A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers.

B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role as a driver of tumor immune inhibition. Recent studies have reported B7-H3 to be a suitable target for chimeric antigen receptor-modified T cell (CAR-T) therapy using CARs constructed from established anti-B7-H3 antibodies converted into single-chain Fv format (scFv). We constructed and screened binders in an scFv library to generate a new anti-B7-H3 CAR-T with favorable properties. This allowed access to numerous specificities ready formatted for CAR evaluation. Selected anti-human B7-H3 scFvs were readily cloned into CAR-T and evaluated for anti-tumor reactivity in cytotoxicity, cytokine, and proliferation assays. Two binders with divergent complementarity determining regions were found to show optimal antigen-specific cytotoxicity and cytokine secretion. One binder in second-generation CD28-CD3ζ CAR format induced sustained in vitro proliferation on repeat antigen challenge. The lead candidate CAR-T also demonstrated in vivo activity in a resistant neuroblastoma model. An empirical approach to B7-H3 CAR-T discovery through screening of novel scFv sequences in CAR-T format has led to the identification of a new construct with sustained proliferative capacity warranting further evaluation.

Diagnosis and management of the postoperative surgical and medical complications of bariatric surgery.

Perioperative complications following bariatric surgery (BS) have been poorly analysed and their management is not clearly assessed. The associated frequency of ICU admission is difficult to estimate. Among surgical complications, digestive perforations are the most frequent. The most common postoperative complications of sleeve gastrectomy are fistulas, but bleeding on the stapling line is also commonly reported. Complication rates are higher after Roux-en-Y gastric bypass, mainly due to anastomotic leaks. Medical complications are mainly thromboembolic or respiratory complications. All these surgical and medical complications are not easily detected; clinical signs can be atypical or insidious, often resulting in delayed management. Respiratory signs can be predominant and lead erroneously to pulmonary or thromboembolic diseases. Diagnostic criteria are based on minor clinical signs, tachycardia being probably the most frequent one. Lately, complications are revealed by haemodynamic instability, respiratory failure or renal dysfunction and radiographic findings. Management decision according to these abnormal signs is based on a combined multidisciplanary approach including surgical and/or endoscopic procedures and medical care, depending on the nature and severity of the surgical complication. Medical management is based on supportive ICU care of organ dysfunctions, curative anticoagulation if required, nutritional support, and appropriate anti-infective therapy. Pharmacological data are limited in morbidly obese patients and the appropriate doses are debated, especially for anti-infective agents. Complicated BS cases have a poor outcome, probably largely related to delayed diagnosis and reoperation.