Viewing the immune checkpoint VISTA: landscape and outcomes across cancers.

BACKGROUND: Optimizing immune checkpoint inhibitor (ICI) therapy may require identification of co-targetable checkpoint pathways via immune profiling. Herein, we analyzed the transcriptomic expression and clinical correlates of V-domain immunoglobulin suppressor of T-cell activation (VISTA), a promising targetable checkpoint. PATIENTS AND METHODS: RNA sequencing was carried out on 514 tissues reflecting diverse advanced/metastatic cancers. Expression of eight immune checkpoint markers [lymphocyte-activation gene 3 (LAG-3), tumor necrosis factor receptor superfamily 14 (TNFRSF14), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), programmed death-ligand 2 (PD-L2), B- and T-lymphocyte attenuator (BTLA), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), cytotoxic T-lymphocyte antigen 4 (CTLA-4)], in addition to VISTA, was analyzed, along with clinical outcomes. RESULTS: High VISTA RNA expression was observed in 32% of tumors (66/514) and was the most common highly expressed checkpoint among the nine assessed. High VISTA expression was independently correlated with high BTLA, TIM-3, and TNFRSF14, and with a diagnosis of pancreatic, small intestine, and stomach cancer. VISTA transcript levels did not correlate with overall survival (OS) from metastatic/advanced disease in the pan-cancer cohort or with immunotherapy outcome (progression-free survival and OS from the start of ICI) in 217 ICI-treated patients. However, in ICI-treated pancreatic cancer patients (n = 16), median OS was significantly shorter (from immunotherapy initiation) for the high- versus not-high-VISTA groups (0.28 versus 1.21 years) (P = 0.047); in contrast, VISTA levels were not correlated with OS in 36 pancreatic cancer patients who did not receive ICI. CONCLUSION: High VISTA expression correlates with high BTLA, TIM-3, and TNFRSF14 checkpoint-related molecules and with poorer post-immunotherapy survival in pancreatic cancer, consistent with prior literature indicating that VISTA is prominently expressed on CD68+ macrophages in pancreatic cancers and requiring validation in larger prospective studies. Immunomic analysis may be important for individualized precision immunotherapy.

Advanced basal cell cancer: concise review of molecular characteristics and novel targeted and immune therapeutics.

Metastatic basal cell carcinoma is an ultra-rare manifestation of a common disease, appearing in 0.0028%-0.5% of basal cell carcinomas. Initial therapeutic efforts focused on cytotoxic chemotherapy administration. However, it is now known that the Hedgehog signaling pathway is crucial for basal cell proliferation and Hedgehog pathway mutations may lead to tumorigenesis; thus, small-molecule inhibitors of alterations in the components of this pathway, including smoothened (SMO) and GLI, have been the focus of recent therapeutic developments. Indeed, the European Medicines Agency and the Food and Drug Administration have approved the SMO inhibitors, vismodegib and sonidegib, with additional GLI inhibitors currently in clinical trials. Molecular profiling of these tumors has revealed other potential targets for therapy, including high tumor mutational burden and PD-L1 amplification, which predict response to immune checkpoint blockade (PD-1 and PD-L1 inhibitors). An illustrative patient with a giant, advanced, unresectable basal cell carcinoma who obtained an ongoing complete remission after treatment with a combination of an immune checkpoint inhibitor (due to the tumor's high mutational burden) and the Hedgehog inhibitor vismodegib is described. A fuller understanding of the genomic portfolio of these patients can assist in developing novel, rational therapeutic approaches that should continue to improve responses and outcomes.

Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band-based dosing.

Improved antiretroviral therapies are needed for the treatment of HIV-infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV-infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.

Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults.

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.