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Abstract Background High-affinity tumor antigen-specific T-cell receptor (TCR) gene is required to engineer potent T cells for therapeutic treatment of cancer patients. However, discovery of suitable therapeutic TCR genes is hampered by the fact that naturally occurring tumor antigen-specific TCRs are generally of low-affinity, and artificial modification of TCRs can mediate cross-reactivity to other antigens expressed in normal tissues. Here, we discovered a naturally occurring T-cell clone which expressed high-affinity HLA-A*02:01 (A*02)-restricted TCR against NY-ESO-1 from a patient who had NY-ESO-1-expressing ovarian tumor. Methods A*02-restricted NY-ESO-1-specific T-cell clones were established from peripheral blood of patients who had NY-ESO-1-expressing ovarian tumors. TCR α and β chain genes were retrovirally transduced into polyclonally activated T cells. Phenotype and function of the parental and TCR-transduced T cells were analyzed by flow cytometry, ELISA and cytotoxicity assay. In vivo therapeutic efficacy was investigated in a xenograft model using NOD/SCID/IL-2Rγ-deficient (NSG) mice. Results A rare population of NY-ESO-1-specific T cells, which we named 19305DP, expressed cell surface CD4, CD8α, and CD8β but not CD56 and recognized A*02+NY-ESO-1+ cancer cell lines in a CD4- and CD8-independent manner. 19305DP showed a gene expression profile that is consistent with a mixed profile of CD4+ and CD8+ single-positive T cells. Both CD4+ and CD8+ T cells that were retrovirally transduced with 19305DP-derived TCR gene (19305DP-TCR) showed strong reactivity against A*02+NY-ESO-1+ cancer cells, whereas TCR genes from the conventional A*02-restricted NY-ESO-1-specific CD8+ single-positive T-cell clones functioned only in CD8+ T cells. Both 19305DP-TCR gene-engineered CD4+ and CD8+ T cells eliminated A*02+NY-ESO-1+ tumor xenografts in NSG mice. Finally, based on reactivity against a series of alanine-substituted peptides and a panel of normal human tissue-derived primary cells, 19305DP-TCR was predicted to have no cross-reactivity against any human non-NY-ESO-1 proteins. Conclusion Together, our results indicate that the naturally occurring 19305DP-TCR derived from CD4+CD8+ double-positive αβ T cells, is a promising therapeutic TCR gene for effective and safe adoptive T-cell therapy in A*02+ patients with NY-ESO-1-expressing tumor.

Background and Aims: Inadequate reporting of smoking cessation intervention trials is common and leads to significant challenges for researchers. The aim of this study was to tailor CONSORT (Consolidated Standards of Reporting Trials)‐SPI (Social and Psychological Interventions) guidelines to improve reporting of trials of behavioural interventions to promote smoking cessation. Method: Informed by missing data from the IC‐SMOKE (Intervention and Comparison group support provided in SMOKing cEssation) systematic review project, this study used a multi‐stage Delphi process to examine which items could be added or modified to improve the reporting of smoking cessation trials. The first stage involved an on‐line survey of 17 international experts in smoking cessation and trial methodology voting on the importance of items for inclusion in the updated guidelines. This was followed by a face‐to‐face expert consensus meeting attended by 15 of these experts, where the final inclusion and exclusion of new items and modifications were agreed upon. A nine‐point Likert scale was used to establish consensus, with suggested modifications requiring agreement of 75% or more. Disagreements in the first stage were presented again at the second stage for discussion and a second round of voting. Only items which reached the threshold for agreement were included. Results: The experts agreed on the inclusion of 10 new items and the specification of 12 existing items. This included modifications that could apply to trials more widely (e.g. the rationale for the comparator), but also modifications that were very specific to smoking cessation trials (e.g. the reporting of smoking cessation outcomes). Conclusions: A Delphi study has developed a modified CONSORT‐SPI guideline (CONSORT‐SPI‐SMOKE) to improve the reporting of trials of behavioural interventions to promote smoking cessation. [ABSTRACT FROM AUTHOR]

Introduction: This study estimates the extent to which individuals' smoking cessation and relapse patterns are associated with the smoking behaviour of their household members.Methods: Longitudinal data on household members' smoking behaviour was sourced from a representative sample of 12,723 Australians who ever reported smoking between 2001 and 2019. Controlling for a rich set of confounders, multivariate regression analyses were used to predict the likelihood of smoking cessation and relapse given other household members' smoking status and their relationship type. The models were then used to forecast smoking prevalence over ten years across different household types.Results: Individuals living with a smoking spouse were less likely to quit [OR0.77 (95%CI 0.72;0.83)] and more likely to relapse [OR1.47 (95%CI 1.28;1.69)] compared to those living with non-smoking spouses. Subsequently, the proportion of smokers living with other smoking household members increased by 15% between 2011 and 2019. A ten-year forecast using the smoking cessation and relapse models predicts that, on average, smokers living with non-smokers will reduce by 43%, while those living alone or with a smoking partner will only reduce by 26% and 28% respectively.Conclusions: Over time, those who are still smoking are more likely to live with other smokers. Therefore, the current cohort of smokers are increasingly less likely to quit and more likely to relapse. Smoking projection models that fail to account for this dynamic risk may overstate the downstream health benefits and health cost savings. Interventions which encourage smoking cessation at the household level, particularly for spouses, may assist individuals to quit and abstain from smoking.Implications: The current and future paradigm shift in the smoking environment suggests that smoking cessation and relapse prevention policies should consider household structure. Policies designed to affect smoking at the household level are likely to be particularly effective. When estimating the long-term benefits of current smoking policies intrahousehold smoking behaviour needs to be considered. [ABSTRACT FROM AUTHOR]

Introduction: Aboriginal clients accessing Aboriginal community‐controlled residential alcohol and other drug rehabilitation services in New South Wales, Australia believe they have better outcomes due to culturally appropriate care. However, there is a paucity of published treatment outcome data. This study aims to identify predictors of treatment outcomes based on client characteristics at intake. Methods: A cross‐sectional, retrospective, observational study of 2326 admissions to six services between January 2011 and December 2016. The outcomes were: (i) leaving treatment early; (ii) self‐discharge or house discharge (by staff); and (iii) re‐admission within two years. The predictors examined were Aboriginal status, age, justice system referral and primary substance of concern. Competing risk and Poisson regression analyses were used to identify trends in the data. Results: The mean age of clients was 33 years, and the majority (56%) stayed at least 6 weeks. Aboriginal clients whose primary substance of concern was stimulants were almost eight times more likely to re‐admitted within 2 years than other clients (risk ratio 7.91; P < 0.001). Aboriginal clients who were also referred from justice were more likely to self‐discharge (risk ratio 1.87; P < 0.001). Furthermore, Aboriginal clients who were aged older than 30 were less likely to have a re‐admission (risk ratio 0.32; P ≤ 0.001). Discussion and Conclusions: This study showed client characteristics that are predictive of harmful outcomes include age under 30, justice client, primary substance of use and their interactions. Future research could build on these results to aid ongoing development of residential rehabilitation programs for Aboriginal peoples. [ABSTRACT FROM AUTHOR]