Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR

CAR T cells recognizing CD19 effectively treat relapsed and refractory B-ALL and DLBCL. However, CD19 loss is a frequent cause of relapse. Simultaneously targeting a second antigen, CD22, may decrease antigen escape, but is challenging: its density is approximately 10-fold less than CD19, and its large structure may hamper immune synapse formation. The characteristics of the optimal CD22 CAR are underexplored. We generated 12 distinct CD22 antibodies and tested CARs derived from them to identify a CAR based on the novel 9A8 antibody, which was sensitive to low CD22 density and lacked tonic signaling. We found no correlation between affinity or membrane proximity of recognition epitope within Ig domains 3–6 of CD22 with CART function. The optimal strategy for CD19/CD22 CART co-targeting is undetermined. Co-administration of CD19 and CD22 CARs is costly; single CARs targeting CD19 and CD22 are challenging to construct. The co-expression of two CARs has previously been achieved using bicistronic vectors. Here, we generated a dual CART product by co-transduction with 9A8-41BBζ and CAT-41BBζ (obe-cel), the previously described CD19 CAR. CAT/9A8 CART eliminated single- and double-positive target cells in vitro and eliminated CD19- tumors in vivo. CAT/9A8 CART is being tested in a phase I clinical study (NCT02443831)

Development of delivery indicators and delivery enablers for cardiovascular disease in the UK: a modified Delphi study

Introduction Standards to define and measure quality in healthcare for cardiovascular disease risk reduction and secondary prevention are available, but there is a paucity of indicators that could serve as facilitators of structural change at a system level. This research study aimed to develop a range of delivery indicators to help cardiac clinical networks assess delivery of and progress towards cardiovascular disease objectives. Methods This study used an adapted version of the European Society of Cardiology’s four-step process for the development of quality indicators. The four steps in this study were as follows: identify critical factors of enablement, construct a list of candidate indicators, select a final set of indicators and assess availability of national data for each indicator. In this iterative process, a core project group of six members was supported by a wider review group of 21 people from the National Health Service (NHS) clinical and management personnel database. Results The core project group identified six relevant cardiovascular disease priorities in the NHS Long Term Plan and used an iterative process to identify 21 critical factors that impact on their implementation. A total of 57 potential indicators that could be measures of implementation were developed. The core project group agreed on a set of 38 candidate indicators that were circulated to the review group for rating. Based on these scores, the core project group excluded 5 indicators to arrive at a final set of 33 delivery indicators. National datasets were available for 22 of the final indicators, which were designated as delivery indicators. The remaining 11, for which national datasets were not available but locally available datasets could be used, were designated as delivery enablers. Conclusion The suite of delivery indicators and delivery enablers for cardiovascular disease could allow a more focused evaluation of factors that impact on delivery of healthcare for cardiovascular disease