 0.39% (95% CI, 0.15%-0.71%), 3.99% (95% CI, 2.36%-5.95%), respectively. Programmed cell death protein 1 (PD-1) inhibitors monotherapy and ICIs combination therapy had significantly higher incidences of any grade trAEs (odds ratio [OR], 1.25, 95% CI, 1.05-1.49 and 1.36, 95% CI, 1.15-1.60, respectively), grade three or more trAEs (OR, 1.41, 95% CI, 1.08-1.84 and 1.79, 95% CI, 1.39-2.30, respectively), trAEs leading to discontinuation of treatment (OR, 3.98, 95% CI, 2.06-7.70 and 10.14, 95% CI, 5.49-18.70, respectively) compared with programmed death-ligand 1 (PD-L1) inhibitors monotherapy. ICIs combination therapy had a significantly higher incidence of grade three or more trAEs compared with PD-1 inhibitors monotherapy (OR, 1.27, 95% CI, 1.03-1.55); however, the incidences of any grade trAEs and trAEs leading to discontinuation of treatment were not significant different. CONCLUSIONS: Our study suggests that the incidences of grade three or more trAEs, treatment-related deaths, and trAEs leading to discontinuation of treatment are low in R/M HNSCC patients treated with ICIs. PD-L1 inhibitors monotherapy may be safer compared with PD-1 inhibitors monotherapy and ICIs combination therapy.
Assuntos
Carcinoma , Neoplasias de Cabeça e Pescoço , Humanos , Antígeno B7-H1 , Terapia Combinada , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/toxicidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
Wider use of checkpoint inhibitor therapy spurs efforts to predict and treat immune complications.
Assuntos
Inibidores de Checkpoint Imunológico , Doenças do Sistema Imunitário , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/toxicidade , Doenças do Sistema Imunitário/induzido quimicamente , Doenças do Sistema Imunitário/mortalidade , Neoplasias/tratamento farmacológicoRESUMO
Unprecedented advances have been made in cancer treatment with the use of immune checkpoint blockade (ICB). However, responses are limited to a subset of patients, and immune-related adverse events (irAEs) can be problematic, requiring treatment discontinuation. Iterative insights into factors intrinsic and extrinsic to the host that impact ICB response and toxicity are critically needed. Our understanding of the impact of host-intrinsic factors (such as the host genome, epigenome, and immunity) has evolved substantially over the past decade, with greater insights on these factors and on tumor and immune co-evolution. Additionally, we are beginning to understand the impact of acute and cumulative exposures-both internal and external to the host (i.e., the exposome)-on host physiology and response to treatment. Together these represent the current day hallmarks of response, resistance, and toxicity to ICB. Opportunities built on these hallmarks are duly warranted.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/toxicidade , Animais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteínas de Checkpoint Imunológico/metabolismo , Imunidade/efeitos dos fármacos , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologiaRESUMO
The development of immune checkpoint inhibitors (ICIs) has changed the treatment paradigm for cancer. The ICIs nivolumab, pembrolizumab, and cemiplimab target programmed cell death protein 1, and durvalumab, avelumab, and atezolizumab target programmed death ligand 1. Ipilimumab targets cytotoxic T lymphocyte-associated antigen-4. Used as monotherapy or in combination, they have shown remarkable efficacy in melanoma, lung cancer, and many other solid tumors, and indications continue to evolve. These checkpoint inhibitors are typically well tolerated; however, they may cause immune-mediated adverse effects, resulting in inflammation of any organ system. Pulmonary toxicity is vital to recognize, and it can be more challenging to diagnose in patients with lung cancer, given the nature of the disease course and treatment.
Assuntos
Inibidores de Checkpoint Imunológico/toxicidade , Pulmão/efeitos dos fármacos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
BACKGROUND AND OBJECTIVES: To describe the marked clinical and biological responses of a targeted treatment with anti-interleukin-6 (IL-6)-receptor antibody and Janus kinase (JAK) inhibitors in a patient with a severe, corticoresistant CNS toxicity of immune-checkpoint inhibitor (ICI) therapy. METHODS: A 58-year-old man was admitted for subacute paraparesis, urinary retention, and ascending paresthesia. He was under treatment with ipilimumab and nivolumab for metastatic melanoma. Spine MRI disclosed multiple T2-hyperintense, contrast-enhancing longitudinally extensive lesions. A diagnosis of ICI-related acute transverse myelitis was made. RESULTS: ICIs were immediately discontinued, and the patient received high-dose glucocorticoids plus 1 session of plasma exchange, but he did not improve. Based on the marked elevation of CSF IL-6 (505 pg/mL), a second-line targeted therapy with anti-IL-6-receptor tocilizumab (8 mg/kg/mo for 3 infusions) plus JAK inhibitor ruxolitinib (50 mg/d) was administered. Patient neurologic status started to improve shortly after, with corresponding radiologic resolution. At 9 months, the patient was able to walk independently, presenting only slight residual disability while remaining in oncologic partial response. DISCUSSION: Our case suggests that some patients with severe, corticoresistant CNS immune-related toxicities of ICIs may benefit from cytokine blockade. Cytokine measurement in serum and CSF might help in selecting patients for personalized treatment strategies.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Inibidores de Checkpoint Imunológico/toxicidade , Inibidores de Janus Quinases/farmacologia , Melanoma/tratamento farmacológico , Mielite Transversa , Síndromes Neurotóxicas , Nitrilas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Interleucina-6/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Humanos , Ipilimumab/toxicidade , Inibidores de Janus Quinases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mielite Transversa/induzido quimicamente , Mielite Transversa/tratamento farmacológico , Mielite Transversa/imunologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/imunologia , Nitrilas/administração & dosagem , Nivolumabe/toxicidade , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagemRESUMO
Importance: Immune checkpoint inhibitors can produce distinct toxic effects that require prompt recognition and timely management. Objective: To develop a technology-enabled, dynamically adaptive protocol that can provide the accurate information needed to inform specific remedies for immune toxic effects in patients treated with immune checkpoint inhibitors. Design, Setting, and Participants: An open-label cohort study was conducted at a single tertiary referral center from September 6, 2019, to September 3, 2020. The median follow-up duration was 63 (interquartile range, 35.5-122) days. Fifty patients with genitourinary cancers treated with immune checkpoint inhibitors were enrolled. Interventions: A fit-for-purpose electronic platform was developed to enable active patient and care team participation. A smartphone application downloaded onto patients' personal mobile devices prompted them to report their symptoms at least 3 times per week. The set of symptoms and associated queries were paired with alert thresholds for symptoms requiring clinical action. Main Outcomes and Measures: The primary end point of this interim analysis was feasibility, as measured by patient and care team adherence, and lack of increase in care team staffing. Operating characteristics were estimated for each symptom alert and used to dynamically adapt the alert thresholds to ensure sensitivity while reducing unnecessary alerts. Results: Of the 50 patients enrolled, 47 had at least 1 follow-up visit and were included in the analysis. Median age was 65 years (range, 37-86), 39 patients (83%) were men, and 39 patients (83%) had metastatic cancer, with the most common being urothelial cell carcinoma and renal cell carcinoma (22 [47%] patients each). After initial onboarding, no further care team training or additional care team staffing was required. Patients had a median study adherence rate of 74% (interquartile range, 60%-86%) and 73% of automated alerts were reviewed within 3 days by the clinic team. Symptoms with the highest positive predictive value for adverse events requiring acute intervention included dizziness (21%), nausea/vomiting (26%), and shortness of breath (14%). The symptoms most likely to result in unnecessary alerts were arthralgia and myalgia, fatigue, and cough. Conclusions and Relevance: The findings of this cohort study suggest an acceptable and fiscally sound method can be developed to create a dynamic learning system to detect and manage immune-related toxic effects.
Assuntos
Monitoramento Biológico/métodos , Inibidores de Checkpoint Imunológico/toxicidade , Inibidores de Checkpoint Imunológico/uso terapêutico , Aplicativos Móveis , Medidas de Resultados Relatados pelo Paciente , Testes de Toxicidade/métodos , Neoplasias Urogenitais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Monitoramento Biológico/instrumentação , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Texas , Testes de Toxicidade/instrumentaçãoRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) have made a paradigm shift in clinical oncology due to unprecedented long-term remissions. However, only a small proportion of patients respond to ICI therapy. It is, therefore, essential to understand the mechanisms driving therapy resistance and to develop strategies for increasing response rates. We previously demonstrated that in response to various cancer treatment modalities, the host activates a range of biological processes that promote tumor regrowth and metastasis. Here, we characterize the host-mediated response to ICI therapy, and investigate its contribution to therapy resistance. METHODS: Tumor cell migration, invasion and motility were assessed in the presence of plasma from ICI-treated mice and patients. Immune cell composition in peripheral blood and tumors of ICI-treated mice was assessed by flow and mass cytometry. Plasma host factors driving tumor aggressiveness were identified by proteomic profiling, followed by bioinformatic analysis. The therapeutic effect of inhibiting host-mediated processes in ICI-treated mice was assessed in a tumor model. RESULTS: Tumor cells exhibit enhanced migratory and invasive properties in vitro on exposure to plasma from anti-PD1-treated mice. Moreover, mice intravenously injected with plasma-exposed tumor cells display increased metastatic burden and mortality rate in comparison to control arms. Furthermore, tumors from anti-PD1-treated mice as well as Matrigel plugs containing plasma from anti-PD1-treated mice are highly infiltrated with immune cell types associated with both antitumor and protumor activity. These collective findings suggest that anti-PD1 treatment induces a systemic host response that potentially counteracts the drug's therapeutic activity. Proteomic profiling of plasma from anti-PD1-treated mice reveals an activation of multiple biological pathways associated with tumor aggressiveness. Consequently, blocking IL-6, one of the key drivers of the identified biological pathways, counteracts ICI-induced metastatic properties in vitro and improves ICI treatment efficacy in vivo. Lastly, plasma samples from ICI-treated non-small cell lung cancer patients differentially affect tumor cell aggressiveness in vitro, with enhanced tumor cell motility correlating with a worse clinical outcome. CONCLUSIONS: ICI therapy induces host-mediated processes that contribute to therapy resistance. Identification and analysis of such processes may lead to the discovery of biomarkers for clinical response and strategies for overcoming therapy resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/tratamento farmacológico , Células A549 , Imunidade Adaptativa/efeitos dos fármacos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Movimento Celular/efeitos dos fármacos , Citocinas/sangue , Feminino , Humanos , Inibidores de Checkpoint Imunológico/toxicidade , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos SCID , Invasividade Neoplásica , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Novel immune-modulating anticancer drugs are being used with increasing frequency. With increased use, there are more frequent cases of toxicities caused by these drugs, termed immune-related adverse events (irAEs). We present a case in which we successfully treated a case of severe, steroid-refractory, nivolumab-induced myocarditis with therapeutic plasma exchange (TPE). Nivolumab is an immune checkpoint inhibitor (ICI) which blocks programmed death receptor-1 (PD-1). This blockade allows for enhanced T-cell function and increased anti-tumor response. The patient presented with signs and symptoms of heart failure and was found to have a significantly depressed cardiac ejection fraction. Over the course of her five TPE procedures, she improved clinically and was discharged home with improved left ventricular ejection function. This case suggests an emerging role of TPE in the management of severe ICI-induced toxicity, such as myocarditis.
Assuntos
Inibidores de Checkpoint Imunológico/toxicidade , Troca Plasmática/métodos , Abatacepte , Corticosteroides/uso terapêutico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/secundário , Idoso , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Sistema Imunitário , Ácido Micofenólico/efeitos adversos , Miocardite/induzido quimicamente , Neoplasias/tratamento farmacológico , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/biossíntese , Esteroides/químicaRESUMO
Activating stimulator of interferon genes to turn immunologically refractive cold tumor hot is an exciting therapeutic approach to increase the clinical responsiveness of some human cancers to immune checkpoint inhibitors. DNA damaging drugs and PARP inhibitors are two types of agents that have demonstrated this potential. Inhibitors of Chk1 or Wee1 induce DNA damage in cancer cells in predominantly the S-phase population. Increased cytoplasmic single-stranded and double-stranded DNA (dsDNA) from this DNA damage resulted in increased tank-binding kinase 1 (TBK1) phosphorylation in a range of cancer cell lines. However, despite robust increases in pTBK1, no downstream consequences of TBK1 phosphorylation were observed (namely no increase in pIRF3/7, interferon regulatory factor (IRF)-dependent gene expression or a type I IFN response). In combination with cytotoxic chemotherapy such as gemcitabine or camptothecin (CPT), Chk1 inhibition increased cytoplasmic dsDNA compared with the cytotoxic alone but attenuated the cytotoxic chemotherapy-induced increase in IRF1 protein and STAT1 phosphorylation through inhibition of nuclear RelB translocation. Despite increased cytoplasmic DNA and TBK1 activation, inhibition of Chk1, ataxia telangiectasia and Rad3-related protein, or Wee1 failed to activate a type I IFN response. We discuss the potential underlying mechanisms for this lack of IRF-dependent gene response and how this might influence the clinical strategies of combining Chk1 or Wee1 inhibitors with immune checkpoint inhibitors.
Assuntos
Dano ao DNA , Inibidores de Checkpoint Imunológico/toxicidade , Imunidade Inata , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/metabolismo , Células HT29 , Humanos , Fator Regulador 3 de Interferon/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT1/metabolismoRESUMO
INTRODUCTION: New cancer treatments with immunotherapy have led to unique toxicities affecting cancer patients. As cancer-related visits to the emergency department increase, the emergency physician and the medical toxicologist should be aware of immunotherapy-related toxicities. In this review we discuss immune related adverse events (irAEs) from chimeric antigen receptor T (CAR-T) cell therapy and immune checkpoint inhibitors (ICI). DISCUSSION: While presentation of the irAEs may mimic common conditions, it is important to recognize them as they may be life-threatening. A thorough history and examination of the patient, including their cancer treatment history in the past year is crucial. Conditions such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), which can occur after CAR-T treatment, can progress rapidly to a fatal outcome if not recognized and managed in a timely manner. ICI can affect any organ system and irAEs may present like a typical autoimmune disease of the affected organ. While most of the irAEs we discuss in this review will benefit from treatment with glucocorticoids, it is important to know the grade of the condition, as it will determine the treatment dose, route and further management considerations. CONCLUSION: Patients experiencing irAEs from ICI and CAR-T can present with subtle symptoms that can rapidly progress if not recognized early. The emergency physician and the medical toxicologist should keep in mind these toxicities and the patient's oncologic history to adequately recognize and manage these conditions.
Assuntos
Antídotos/uso terapêutico , Serviços Médicos de Emergência/normas , Inibidores de Checkpoint Imunológico/toxicidade , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/normas , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Guias de Prática Clínica como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/toxicidade , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Síndromes Neurotóxicas/etiologia , Estados UnidosRESUMO
Checkpoint inhibitor (CPI) therapy has significantly improved overall survival for metastatic melanoma, and is now approved for use in the adjuvant setting. Modulating the immune system is recognized to cause cutaneous immune-related adverse events (irAEs). We conducted a retrospective observational cohort study of adult patients with melanoma at our tertiary referral centre, who received CPI therapy from 2006 to March 2018. This is the single largest study of cutaneous irAEs occurring on CPI therapy in patients with melanoma to date and encompasses 12 years. The results showed that cutaneous toxicity occurs in 24% of patients but is generally manageable, with < 5% patients discontinuing treatment.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Inibidores de Checkpoint Imunológico/toxicidade , Melanoma/tratamento farmacológico , Dermatopatias/induzido quimicamente , Suspensão de Tratamento/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Estudos Retrospectivos , Dermatopatias/patologia , Suspensão de Tratamento/tendências , Adulto JovemRESUMO
Dasatinib is a targeted cancer therapy, while programmed death ligand 1 (PD-L1) inhibitors are a form of immune checkpoint therapy used to treat various types of cancers. Several studies showed the potential efficacy of these drugs in the management of triple-negative breast cancer- an aggressive subtype of breast cancer, which can develop during pregnancy. Nevertheless, side effects of Dasatinib (DA) and PD-L1 drugs during pregnancy, especially in the early stages of embryogenesis are not explored yet. The aim of this study is to assess the individual and combined toxicity of DA and PD-L1 inhibitors during the early stages of embryogenesis and to evaluate their effect(s) on angiogenesis using the chorioallantoic membrane (CAM) model of the embryo. Our results show that embryos die at greater rates after exposure to DA and PD-L1 inhibitors as compared to their matched controls. Moreover, treatment with these drugs significantly inhibits angiogenesis of the CAM. To further elucidate key regulator genes of embryotoxicity induced by the actions of PD-L1 and DA, an RT-PCR analysis was performed for seven target genes that regulate cell proliferation, angiogenesis, and survival (ATF3, FOXA2, MAPRE2, RIPK1, INHBA, SERPINA4, and VEGFC). Our data revealed that these genes are significantly deregulated in the brain, heart, and liver tissues of exposed embryos, compared to matched control tissues. Nevertheless, further studies are necessary to evaluate the effects of these anti breast cancer drugs and elucidate their role during pregnancy.
Assuntos
Acetamidas/toxicidade , Inibidores da Angiogênese/toxicidade , Antígeno B7-H1/antagonistas & inibidores , Membrana Corioalantoide/irrigação sanguínea , Dasatinibe/toxicidade , Inibidores de Checkpoint Imunológico/toxicidade , Neovascularização Fisiológica/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Piridinas/toxicidade , Animais , Antígeno B7-H1/metabolismo , Embrião de Galinha , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento , Neovascularização Fisiológica/genética , Transdução de SinaisRESUMO
BACKGROUND: The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors. METHODS: Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab's safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay. RESULTS: Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1-2 severity; anemia (4.9%) was the most common grade 3-4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials. CONCLUSIONS: Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies. TRIAL REGISTRATION NUMBER: NCT02407990.
Assuntos
Anticorpos Monoclonais Humanizados/toxicidade , Drogas em Investigação/toxicidade , Inibidores de Checkpoint Imunológico/toxicidade , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Área Sob a Curva , Colite/induzido quimicamente , Colite/epidemiologia , Colite/imunologia , Relação Dose-Resposta a Droga , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacocinética , Feminino , Seguimentos , Meia-Vida , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacocinética , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/imunologia , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Pneumonia/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Adulto JovemRESUMO
Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune-related NAEs in cancer patients. Medical records of ICI-treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno-related NAEs. A total of 1185 ICIs-treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty-four from the overall ICIs-treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1-10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain-Barre-like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS-related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune-modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune-related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.
Assuntos
Antineoplásicos Imunológicos/toxicidade , Doenças do Sistema Nervoso Central/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Inibidores de Checkpoint Imunológico/toxicidade , Neoplasias/tratamento farmacológico , Doenças Neuromusculares/fisiopatologia , Síndromes Neurotóxicas/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Doenças do Sistema Nervoso Central/induzido quimicamente , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/epidemiologia , Ensaios Clínicos como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Fatores Imunológicos/farmacologia , Incidência , Masculino , Pessoa de Meia-Idade , Doenças Neuromusculares/induzido quimicamente , Doenças Neuromusculares/tratamento farmacológico , Doenças Neuromusculares/epidemiologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/etiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/epidemiologiaRESUMO
A successful pregnancy requires sophisticated regulation of uterine microenvironment to guarantee the existence of semi-allogeneic conceptus without immune rejection. T follicular regulatory (Tfr) cells exert a suppressive effect on Tfh-cell expansion, B-cell response, and antibody production. Although accumulating evidence has demonstrated that dysregulations of Tfr cells can bring on various immunological diseases, their immunomodulatory roles during pregnancy still remain unheeded. Herein, we introduced an allogeneic normal-pregnant mouse model and found that CD4+CXCR5hiPD-1hiFoxp3+ Tfr cells were preferentially accumulated in the uterus at mid-gestation and displayed a distinct phenotype. In addition, the absence of PDL1 resulted in increased fetal resorption by favoring Tfr cells accumulation and upregulating PD-1 expression on these cells. However, PDL1 blockade affected neither the ratio of Tfh/Tfr cells nor the maturation and differentiation of B cells. Overall, our results are the first to present a correlation of Tfr cells accumulation with healthy allogeneic pregnancy and PDL1 blockade-induced miscarriage, and to indicate that appropriate assembly of Tfr cells is important for pregnancy maintenance. Since blockade of PD-1-PDL1 pathway leads to more Tfr cells and fetal losses, the reproductive safety must be taken into consideration when PD-1/PD-L1 checkpoint blockade immunotherapy is used in pregnancy.
Assuntos
Aborto Espontâneo/induzido quimicamente , Linfócitos B/efeitos dos fármacos , Antígeno B7-H1/antagonistas & inibidores , Reabsorção do Feto/induzido quimicamente , Inibidores de Checkpoint Imunológico/toxicidade , Células T Auxiliares Foliculares/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Útero/efeitos dos fármacos , Aborto Espontâneo/imunologia , Aborto Espontâneo/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígeno B7-H1/metabolismo , Feminino , Reabsorção do Feto/imunologia , Reabsorção do Feto/metabolismo , Idade Gestacional , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Gravidez , Receptor de Morte Celular Programada 1/metabolismo , Medição de Risco , Transdução de Sinais , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Útero/imunologia , Útero/metabolismoRESUMO
BACKGROUND: The use of immunotherapeutic agents, specifically immune checkpoint inhibitors (ICIs) for solid malignancies, is rapidly rising, and many new agents and treatment combinations are in development. However, ICIs have a unique side-effect profile of immune-related adverse events (irAEs) compared with chemotherapeutic agents or targeted therapies. METHODS: In this report the diverse spectrum of irAEs is highlighted using two patients with metastatic melanoma undergoing treatment with ICIs. We supplement these case reports with a brief literature review of the data regarding the safety of surgical intervention in patients taking irAEs. RESULTS: The report describes the basic approach to the detection and management of irAEs, notes important perioperative considerations, and discusses the safety of surgical intervention for these patients. CONCLUSIONS: Overall, these irAEs represent a diverse group of pathologies with variable timing and sometimes subtle presentation requiring careful monitoring and heightened clinical suspicion for potential toxicity by all providers, including surgeons.