RESUMO
Adoptive T cell therapy has emerged as a powerful strategy to treat human cancers especially haematological malignancies. Extension of these therapies to solid cancers remains a significant challenge especially in the context of defining immunological correlates of clinical responses. Here we describe results from a clinical study investigating autologous Epstein-Barr virus (EBV)-specific T cells generated using a novel AdE1-LMPpoly vector to treat patients with nasopharyngeal carcinoma (NPC) either pre-emptively in at-risk patients with no or minimal residual disease (N/MRD) or therapeutically in patients with active recurrent/metastatic disease (ARMD). Tolerability, safety and efficacy, including progression-free survival (PFS) and overall survival (OS), were evaluated following adoptive T-cell immunotherapy. Twenty-nine patients, including 20 with ARMD and nine with N/MRD, successfully completed T-cell therapy. After a median follow-up of 18.5 months, the median PFS was 5.5 months (95% CI 2.1 to 9.0 months) and the median OS was 38.1 months (95% CI 17.2 months to not reached). Post-immunotherapy analyses revealed that disease stabilization in ARMD patients was significantly associated with the functional and phenotypic composition of in vitro-expanded T cell immunotherapy. These included a higher proportion of effector CD8+ T-cells and an increased number of EBV-specific T-cells with broader antigen specificity. These observations indicate that adoptive immunotherapy with AdE1-LMPpoly-expanded T cells stabilizes relapsed, refractory NPC without significant toxicity. Promising clinical outcomes in N/MRD patients further suggest a potential role for this approach as a consolidation treatment following first-line chemotherapy.
RESUMO
BACKGROUND: Independent risk factors associated with hepatitis B (HBV)-related hepatocellular carcinoma (HCC) after resection remains unknown. An accurate risk score for HCC recurrence is lacking. METHODS: We prospectively followed up 200 patients who underwent liver resection for HBV-related HCC for at least 2 years. Demographic, biochemical, tumor, virological and anti-viral treatment factors were analyzed to identify independent risk factors associated with recurrence after resection and a risk score for HCC recurrence formulated. RESULTS: Two hundred patients (80% male) who underwent liver resection for HBV-related HCC were recruited. The median time of recurrence was 184 weeks (IQR 52-207 weeks) for the entire cohort and 100 patients (50%) developed HCC recurrence. Stepwise Cox regression analysis identified that one-month post resection HBV DNA >20,000 IU/mL (p = 0.019; relative risk (RR) 1.67; 95% confidence interval (C.I.): 1.09-2.57), the presence of lymphovascular permeation (p<0.001; RR 2.69; 95% C.I.: 1.75-4.12), microsatellite lesions (p<0.001; RR 2.86; 95% C.I.: 1.82-4.51), and AFP >100ng/mL before resection (p = 0.021; RR 1.63; 95% C.I.: 1.08-2.47) were independently associated with HCC recurrence. Antiviral treatment before resection (p = 0.024; RR 0.1; 95% C.I.: 0.01-0.74) was independently associated with reduced risk of HCC recurrence. A post-resection independent predictive score (PRIPS) was derived and validated with sensitivity of 75.3% and 60.6% and specificity of 55.7% and 79.2%, to predict the 1- and 3-year risks for the HCC recurrence respectively with the hazard ratio of 2.71 (95% C.I.: 2.12-3.48; p<0.001). The AUC for the 1- and 3-year prediction were 0.675 (95% C.I.: 0.6-0.78) and 0.746 (95% C.I.: 0.69-0.82) respectively. CONCLUSION: Several tumor, virological and biochemical factors were associated with a higher cumulative risk of HCC recurrence after resection. PRIPS was derived for more accurate risk assessment. Regardless of the HBV DNA level, antiviral treatment should be given to patients before resection to reduce the risk of recurrence.