RESUMO
PURPOSE: The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS: We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti-SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS: Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses (P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type (P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses (P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION: Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.
Assuntos
Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Neoplasias/imunologia , SARS-CoV-2/imunologia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: For patients with a history of drug hypersensitivity reaction (HSR) during anesthesia, strategies to minimize risk with subsequent anesthesia are unclear. Identification of the cause of HSR during anesthesia remains challenging. OBJECTIVE: To determine the success of a comprehensive allergy evaluation and management plan for patients with HSR during anesthesia, including identification of the causative agent and review of outcomes during subsequent anesthesia exposure. METHODS: We performed chart reviews of patients referred for the evaluation of HSR during anesthesia between 2003 and 2012. Data collection included patient characteristics, signs/symptoms of HSR during anesthesia, and subsequent outcomes. Patients underwent comprehensive allergy evaluation including skin testing for identifying potential culprit agents, and the results were used to provide recommendations for any subsequent anesthesia. RESULTS: Over the 10-year study period, 73 patients with HSR during anesthesia were referred for further evaluation. Thirteen patients (18%) had positive skin test results to a drug received during anesthesia. One patient with a positive skin test result was diagnosed with mastocytosis. The causative agents identified in these 13 patients included latex, ß-lactam antibiotics, neuromuscular blockers, tetracaine, odansetron, and fentanyl. On follow-up, 47 of the 73 patients (64%) subsequently underwent procedures requiring anesthesia. Using our recommendations from evaluation and testing, 45 of these 47 patients (96%) successfully tolerated subsequent anesthesia. The 2 patients who developed recurrent HSR during anesthesia were later diagnosed with mast cell disorders. CONCLUSIONS: Our comprehensive evaluation and management plan minimizes risk with subsequent anesthesia even when the cause of HSR could not be identified. Baseline tryptase levels may be helpful in this patient population to diagnose mast cell disorders.
Assuntos
Anestesia/efeitos adversos , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Testes Cutâneos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.
Assuntos
Membrana Celular/metabolismo , Proteína Ligante Fas/metabolismo , Glaucoma/metabolismo , Glaucoma/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Animais , Morte Celular , Membrana Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Modelos Animais de Doenças , Proteína Ligante Fas/farmacologia , Glaucoma/complicações , Injeções , Camundongos , Camundongos Mutantes , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Ligação Proteica/efeitos dos fármacos , Degeneração Retiniana/complicações , Degeneração Retiniana/patologia , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Solubilidade/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/farmacologia , Receptor fas/metabolismoRESUMO
Fas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein. The two different forms of FasL are reported to have opposite functions-membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage.
Assuntos
Neoplasias Oculares/patologia , Proteína Ligante Fas/imunologia , Metástase Neoplásica/prevenção & controle , Animais , Membrana Celular/imunologia , Neoplasias Oculares/imunologia , Proteína Ligante Fas/genética , Citometria de Fluxo , Genes Reporter , Inflamação/imunologia , Inflamação/prevenção & controle , Leucemia L5178/imunologia , Camundongos , Camundongos Endogâmicos DBA , TransfecçãoRESUMO
PURPOSE: Ocular immune privilege promotes tumor growth by hindering the development of innate and adaptive immunity. A prior study showed that ocular tumors expressing the membrane-only form of Fas ligand (FasL) terminate immune privilege, induce vigorous inflammation, undergo rejection, and induce systemic protective immunity. In these previous experiments the tumor cells used were genetically engineered to express membrane FasL. As an initial step toward developing an immunotherapy for intraocular tumors, the present study was conducted to examine whether injection of microvesicles expressing membrane FasL into ocular tumors (that are FasL negative) would have a similar effect. METHODS: Microvesicles expressing either no FasL or membrane-only Fas ligand were coinjected with L5178Y-R lymphoma cells into the anterior chambers (AC) of DBA/2 mice. RESULTS: Tumor cells coinjected with control vesicles grew progressively in the AC, and all mice died of metastatic disease by day 15. By contrast, a single injection of membrane FasL vesicles induced a potent inflammatory response characterized by GR1+ neutrophils and F4/80+ macrophages and significantly improved survival from 0% in untreated mice to 58% in mFasL-treated mice. Among the surviving mice, the ocular tumor was eliminated in 55%, and the mice exhibited systemic protection from a second tumor challenge. In the remaining 45%, the ocular tumor was not eliminated, but the mice were protected from liver metastases. CONCLUSIONS: Bioactive membrane FasL microvesicles coinjected with tumor cells induce a potent inflammatory response that terminates immune privilege, eliminates ocular tumors, and prevents metastatic disease.
Assuntos
Neoplasias Oculares/terapia , Imunidade Inata , Imunoterapia , Leucemia L5178/terapia , Glicoproteínas de Membrana/uso terapêutico , Animais , Câmara Anterior/patologia , Antígenos de Diferenciação/imunologia , Membrana Celular , Citotoxicidade Imunológica/imunologia , Neoplasias Oculares/imunologia , Neoplasias Oculares/patologia , Proteína Ligante Fas , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Ceratite/imunologia , Leucemia L5178/imunologia , Leucemia L5178/patologia , Ligantes , Neoplasias Hepáticas/secundário , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos DBA , Microscopia Confocal , Transplante de Neoplasias , Neutrófilos/imunologia , Células Tumorais CultivadasRESUMO
A number of studies have documented a critical role for tumor-specific CD4(+) cells in the augmentation of immunotherapeutic effector mechanisms. However, in the context of an extensive tumor burden, chronic stimulation of such CD4(+) T cells often leads to the up-regulation of both Fas and Fas ligand, and coexpression of these molecules can potentially result in activation-induced cell death and the subsequent loss of effector activity. To evaluate the importance of T cell persistence in an experimental model of immunotherapy, we used DO11 Th1 cells from wild-type, Fas-deficient, and Fas ligand-deficient mice as effector populations specific for a model tumor Ag consisting of an OVA-derived transmembrane fusion protein. We found that the prolonged survival of Fas-deficient DO11 Th1 cells led to a more sustained tumor-specific response both in vitro and in vivo. Importantly, both Fas- and Fas ligand-deficient Th1 cells delayed tumor growth and cause regression of established tumors more effectively than wild-type Th1 cells, indicating that resistance to activation-induced cell death significantly enhances T cell effector activity.
Assuntos
Apoptose , Linfócitos T CD4-Positivos/imunologia , Ativação Linfocitária , Neoplasias Experimentais/imunologia , Animais , Linhagem Celular , Proteína Ligante Fas , Feminino , Masculino , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Células Th1/imunologia , Receptor fas/fisiologiaRESUMO
It has been proposed that the constitutive expression of Fas ligand (FasL) in the eye maintains immune privilege, in part through inducing apoptosis of infiltrating Fas(+) T cells. However, the role of FasL in immune privilege remains controversial due to studies that indicate FasL is both pro- and anti-inflammatory. To elucidate the mechanism(s) by which FasL regulates immune privilege, we used an ocular tumor model and examined the individual roles of the membrane-bound and soluble form of FasL in regulating ocular inflammation. Following injection into the privileged eye, tumors expressing only soluble FasL failed to trigger inflammation and grew progressively. By contrast, tumors expressing only membrane FasL 1) initiated vigorous neutrophil-mediated inflammation, 2) terminated immune privilege, and 3) were completely rejected. Moreover, the rejection coincided with activation of both innate and adaptive immunity. Interestingly, a higher threshold level of membrane FasL on tumors is required to initiate inflammation within the immune privileged eye, as compared with nonprivileged sites. The higher threshold is due to the suppressive microenvironment found within aqueous humor that blocks membrane FasL activation of neutrophils. However, aqueous humor is unable to completely block the proinflammatory effects of tumor cells that express high levels of membrane FasL. In conclusion, our data indicate that the function of FasL on intraocular tumors is determined by the microenvironment in conjunction with the form and level of FasL expressed.
Assuntos
Olho/imunologia , Imunidade Inata/imunologia , Glicoproteínas de Membrana/fisiologia , Receptor fas/metabolismo , Animais , Câmara Anterior/imunologia , Câmara Anterior/patologia , Humor Aquoso/imunologia , Quimiocina CXCL2 , Quimiocinas/biossíntese , Relação Dose-Resposta Imunológica , Olho/patologia , Neoplasias Oculares/imunologia , Neoplasias Oculares/metabolismo , Neoplasias Oculares/mortalidade , Neoplasias Oculares/patologia , Proteína Ligante Fas , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Inflamação/imunologia , Interleucina-1/antagonistas & inibidores , Interleucina-1/biossíntese , Leucemia L5178/imunologia , Leucemia L5178/metabolismo , Leucemia L5178/mortalidade , Leucemia L5178/patologia , Ligantes , Masculino , Glicoproteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos MRL lpr , Camundongos SCID , Transplante de Neoplasias , Neutrófilos/imunologia , Neutrófilos/metabolismo , Coelhos , Especificidade da Espécie , Células Tumorais Cultivadas/imunologia , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/transplanteRESUMO
Experimental and physiological expression of the pro-apoptotic molecule Fas-ligand can induce inflammation under certain conditions. Discussed here are the experimental situations, possible mechanisms, and pathways that mediate this response.