Summary Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs.

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Background Chronic disease is a significant burden on the global population. The Helping Everyone Achieve Long Term Health (HEALTH) Passport is a paper-based approach previously utilized to help adults modify clinical risk factors through lifestyle, which may be effective in improving the long-term health of school-age children. This study investigates the feasibility of in-school use by engaging trainee teachers in primary and secondary education. Methods Two hundred and fifty six unique responses were collated to evaluate current teaching of the main health risk factors and HEALTH Passports specifically adapted for schools. Trainees attended workshops with pre- and post-questionnaires used to measure training efficacy and evaluate the Passports’ suitability for in-school use. Narrative analysis of feedback was performed. Results Feedback received for both Passports was positive overall. Trainees highlighted the need for the Passports to be further age differentiated. Significantly increased confidence (P < 0.01) in knowledge of exercise, type 2 diabetes, weight and blood pressure was shown. Confidence in smoking, drugs and alcohol knowledge was reduced highlighting the requirement for further teacher training. Conclusions The HEALTH Passport has potential as an intervention to improve health literacy in school-age children. Age adaptation is needed with references to weight measures removed. Emotional well-being should be focused on, and data management stringently assessed for child protection.

This book contains the abstracts of the papers presented at The 3rd Annual Graduate Entry Research in Medicine Conference (GERMCON 2020) Organized by Warwick Medical School, University of Warwick in collaboration with Swansea University Medical School, Swansea University, Wales, UK held on 12–18 October 2020. This was especially important for Graduate Entry Medical (GEM) students, who have less opportunity and time to engage in research due to their accelerated medical degree.