Experiences and perspectives on chimeric antigen receptor (CAR) T-cell therapy among recipients, carers and referrers (RE-TELL): a qualitative study to inform CAR T-cell service design.

OBJECTIVES: RE-TELL is a qualitative study, which aims to understand patient, support person, clinician and coordinator experiences and perspectives of chimeric antigen receptor (CAR) T-cell therapy, to inform design of a clinical CAR T-cell service in Aotearoa New Zealand. DESIGN: Semistructured qualitative interviews focused on domains of: experience through treatment, elements that work well and those that could be improved on. Interviews used thematic analysis to identify key themes. A workshop was held to obtain participants' reflections on interim analysis and proposed improvements. PARTICIPANTS: New Zealanders with experience of CAR T-cell therapy, including recipients, support persons, clinicians and coordinators. RESULTS: We interviewed 19 participants comprising 5 CAR T-cell recipients, 3 support persons, 6 clinicians and 5 coordinators. Four participants identified as Maori. Thematic analysis identified three global themes. The first, 'sociocultural factors impact CAR T access', identified potential sources of inequity including geographic, financial and informed consent barriers. The second, 'varying emotions, roles and enablers', identified an easier treatment experience compared with alternatives; an underwhelming cell administration process; frustration with inpatient monitoring; burden on support persons and importance of 'bridge' organisations such as charities and patient support groups. Lastly, 'golden opportunities: reimagining CAR T service delivery', suggested: improved geographical access to CAR T-cell therapy, while retaining consolidated clinician experience; a 'dashboard' with information on CAR T-cell treatment, time frames and manufacture; a health navigator to co-ordinate non-medical aspects of treatment and signpost care; embedding of indigenous data sovereignty and ownership of cells; a cell infusion ceremony, incorporating family involvement and Maori cultural elements and outpatient administration and monitoring where possible. CONCLUSION: This study documented the current experience of New Zealanders receiving CAR T-cell therapy and identified opportunities for future service development. These insights are relevant to service design within Aotearoa New Zealand, and other countries developing equitable CAR T-cell services.

The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition.

OBJECTIVE: The minor allele (A) of the rs373863828 variant (p.Arg457Gln) in CREBRF is restricted to indigenous peoples of the Pacific islands (including New Zealand Maori and peoples of Polynesia), with a frequency of up to 25% in these populations. This allele associates with a large increase in body mass index (BMI) but with significantly lower risk of type-2 diabetes (T2D). It remains unclear whether the increased BMI is driven by increased adiposity or by increased lean mass. METHODS: We undertook body composition analysis using DXA in 189 young men of Maori and Pacific descent living in Aotearoa New Zealand. Further investigation was carried out in two orthologous Arg458Gln knockin mouse models on FVB/NJ and C57BL/6j backgrounds. RESULTS: The rs373863828 A allele was associated with lower fat mass when adjusted for BMI (p < 0.05) and was associated with significantly lower circulating levels of the muscle inhibitory hormone myostatin (p < 0.05). Supporting the human data, significant reductions in adipose tissue mass were observed in the knockin mice. This was more significant in older mice in both backgrounds and appeared to be the result of reduced age-associated increases in fat mass. The older male knockin mice on C57BL/6j background also had increased grip strength (p < 0.01) and lower levels of myostatin (p < 0.05). CONCLUSION: Overall, these results prove that the rs373863828 A-allele is associated with a reduction of myostatin levels which likely contribute to an age-dependent lowering of fat mass, at least in males.

The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Maori and Pacific ancestry.

AIMS/HYPOTHESIS: The minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased BMI, but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Maori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes. METHODS: A mixed meal tolerance test was completed by 172 men (56 with the A allele) of Maori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled IVGTT and hyperinsulinaemic-euglycaemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation. RESULTS: The A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins glucagon-like polypeptide-1 or gastric inhibitory polypeptide. Consistent with this point, following an i.v. infusion of a glucose bolus, participants with an A allele had higher early (p < 0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p > 0.05) in insulin sensitivity index or glucose disposal during hyperinsulinaemic-euglycaemic clamp. CONCLUSIONS/INTERPRETATION: rs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase insulin release to reduce the risk of type 2 diabetes.