γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma.

B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.

Vaccination with nanoparticles displaying gH/gL from Epstein-Barr virus elicits limited cross-protection against rhesus lymphocryptovirus.

Epstein-Barr virus (EBV) is associated with infectious mononucleosis, cancer, and multiple sclerosis. A vaccine that prevents infection and/or EBV-associated morbidity is an unmet need. The viral gH/gL glycoprotein complex is essential for infectivity, making it an attractive vaccine target. Here, we evaluate the immunogenicity of a gH/gL nanoparticle vaccine adjuvanted with the Sigma Adjuvant System (SAS) or a saponin/monophosphoryl lipid A nanoparticle (SMNP) in rhesus macaques. Formulation with SMNP elicits higher titers of neutralizing antibodies and more vaccine-specific CD4+ T cells. All but one animal in the SMNP group were infected after oral challenge with the EBV ortholog rhesus lymphocryptovirus (rhLCV). Their immune plasma had a 10- to 100-fold lower reactivity against rhLCV gH/gL compared to EBV gH/gL. Anti-EBV neutralizing monoclonal antibodies showed reduced binding to rhLCV gH/gL, demonstrating that EBV gH/gL neutralizing epitopes are poorly conserved on rhLCV gH/gL. Prevention of rhLCV infection despite antigenic disparity supports clinical development of gH/gL nanoparticle vaccines against EBV.

From menorrhagia to manometers.

We present a case that illustrates the challenges in making a unifying diagnosis and bringing together symptoms which, at first, seem unrelated. We aim to illustrate the process of decision-making and the practice of working along several parallel processes to reach a single explanation for a child to present unwell.

Ophthalmological Care of Patients With Craniofacial Disorders.

Patients presenting with craniofacial conditions present a unique challenge from an ophthalmological view point. There are no set guidelines as to their management or their long-term monitoring and follow-up. Largely, this should be the remit of a dedicated craniofacial team. Here we present pertinent ophthalmological pathology occurring in combination with craniosynostosis alongside the protocol employed in Birmingham Children's Hospital for the management of these patients.

Trabeculectomy or Transscleral Cyclophotocoagulation as Initial Treatment of Secondary Childhood Glaucoma in Northern Tanzania.

PURPOSE: The purpose is to describe the outcome of trabeculectomy with transscleral cyclophotocoagulation (TSCPC) as an initial intervention for secondary childhood glaucoma in Northern Tanzania. METHODS: A retrospective, consecutive case series was analyzed of all children with secondary childhood glaucoma who underwent initial trabeculectomy or TSCPC between 2000 and 2013 at a referral eye unit in Northern Tanzania. Retrospective data were collected on causes of glaucoma, intraocular pressure (IOP), visual acuity, complications, and subsequent interventions. Outcomes were evaluated using Kaplan-Meier survival analysis and compared with Cox regression analysis. The main outcome measure was failure (IOP>21 mm Hg). RESULTS: Thirty-six eyes of 27 children (male, 21; median age, 9 y; range, 0.3 to 15 y) with secondary childhood glaucoma underwent trabeculectomy (19 eyes, 53%) or TSCPC (17 eyes, 47%). Causes included ocular trauma (13, 36%), previous cataract surgery (12, 33%), congenital aniridia (5, 14%), Sturge-Weber syndrome (2, 6%), steroid-induced glaucoma (2, 6%), uveitis (1, 3%), and unspecified leucoma (1, 3%). After 12 months, success was achieved in 48% after trabeculectomy and 18% after TSCPC, with visual acuity remaining unchanged in 11 of 14 (79%) and 4 of 5 eyes (80%), respectively. One third of the children did not return for follow-up after 1 year. Distance to the hospital (>100 km) was a significant risk factor for trabeculectomy failure (P=0.031). CONCLUSIONS: A high proportion of secondary childhood glaucoma in Northern Tanzania was caused by trauma and previous cataract surgery. Trabeculectomy was associated with better IOP control but also a higher complication rate. The ability to maintain visual function was comparable after both interventions. Failure was associated with a journey to the eye hospital (>100 km) possibly leading to late presentation with advanced disease and erratic follow-up.