RESUMO
Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805 .
Assuntos
Antígenos de Neoplasias , Proteínas Ligadas por GPI , Imunoterapia Adotiva , Proteínas de Neoplasias , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Pessoa de Meia-Idade , Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Proteínas Ligadas por GPI/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Metástase Neoplásica , Linfócitos T/imunologia , Linfócitos T/transplante , Antígeno Prostático Específico/sangueRESUMO
To understand use of tuberculosis (TB) services for migrant workers, we conducted a cross-sectional census of 95 migrant workers with TB from Armenia by using medical record reviews and face-to-face interviews. Prolonged time between diagnosis and treatment, treatment interruption, and treatment defaults caused by migrant work might increase the risk for multidrug-resistant TB.