Inhibition of Arenaviruses by Combinations of Orally Available Approved Drugs.

Neglected diseases caused by arenaviruses such as Lassa virus (LASV) and filoviruses like Ebola virus (EBOV) primarily afflict resource-limited countries, where antiviral drug development is often minimal. Previous studies have shown that many approved drugs developed for other clinical indications inhibit EBOV and LASV and that combinations of these drugs provide synergistic suppression of EBOV, often by blocking discrete steps in virus entry. We hypothesize that repurposing of combinations of orally administered approved drugs provides effective suppression of arenaviruses. In this report, we demonstrate that arbidol, an approved influenza antiviral previously shown to inhibit EBOV, LASV, and many other viruses, inhibits murine leukemia virus (MLV) reporter viruses pseudotyped with the fusion glycoproteins (GPs) of other arenaviruses (Junin virus [JUNV], lymphocytic choriomeningitis virus [LCMV], and Pichinde virus [PICV]). Arbidol and other approved drugs, including aripiprazole, amodiaquine, sertraline, and niclosamide, also inhibit infection of cells by infectious PICV, and arbidol, sertraline, and niclosamide inhibit infectious LASV. Combining arbidol with aripiprazole or sertraline results in the synergistic suppression of LASV and JUNV GP-bearing pseudoviruses. This proof-of-concept study shows that arenavirus infection in vitro can be synergistically inhibited by combinations of approved drugs. This approach may lead to a proactive strategy with which to prepare for and control known and new arenavirus outbreaks.

Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma.

ABSTRACT: More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1-associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities. Patients who started durvalumab before JCAR014 infusion had later onset and shorter duration of cytokine release syndrome and inferior efficacy, which was associated with slower accumulation of CAR T cells and lower concentrations of inflammatory cytokines in the blood. Initiation of durvalumab before JCAR014 infusion resulted in an early increase in soluble PD-L1 (sPD-L1) levels that coincided with the timing of maximal CAR T-cell accumulation in the blood. In vitro, sPD-L1 induced dose-dependent suppression of CAR T-cell effector function, which could contribute to inferior efficacy observed in patients who received durvalumab before JCAR014. Despite the lack of efficacy improvement and similar CAR T-cell kinetics early after infusion, ongoing durvalumab therapy after JCAR014 was associated with re-expansion of CAR T cells in the blood, late regression of CD19+ and CD19- tumors, and enhanced duration of response. Our results indicate that the timing of initiation of PD-L1 blockade is a key variable that affects outcomes after CD19 CAR T-cell immunotherapy for adults with LBCL.