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Work conditions and major life events can impact individual sleep quality, and subsequently impact mental health. This study aims to investigate effect of sleep quality on mental health of working Australians. We pioneer to employ a novel method in public health studies, a quasi-experimental (Instrumental Variable) approach, which can address reciprocal relationships between sleep and mental health in order to estimate causal effect of sleep quality on mental health on a sample of 14,480 working Australians aged 25-64 from the Household, Income and Labour Dynamics in Australia (HILDA) survey waves 2013 and 2017. We find that work conditions such as high job demand, long workhours, long unpaid workhours, shift work, and major life events adversely affect sleep quality, and hence the changes in sleep quality strongly affect mental health of working Australians. The finding underscores the need for policies that should address current employment conditions by reducing long workhours, high work demand, irregular work shifts, and providing better support including emotional support programs, and creating worker-friendly settings to mitigate poor sleep quality in the Australian workforce. Doing so would help improve workers’ sleep quality, and ultimately mental health and overall health outcomes.

Using the RIF-decomposition to explore changes in wage inequality during the economic transformation in Vietnam, we find that real wages increased substantially during the period 1998-2010, but wage growth slowed down in the following period 2010-2020. Wage inequality increased in the former period, but declined considerably in the later one. Overall changes in wage inequality over the former period was mainly contributed by changes in labor market, job and workers’ observed characteristics, but in the later period the change was mainly contributed by the changes in returns to job and workers’ observed characteristics (wage structure effect). The economic structure change and increased supply of higher educated workforce have substantially contributed to the changing wage inequality over the past two decades. A rapid increase in supply of higher educated workers in the later stage of economic transformation has resulted in declining returns to education and thus has contributed to a decline in wage inequality.

Experiencing poor sleep quality affects an individual’s health and wellbeing. Sleep quality may be influenced by work conditions, with working under high intensity a possible contributor. Using data from the Household, Income and Labour Dynamics in Australia (HILDA) survey waves 2013 and 2017, this study investigates whether experiencing poor sleep quality is associated with work intensity. This study uses a nationally representative sample of working Australian individuals aged 25–64 from the HILDA survey and finds a strong positive association between work intensity and sleep quality, with an individual’s sleep quality worsening as their work intensity increased. The association between work intensity and sleep quality is even stronger than that between long work hours and sleep quality.

There is increasing interest in targeting CD33 in malignant and non-malignant disorders. In acute myeloid leukemia, longer survival with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this strategy. Still, GO benefits only some patients, prompting efforts to develop more potent CD33-directed therapeutics. As one limitation, CD33 antibodies typically recognize the membrane-distal V-set domain. Using various artificial CD33 proteins, in which this domain was differentially positioned within the extracellular portion of the molecule, we tested whether targeting membrane-proximal targeting epitopes enhances the effector functions of CD33 antibody-based therapeutics. Consistent with this idea, a CD33V-set/CD3 bispecific antibody (BsAb) and CD33V-set-directed chimeric antigen receptor (CAR)-modified T cells elicited substantially greater cytotoxicity against cells expressing a CD33 variant lacking the entire C2-set domain than cells expressing full-length CD33, whereas cytotoxic effects induced by GO were independent of the position of the V-set domain. We therefore raised murine and human antibodies against the C2-set domain of human CD33 and identified antibodies that bound CD33 regardless of the presence/absence of the V-set domain (“CD33PAN antibodies”). These antibodies internalized when bound to CD33 and, as CD33PAN/CD3 BsAb, had potent cytolytic effects against CD33+ cells. Together, our data provide rationale for further development of CD33PAN antibody-based therapeutics.

Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) and Rosetta protein modeling software for structural prediction of 4298 CDP scaffolds and performed in silico prescreening for CDP binders to targets of interest. Mammalian display screening of a library of docking-enriched, methionine and tyrosine scanned (DEMYS) CDPs against PD-L1 yielded binders from four distinct CDP scaffolds. One was affinity-matured, and cocrystallography yielded a high-affinity ( K D = 202 pM) PD-L1–binding CDP that competes with PD-1 for PD-L1 binding. Its subsequent incorporation into a CD3-binding bispecific T cell engager produced a molecule with pM-range in vitro T cell killing potency and which substantially extends survival in two different xenograft tumor-bearing mouse models. Both in vitro and in vivo, the CDP-incorporating bispecific molecule outperformed a comparator antibody-based molecule. This CDP modeling and DEMYS technique can accelerate CDP therapeutic development.

It is well known that physical and mental health are closely related, with growing evidence for biological and behavioural pathways. Mostly the research has focussed on mental health as the key driver of this inter-connection; the extent physical health shapes mental health has received less attention. We aim to derive robust estimates of the unique role physical health may play in shaping mental health outcomes. To do so we use a novel approach, incorporating longitudinal and instrumental variable methods which can address the reciprocal relationship between physical and mental health, and the endogeneity of physical health, before estimating the physical to mental health pathway. A sample of 209,442 observations (or 24,966 unique individuals) aged 15 and over spanning 18 years (2002–2019) was extracted from the Household Income and Labour Dynamics in Australian Survey (HILDA). We find that physical activity and health shocks erode mental health via their impact on physical health with a one point improvement (or worsening) in physical health scores (0–100) resulting in a rise (or decline) of 0.43 points (or 43%) in mental health score.

Assumptions about time, value, labour, and health coalesce in the policy decision to extend the pension eligibility age in Australia from 65 to 67 years. Acknowledging the multiple, often incompati...

Background The COVID-19 outbreak has spread to almost every country around the world and caused more than 3 million deaths. The pandemic has triggered enormous disruption in people’s daily lives with profound impacts globally. This has also been the case in Australia, despite the country’s comparative low mortality and physical morbidity due to the virus. This scoping review aims to provide a broad summary of the research activity focused on mental health during the first 10 months of the pandemic in Australia. Results A search of the Australian literature was conducted between August-November 2020 to capture published scientific papers, online reports and pre-prints, as well as gaps in research activities. The search identified 228 unique records in total. Twelve general population and 30 subpopulation group studies were included in the review. Conclusions Few studies were able to confidently report changes in mental health driven by the COVID-19 context (at the population or sub-group level) due to a lack of pre-COVID comparative data and non-representative sampling. Never-the-less, in aggregate, the findings show an increase in poor mental health over the early period of 2020. Results suggest that young people, those with pre-existing mental health conditions, and the financially disadvantaged, experienced greater declines in mental health. The need for rapid research appears to have left some groups under-researched (e.g. Culturally and Linguistically Diverse populations and Indigenous peoples were not studied), and some research methods under-employed (e.g. there was a lack of qualitative and mixed-methods studies). There is a need for further reviews as the follow-up results of longitudinal studies emerge and understandings of the impact of the pandemic are refined.

We provide new insights into the relationship between foreign investment and the labour productivity of domestic firms in the Vietnamese manufacturing industry. Using quantile regression analysis of a panel of firm-level data over a 2010–2015 study period, we find that the presence of foreign investment has a positive impact on domestic firm labour productivity through competition effects within the industry at the middle and high quantiles. We do not find significant evidence to support a positive relationship between foreign investment in downstream sectors and domestic firm labour productivity in upstream sectors, however. There are some indications that suggest a positive relationship between foreign suppliers in upstream sectors and labour productivity of domestic buyers in downstream sectors at the low and middle quantiles.

BackgroundAustralians born in 2012 can expect to live about 33 years longer than those born 100 years earlier. However, only seven of these additional years are spent in the workforce. Longer life expectancy has driven policies to extend working life and increase retirement age, the current Australian policy, which has increased the eligibility for the pension from 65 to 67 by 2023, assumes that an improvement in longevity corresponds with an improvement in health expectancy. However, there is mixed evidence of health trends in Australia over the past two decades. Although some health outcomes are improving among older age groups, many are either stable or deteriorating. This raises the question of how health trends intersect with policy for older Australians aged from 50-70. This paper considers the interplay between older workers’ health and workforce participation rates over the past 15 years when extended workforce participation has been actively encouraged. MethodsWe compared health and economic outcomes of the older people in following years with the base year (start of the study period), adjusting for some key socio-economic characteristics such as age, sex, ethnicity, education and equivalized household income by applying the Random effects estimator with maximum likelihood estimation technique.Results We find that regardless of increasing longevity, the health of older adults aged between 50-70 has slightly deteriorated. In addition, health gaps between those who were working into their older age and those who were not have widened over the 15-year period. Finally, we find that widening health gaps linked to workforce participation are also accompanied by rising economic inequality in incomes, financial assets and superannuation. With the exception of a small group of healthy and very wealthy retirees, the majority of the older Australians who were not working had low incomes, assets, superannuation, and poor health.ConclusionsThe widening economic and health gap within older population over time indicates a clear and urgent need to add policy actions on income and health, to those that seek to increase workforce participation among older adults.

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 cytokine release syndrome, 9%; grade ≥3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

This study investigated the role of provincial governance on the growth of per capita income of Vietnamese households, using a balanced panel dataset for the period 2012-2014. Whereas we found no evidence for the influence of provincial governance when a linear fixed-effect regression estimator was used, the results from a fixed-effect quantile regression estimator reveal that provincial governance has a positive effect on several groups (but not the poorest) and the effect tends to be greater for better-off households. In addition, we find that wage employment plays a larger role in the income growth of poorer households, while returns on education are higher for richer households. The findings suggest that a mean regression approach that looks only at the role of explanatory variables on mean household welfare and does not consider differences in the distribution of household welfare, may miss some heterogeneity that is of interest to policy makers.

This study explores the dynamics of income and income inequality in Vietnam from 2004 to 2014. Two main population subgroups are investigated: the ethnic majority, known as the Kinh people, and the minority group, which includes 53 minor ethnicities in Vietnam. The findings show that the income gap among ethnic groups has increased over the last decade. The Gini index decomposition indicates that wages and nonfarm business income are the two main determinants of income inequality. Cultivation and agricultural side-line incomes were relatively evenly distributed, despite their recent smaller equalizing effect. Both sub-population groups have experienced a declining contribution from the agricultural sector to overall household income. Changes in income inequality in Vietnam by income source reflect the change in the structure of the economy from reliance on agriculture to non-agricultural economic activities.

Introduction Lymphodepletion chemotherapy followed by infusion of autologous T cells engineered to express a CD19-targeted chimeric antigen receptor (CAR) has shown high response rates in relapsed or refractory high-risk chronic lymphocytic leukemia (CLL). Durable remissions were observed, particularly in patients (pts) who achieved minimal residual disease (MRD)-negative (neg) complete response (CR) in the marrow with no detectable malignant clone by IGH sequencing. Here, we present long-term outcomes of CLL pts treated with CD19 CAR-T cell immunotherapy, and single-cell cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analyses of infusion products (IPs) to identify intrinsic T cell characteristics associated with outcomes. Methods Pts were treated on a phase 1/2 clinical trial (NCT01865617) of CD19 CAR-T cell immunotherapy in two cohorts: no ibrutinib (ibr) cohort (No-ibr; ibr discontinued prior to leukapheresis or lymphodepletion) or concurrent ibr cohort (Con-ibr; ibr started at least 2 weeks prior to leukapheresis and continued until at least 3 months after CAR-T cell infusion). Responses were evaluated according to the 2018 International Workshop on CLL (iwCLL) criteria (Hallek et al. Blood 2018). MRD in the marrow was assessed 4 weeks after CAR-T cell infusion using flow cytometry (sensitivity, 10 -4) and IGH sequencing (sensitivity, 10 -6). Multiomics profiling was performed on IPs from 25 pts selected based on distribution of ibr washout time before leukapheresis and clinical response (Table 1). All pts received cyclophosphamide and fludarabine lymphodepletion and 2 x 10 6 CAR-T cells/kg. CD3 + CAR-T cells isolated from IPs underwent CITE-seq (10x Genomics), with generation of gene expression, full-length paired V(D)J, and cell surface protein expression libraries. Differential gene expression (DEG) analyses were performed using Model-based Analysis of Single-cell Transcriptomics (MAST). Blood transcriptome modules were used for Gene Set Enrichment Analysis (GSEA). Results Forty-seven pts (median age, 61 years) with CLL (excluding Richter's transformation without coexisting CLL) received lymphodepletion and CD19 CAR-T cell infusion. Among 29 pts with a pretreatment trackable malignant IGH clone who achieved MRD-neg CR by flow cytometry, at a median follow-up of 23.5 months (interquartile range, 11.0-33.8), the median progression-free survival was 8.5 months (95% confidence interval [CI], 2.9-not reached) for those with a detected post-treatment malignant IGH clone in marrow (n = 11) and could not be estimated (95% CI, 22.2-not reached) in those without a detected post-treatment malignant IGH clone (n = 18; P = .0006; Figure 1A). In the pts without a detected malignant IGH clone 4 weeks after infusion, only 3 (17%) relapsed; 1 died of a myocardial infarction while in ongoing response. We performed multiomics studies on IPs from a selected subset (n = 25) of pts (Table 1) to identify gene expression patterns impacting outcomes. GSEA revealed association with T cell activation, oxidative phosphorylation, transcription initiation and cell cycle modules in IPs of pts who did compared to did not achieve MRD-neg CR (Figure 1B, left), consistent with the hypothesis that CAR-T cell quality is a key determinant of depth and duration of remission in CLL. IPs studied in the multiomics subset were manufactured from pts treated in either the No-ibr or the Con-ibr cohort (Table 1) and our prior data showed a trend towards higher rates of IGH-neg CR in the Con-ibr cohort (85 vs 60%, P = .34). Because ibr administration before leukapheresis might improve CAR-T cell quality and function, we compared IPs of patients in the No-Ibr vs. Con-Ibr cohorts. GSEA revealed that the T cell differentiation via ITK and PKC module was less enriched in IPs of pts in the Con-ibr vs. No-ibr cohort (Figure 1B, right), consistent with ibr-induced inhibition of T cell differentiation as a mechanism for enhanced CAR-T cell quality in the IP. Analyses are ongoing and full results will be presented at the meeting. Conclusion Long-term follow-up confirmed that achieving a malignant IGH-neg response after CAR-T cell therapy is associated with durable remissions in high-risk CLL. Integrated multiomics profiling suggests that CAR-T cell IP quality is a key determinant of MRD-neg CR. Ibr-related inhibition of ITK signaling in T cells can further contribute to the quality of infused CAR-T cells. Figure 1 Figure 1. Disclosures Hirayama: Novartis: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Sheih: Umoja Biopharma: Current Employment. Gauthier: Janssen: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Multerra Bio: Consultancy; Larvol: Consultancy; JMP: Consultancy; Eusapharma: Consultancy. Maloney: A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Consultancy; Kite, a Gilead Company, Juno, and Celgene: Research Funding; Juno: Patents & Royalties. Gottardo: Illumina: Consultancy; 10x Genomics: Current holder of stock options in a privately-held company; Ozette Technologies: Current holder of individual stocks in a privately-held company; Modulus Therapeutics: Current holder of individual stocks in a privately-held company. Turtle: PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; AstraZeneca: Consultancy, Research Funding; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Allogene: Consultancy; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board.

Background: There is increasing interest in targeting CD33 in malignant and non-malignant disorders, but available drugs are ineffective in many patients. As one limitation, therapeutic CD33 antibodies typically recognize the membrane-distal V-set domain. Likewise, currently tested CD33-directed chimeric antigen receptor (CAR) T cells likewise target the V-set domain and have thus far shown limited clinical activity. We have recently demonstrated that binding closer to the cell membrane enhances the effector functions of CD33 antibodies. We therefore raised antibodies against the membrane-proximal C2-set domain of CD33 and identified antibodies that bound CD33 regardless of the presence/absence of the V-set domain ("CD33 PAN antibodies"). Here, we tested their properties as targeting moiety in CD33 PAN CAR T cell constructs, using a clinically validated lentiviral backbone. Methods: To generate CAR T cells, negatively selected CD8 + T cells were transduced with an epHIV7 lentivirus encoding the scFv from a CD33 PAN antibody (clone 1H7 or 9G2) linked to either a short (IgG 4 hinge only), intermediate (hinge plus IgG 4 CH3 domain), or long (hinge plus IgG 4 CH3 domain plus IgG 4 CH2 domain) spacer, the CD28-transmembrane domain, CD3zeta and 4-1BB intracellular signaling domains, and non-functional truncated CD19 (tCD19) as transduction marker. Similar constructs using scFvs from 2 different V-set domain-targeting CD33 antibodies, including hP67.6 (My96; used in gemtuzumab ozogamicin), were generated for comparison. CAR-T cells were sorted, expanded in IL-7 and IL-15, and used in vitro or in vivo against human AML cell lines endogenously expressing CD33 and cell lines engineered to lack CD33 (via CRISPR/Cas9) with/or without forced expression of different CD33 variants. Results: CD33 V-set-directed CAR T cells exerted significantly more cytolytic activity against AML cells expressing an artificial CD33 variant lacking the C2-set domain (CD33 ΔE3-4) than cells expressing full-length CD33 at similar or higher levels, consistent with the notion that CD33 CAR T cell efficacy is enhanced when targeting an epitope that is located closer to the cell membrane. CD33 PAN CAR T cells were highly potent against human AML cells in a strictly CD33-dependent fashion, with constructs containing the short and intermediate-length spacer demonstrating robust cytokine secretion, cell proliferation, and in vitro cytolytic activity, as determined by 51Cr release cytotoxicity assays. When compared to optimized CD33 V-set CAR T cells, optimized CD33 PAN CAR T cells were significantly more potent in cytotoxicity, proliferation, and cytokine production without appreciably increased acquisition of exhaustion markers. In vivo, CD33 PAN CAR T cells extended survival in immunodeficient NOD.SCID. IL2rg -/- (NSG) mice bearing significant leukemic burdens from various cell line-derived xenografts (HL-60, KG1α and MOLM14) with efficient tumor clearance demonstrated in a dose-dependent fashion. Conclusion: Targeting the membrane proximal domain of CD33 enhances the anti-leukemic potency of CAR T cells. Our data provide the rationale for the further development of CD33 PAN CAR T cells toward clinical testing. Disclosures Fiorenza: Link Immunotherapeutics: Consultancy; Bristol Myers Squibb: Research Funding. Godwin: Pfizer: Research Funding; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Turtle: Allogene: Consultancy; Amgen: Consultancy; Arsenal Bio: Consultancy; Asher bio: Consultancy; Astrazeneca: Consultancy, Research Funding; Caribou Biosciences: Consultancy, Current holder of individual stocks in a privately-held company; Century Therapeutics: Consultancy, Other; Eureka therapeutics: Current holder of individual stocks in a privately-held company, Other; Juno therapeutics/BMS: Patents & Royalties, Research Funding; Myeloid Therapeutics: Current holder of individual stocks in a privately-held company, Other; Nektar therapeutics: Consultancy, Research Funding; PACT Pharma: Consultancy; Precision Biosciences: Current holder of individual stocks in a privately-held company, Other; T-CURX: Other; TCR2 Therapeutics: Research Funding. Walter: Kite: Consultancy; Janssen: Consultancy; Genentech: Consultancy; BMS: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amphivena: Consultancy, Other: ownership interests; Selvita: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding.

Evidence exists of a fast increase in the returns to education in Vietnam in the 1990s and 2000s. However, there was a huge change in education policy in the mid-2000s, opening up opportunities for education providers to expand enrolment. This may lead to a decline in the returns to education in later years when the changes have generated sufficient effect. To provide up-to-date estimates of the returns, we re-visit the returns using updated large survey data up to 2014. We apply the OLS and Heckman selection estimators which can correct for selection bias and find that both estimators provide a consistent trend of the returns, which increased quickly up to the global financial crisis in 2008/2009 and then declined afterwards. This raises a question whether higher educated labour force is oversupplied.

Background: CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies, but lack of durable complete response (CR) is still seen in most patients. Enhancing in vivo T cell function or "fitness" is currently an area of intense focus to improve the anti-tumor efficacy of CAR T cell therapy. Supporting this notion, in vivo expansion and persistence of CAR T cells have been associated with better outcomes after CD19 CAR T cell therapy. Homeostatic cytokines, such as IL-15, play a key role in maintaining T cell fitness and formation of long-term immunologic memory. Since the impact of IL-15 on CAR T-cell function and anti-tumor efficacy in humans is not well characterized, we applied multivariable regression modeling to study the relationships between IL-15 serum concentrations, anti-tumor efficacy, and in vivo CAR T cell kinetics using data from 192 patients undergoing CD19 CAR T-cell therapy. Methods: We included patients enrolled on a phase I/II clinical trial (NCT01865617) at our institution who received defined-composition CD19 CAR T cell therapy. Responses were defined according to the 2019 NCCN guidelines for ALL (multiparameter flow-negative marrow CR or CR/PR by PET or CT in the absence of marrow disease), 2018 iwCLL for CLL (CR or PR), and the 2014 Lugano criteria for NHL (CR or PR). Logistic regression and proportional odds logistic regression were used for multivariable modeling of response and CAR T cell kinetics, respectively. In addition to the IL-15 serum concentration, all models included the following predictors: disease type, pre-lymphodepletion (LD) LDH serum concentration, and LD type (cyclophosphamide and fludarabine [CyFlu] versus other). Results: Sixty-four ALL (33%), 49 CLL (25%), and 79 NHL (42%) patients were included. Cyclophophamide and fludarabine-based LD was used in 163 patients (85%). We observed responses to CD19 CAR T cell therapy in 41 of 52 ALL (82%), 32 of 47 CLL (71%), and 38 of 75 NHL patients (54%). Models including pre-LD IL-15 identified interaction effects with disease type (p=0.008), and with pre-LD LDH (p=0.09). The impact of pre-LD IL-15 on response was differentially affected by the pre-LD LDH concentrations across disease types in a multivariable analysis including interaction terms (Fig. A). Adjusting for a pre-LDH value of 333U/L (third quartile), an increase in the pre-LD IL-15 concentration from 2.6 to 16.2pg/µL (1st to 3rd quartile) was associated with a 13.54, 5.61, and 1.33 increase in the odds of response in ALL, CLL, and NHL, respectively. We did not identify interaction effects when considering the day 0, and peak IL-15, or the IL-15 AUCpre-LD-30. Peak IL-15 was strongly associated with response (OR=4.46 per log10 pg/µL increment, p=0.02), with a larger effect size compared to day 0 IL-15 (OR=2.46, p=0.15), and the IL-15 AUCpre-LD-30 (OR=2.87, p=0.05). Higher peak IL-15 was associated with higher response probabilities across all diseases adjusting for the pre-LD LDH concentration (Fig. B). Next, we applied multivariable modeling to predict the CAR transgene AUC between day 0 and day 90 (AUC0-90). We confirmed that higher IL-15 serum concentrations were independently associated with higher CAR transgene AUC0-90; we found a stronger association between CAR transgene AUC0-90 and the peak IL-15 serum concentration (OR=4.71, p Conclusion: Our multivariable analyses show that higher IL-15 serum concentrations are associated with higher probabilities of response and higher CAR transgene expansion and persistence. We estimated distinct relationships between the pre-LD IL-15 serum concentrations and response across disease types. More so in ALL and CLL patients than in NHL patients, high pre-LD IL-15 was associated with efficacy, even in those with high pre-LD LDH concentrations. This suggests that additional factors, such as the tumor microenvironment, might contribute to CAR T cell failure in some NHL patients. Peak IL-15 was independently associated with higher response probabilities across all diseases. Along with the known biological effects of IL-15 on T cell fitness, our findings suggest high levels of IL-15 could improve CD19 CAR T cell efficacy and in vivo persistence. Figure 1 Disclosures Gauthier: JMP, Eusapharma, Multerra Bio: Honoraria. Chou:Nektar Therapeutics: Patents & Royalties. Riddell:Lyell Immunopharma: Other: Founder; Adaptive Biotechnologies, Nohla: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, A Celgene/BMS Company: Consultancy, Current equity holder in publicly-traded company. Maloney:Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; MorphoSys: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria. Turtle:Novartis: Consultancy; Humanigen: Consultancy; Kite/Gilead: Consultancy; Allogene: Consultancy; PACT Pharma: Consultancy; Physician Education Resource: Consultancy; AstraZeneca: Consultancy, Research Funding; Century Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Arsenal Bio: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno/BMS: Patents & Royalties, Research Funding; Nektar Therapeutics: Consultancy, Research Funding; Precision Biosciences: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin ≥2 weeks before leukapheresis and continue for ≥3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with and without concurrent ibrutinib, respectively (P = .91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.

To investigate the effect of number of studies in a meta-analysis on the detection of publication bias using p-value driven methods. The proportion of meta-analyses detected by Egger's, Harbord's, Peters', and Begg's tests to have asymmetry suggestive of publication bias were examined in 5014 meta-analyses from Cochrane reviews. P-values were also assessed in meta-analyses with varying number of studies, while symmetry was held constant. A simulation study was conducted to investigate if the above tests underestimate or overestimate the presence of publication bias. The proportion of meta-analyses detected as asymmetrical via Egger's, Harbord's, Peters', and Begg's tests decreased by 42.6%, 41.1%, 29.3%, and 28.3%, when the median number of studies in the meta-analysis decreased from 87 to 14. P-values decreased as the number of studies increased in the meta-analysis, despite the level of symmetry remaining constant. The simulation study confirmed that when publication bias is present, p-value tests underestimate the presence of publication bias, particularly when study numbers are small. P-value based tests used for detection of publication bias related asymmetry in meta-analysis require careful examination as they underestimate asymmetry. Alternative methods not dependent on the number of studies are preferable. This work was supported by Program Grant #NPRP10-0129-170274 from the Qatar National Research Fund (a member of Qatar Foundation). The findings herein reflect the work and are solely the responsibility of the authors. All authors had full access to all the data in the study, and the corresponding author had final responsibility for the decision to submit for publication. L.F.-K. was supported by an Australian National Health and Medical Research Council Fellowship (APP1158469)

Purpose – Little econometric evidence exists on the determinants of nonfarm participation among ethnic minorities in Vietnam. The purpose of this paper is to examine the intensity of nonfarm participation and its correlates among ethnic minority households in Northwest Mountains – the poorest region of Vietnam. Design/methodology/approach – Factors affecting the level of nonfarm participation were examined by using a fractional logit model. In addition, regression analysis using analysis of variance models were used to compare the mean of household characteristics and assets between households with and without nonfarm employment. Findings – The study found that households depended heavily on agriculture for subsistence and their access to nonfarm employment is very limited. Households with nonfarm employment had much higher levels of education, income, assets and a much lower level of poverty than those without nonfarm participation. The intensity of nonfarm participation is positively associated with education levels, proportion of male working members and fixed assets but negatively correlated with the size of annual crop land and water surface for aquaculture. Also, the presence of nonfarm opportunities and paved roads in a commune increases the intensity of nonfarm participation for households living in that commune. Practical implications – The findings suggest that any poverty alleviation policies should aim at improving the access of ethnic minorities to education and nonfarm job opportunities. Originality/value – The study offers the first evidence of factors affecting the intensity of nonfarm participation among ethnic minorities in the study area.

Introduction CD19 chimeric antigen receptor (CAR)-T cell therapy has shown efficacy in Non-Hodgkin lymphoma (NHL), but the factors associated with durable remission have not been identified. Objectives We report multivariate analyses of factors impacting progression-free survival (PFS) in NHL patients (pts) treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion (LD) and CD19 CAR-T cells. Methods We conducted a phase 1/2 open-label clinical trial (NCT01865617) with the primary objective of evaluating the feasibility and safety of a defined composition of CD19 CAR-T cells after LD in pts with R/R CD19+ B-cell malignancies. PFS was defined as the time from CAR-T cell infusion until disease progression or death. Multivariate models using elastic net were performed for analysis of response and PFS. Results Characteristics of the 57 pts in the study are shown in Tbl 1. Thirty-six (63%) received high-intensity (HI) Cy/Flu and 21 (37%) received low-intensity (LI) Cy/Flu LD (Tbl 1). All pts received 2 × 106 CD19 CAR-T cells/kg. The best overall response (OR) rate was 57%, with 48% complete remission (CR). Pts who achieved CR had a median PFS not reached (median follow-up [fu] 20.2 months; mo), with only 1 relapse beyond 12 mo after CAR-T cell infusion (Fig. 1). Eight of 9 pts with indolent NHL achieved CR (89%) and none relapsed (median fu 14.5 mo). For the 47 pts with aggressive NHL, the best OR rate was 51%, with 40% CR. The median PFS of aggressive NHL pts achieving CR was 20.0 mo (median fu 26.9 mo), and 24-mo probabilities of PFS and OS were 46% and 72%, respectively. In aggressive NHL, multivariate analysis showed that the probability of CR was associated with lower pre-LD serum LDH and greater increase in serum MCP-1 concentration from LD to the day of CAR-T cell infusion. HI LD was associated with more CAR-T cells in blood, but there was no difference in response in pts who received HI (CR 14/31, 45%) compared to LI LD (CR 5/16, 31%; P = .53). Multivariate analysis in aggressive NHL showed that lower pre-LD serum LDH and higher day 0 MCP-1 and peak IL-7 after CAR-T cell infusion were associated with better PFS. The IL-7 peak after CAR-T cell infusion (median day 4) correlated with day 0 IL-7, consistent with an effect of LD. MCP-1 and IL-7 increased after LD, independent of prior bridging therapy, and their concentrations correlated with Cy/Flu LD intensity. However, LD intensity was not independently associated with CR or PFS. Independent of LD intensity, a subset of pts had a robust increase in day 0 MCP-1 and peak IL-7 after LD and achieved better responses (CR 10/16, 63%) compared to those with limited cytokine increase (CR 9/30, 30%; P = .06). Conclusion Multivariate analyses show that cytokines associated with effective LD are, unlike the intensity of Cy/Flu LD, independently associated with CR and PFS. Strategies to augment biological LD efficacy could be tested in studies of CD19 CAR-T cells for aggressive NHL.

Background In relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) who had previously failed ibrutinib, we observed durable responses after CD19 chimeric antigen receptor-modified T-cell immunotherapy (Turtle CJ et al, JCO, 2017; NCT01865617). The combination of CD19 CAR-T cells with ibrutinib might improve response and decrease toxicity. Objectives To evaluate the efficacy and toxicity of CD19 CAR-T cell immunotherapy alone or in combination with ibrutinib for R/R CLL. Methods Our phase 1/2 study of CD19 CAR-T cell immunotherapy established a preferred regimen for R/R CLL pts of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2 × 106 CD19 CAR-T cells/kg (Turtle, JCO, 2017). We then compared outcomes of these pts (No-ibr cohort) with a subsequent cohort receiving Cy/Flu with 2 × 106/kg JCAR014 CAR-T cells with concurrent ibrutinib (420 mg/d) from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion (Ibr cohort). Results We treated 19 and 17 pts in the No-Ibr and Ibr cohorts, respectively. Pt characteristics were comparable (Table 1). Median follow-up in responders was 764 and 98 days in the No-ibr and Ibr cohorts, respectively. Administration of ibrutinib with Cy/Flu and CD19 CAR-T cells was well tolerated in most pts; ibrutinib was reduced or discontinued in 6 pts (35%) at a median of 21 days after JCAR014 infusion. In the Ibr cohort 1 pt with grade 2 CRS (Lee, Blood, 2014) developed fatal presumed cardiac arrhythmia and 1 pt developed a subdural hematoma in the setting of trauma and thrombocytopenia. Although the proportions of pts with grade ≥1 CRS were similar between cohorts (76% vs 89%, P = 0.39), the severity of CRS (grade ≥3 CRS: Ibr, 0%; No-Ibr, 26%; P = 0.05) and serum peak IL-8 (P = 0.04), IL-15 (P = 0.003) and MCP-1 (P = 0.004) concentrations were lower in the Ibr cohort. However, we found higher peak CD4+ CAR-T cell counts (P = 0.06) and comparable peak CD8+ CAR-T cell counts (P = 0.29) in blood in the Ibr compared to the No-Ibr cohort. Sixteen pts (94%) and 18 pts (95%) in the Ibr and No-ibr cohorts, respectively, were evaluable for response. We observed a higher proportion of responders (complete response and partial response) by 2008 IWCLL criteria in the Ibr compared to the No-ibr cohort (88% vs 56%, respectively, P = 0.06). In pts with no disease by BM flow cytometry after treatment (N = 23), a higher proportion of pts in the Ibr cohort had no malignant IgH sequences at 4 weeks (83% vs 60%, P = 0.35). Using multivariable logistic regression (Table 2), treatment in the Ibr cohort and a lower pre-treatment SUVmax were associated with a higher probability of response (Ibr cohort, OR = 14.02, P = 0.05; SUVmax, OR = 1.31 per SUV unit decrease, P Conclusion The combination of ibrutinib with CD19 CAR-T cell immunotherapy was well tolerated in most pts, and might decrease the incidence of severe CRS and improve responses in pts with R/R CLL.