RESUMO
Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p < 0.001). Immunotherapy-naïve status was independently associated with better PFS (p = 0.005). Time-to-best response (TTBR) and ORR (p < 0.001 both) were associated with better OS at univariate analysis. PFS and DOR were moderately correlated with OS (p < 0.001 both). A PD-L1 10% cut-off detected worse/best responders in terms of ORR (univariate p = 0.011, multivariate p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored.
Assuntos
Antineoplásicos Imunológicos , Neoplasias Pulmonares , Neoplasias , Humanos , Antígeno B7-H1 , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Neoplasias/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
PURPOSE: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. PATIENTS AND METHODS: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. RESULTS: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. CONCLUSIONS: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.
Assuntos
Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/tratamento farmacológico , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Adulto , Biomarcadores Tumorais , Receptores de Antígenos Quiméricos/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: It is unclear how characteristics, risk factors, and incidence of coronavirus disease 2019 (COVID-19) in people living with HIV (PLWH) differ from the general population. METHODS: Prospective observational single-center cohort study of adult PLWH reporting symptoms of COVID-19. We assessed clinical characteristics, risk factors for COVID-19 diagnosis and severity, and standardized incidence rate ratio for COVID-19 cases in PLWH cohort and in Barcelona. RESULTS: From 1 March 2020 to 10 May 2020, 53 out of 5683 (0.9% confidence interval 0.7-1.2%) PLWH were diagnosed with COVID-19. Median age was 44 years, CD4 T cells were 618/µl and CD4/CD8 was 0.90. All but two individuals were virologically suppressed. Cough (87%) and fever (82%) were the most common symptoms. Twenty-six (49%) were admitted, six (14%) had severe disease, four (8%) required ICU admission, and two (4%) died. Several laboratory markers (lower O2 saturation and platelets, and higher leukocytes, creatinine, lactate dehydrogenase, C reactive protein, procalcitonin, and ferritin) were associated with COVID-19 severity. No HIV or antiretroviral-related factors were associated with COVID-19 diagnosis or severity. Standardized incidence rate ratios of confirmed or confirmed/probable COVID-19 in PLWH were 38% (95% confidence interval 27-52%, Pâ<â0.0001) and 33% (95% confidence interval 21-50%, Pâ<â0.0001), respectively relative to the general population. CONCLUSION: PLWH with COVID-19 did not differ from the rest of the HIV cohort. Clinical presentation, severity rate, and mortality were not dependent on any HIV-related or antiretroviral-related factor. COVID-19 standardized incidence rate was lower in PLWH than in the general population. These findings should be confirmed in larger multicenter cohort studies.
Assuntos
Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Infecções por HIV/complicações , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Betacoronavirus , Contagem de Linfócito CD4 , COVID-19 , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Prospectivos , Fatores de Risco , SARS-CoV-2 , Espanha/epidemiologiaRESUMO
INTRODUCTION: Research describes higher incidence of neurodevelopmental disorders and learning disabilities in offspring of women affected by lupus. Factors implied are pregnancy and delivery adversities and exposure to maternal antibodies and cytokines. Little is known about the offspring immunological condition or the relation between offspring and maternal condition. OBJECTIVES: This study was conducted in order to analyze immunological configuration, psychopathology, and neuropsychological performance of young offspring of women with lupus, in comparison with healthy controls and in relation to maternal psychophysical condition. METHODS: Twenty-one offspring aged 8-17 of 17 women with lupus and 34 controls were recruited. Pregnancy conditions, stress factors, and immunological, psychopathological, and neuropsychological characteristics were compared. Immunological tests included standard lupus screening, lupus-related autoantibodies, antibodies against GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR) (anti-DWEYS Ab), and levels of ten cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GMCSF, IFN-γ, TNF-α). RESULTS: Offspring had lower leukocyte count (p = 0.001) and higher levels of anti-dsDNA Ab (p = 0.022), anti-DWEYS-GluN2 Ab (p < 0.001), and eight cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α-all p < 0.001-and IFN-γ, p = 0.026) than controls. Their cytokine levels did not differ from their mothers'; 23.9% of offspring met the criteria for a clinical psychiatric diagnosis. No differences were found in intelligence measures. Various neuropsychological scores correlated inversely with maternal psychophysical health. CONCLUSIONS: Offspring's profile suggests proinflammatory and autoimmune activation. Their rate of psychiatric diagnosis appears higher than in the general population, and their cognitive performance is related to maternal psychophysical health. Longitudinal research might investigate whether immunological and psychosocial conditions influence psychopathology and cognition. Graphical abstract The hypothesized sequence for physical and neuropsychological development for the SLE offspring.