CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results.

Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

Corrigendum: Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis.

[This corrects the article DOI: 10.3389/fimmu.2022.1009016.].

Inflammation and immune activation are associated with risk of Mycobacterium tuberculosis infection in BCG-vaccinated infants.

Tuberculosis vaccine development is hindered by the lack of validated immune correlates of protection. Exploring immune correlates of risk of disease and/or infection in prospective samples can inform this field. We investigate whether previously identified immune correlates of risk of TB disease also associate with increased risk of M.tb infection in BCG-vaccinated South African infants, who became infected with M.tb during 2-3 years of follow-up. M.tb infection is defined by conversion to positive reactivity in the QuantiFERON test. We demonstrate that inflammation and immune activation are associated with risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb, and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN-[Formula: see text]2, TNF-[Formula: see text], CXCL10 (IP-10) and complement C2 are also higher in infants that were subsequently infected with M.tb.

Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis.

Studies of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) disease are scarce. In this study, we compared the cellular profile of Mycobacterium tuberculosis (Mtb)-specific T cells in pericardial fluid and peripheral blood in patients with pericardial TB (PCTB). Whole blood and pericardial fluid (PCF) samples were collected at the time of diagnostic sampling, with repeat blood sampling after completion of anti-tubercular treatment (ATT) in 16 PCTB patients, most of them being HIV-1 infected (n=14). These samples were stimulated ex vivo and the phenotypic and functional cellular profile of PCF and blood was assessed by flow cytometry. We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-α producing Mtb-specific granulocytes and Mtb-specific CD4 T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFNγ, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1ß production was lower in the PCF T cells. Bacterial loads were not associated with alterations in the phenotype or function of Mtb-specific CD4 T cells. Upon ATT completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using an ex vivo assay to compare the immune response towards Mtb in PCF and in blood, we identified significant difference in the phenotypic profile of Mtb-specific CD4 T response between these two compartments. Moreover, we show that the activation profile of peripheral Mtb-specific CD4 T cells could be used to monitor treatment response in PCTB.

A Systematic Review of Literature on the Representation of Racial and Ethnic Minority Groups in Clinical Nutrition Interventions.

The racial and ethnic disparities in diet-related chronic diseases are major concerns. This systematic review examines the extent to which diet-induced changes in health outcomes, such as cardiometabolic, inflammation, cancer, bone health, and kidney function outcomes, etc., have been reported and discussed by race or ethnicity in randomized trials with 2 or more diet arms that recruited both minority and non-Hispanic White groups. Databases (i.e., PubMed, Cochrane Library, and Web of Science) were searched up to August 2021. Thirty-four studies that discussed effects of defined dietary interventions on health outcomes by racial or ethnic minority group compared with non-Hispanic Whites were included in the systematic review (PROSPERO registration number: CRD42021229256). Acute trials and those with 1 diet arm that accounted for race or ethnicity in their analyses and studies that focused on a single racial or ethnic group were discussed separately. Most studies were conducted in Black compared with White adults testing effects of energy restriction, macronutrient modification, sodium reduction, or variations of the Dietary Approaches to Stop Hypertension (DASH) diet on cardiometabolic outcomes. There was limited focus on other minority groups. Evidence suggests greater blood pressure reduction for Black adults compared with Whites particularly with DASH (or similar) diets. Overall, there was limited consideration for group-specific eating patterns and diet acceptability. Overall risk of bias was low. With emerging precision nutrition initiatives that aim to optimize metabolic responses in population subgroups through tailored approaches, it is imperative to ensure adequate representation of racial and ethnic subgroups for addressing health disparities. Factors that help explain variability in responses such as socioecological context should be included and adequately powered. Given the racial and ethnic disparities in chronic diseases, studying the adoption, maintenance, and effectiveness of dietary interventions on health outcomes among different groups is critical for developing approaches that can mitigate diet-related health disparities.

High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation.

This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

Induction of Functional Specific Antibodies, IgG-Secreting Plasmablasts and Memory B Cells Following BCG Vaccination.

Tuberculosis (TB) is a major global health problem and the only currently-licensed vaccine, BCG, is inadequate. Many TB vaccine candidates are designed to be given as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does confer protection may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterized, there is a paucity of literature on the humoral response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titers in serum versus plasma with modestly higher titers in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a functional role for BCG vaccine-induced specific antibodies in opsonizing mycobacteria and enhancing macrophage phagocytosis in vitro, which may contribute to the BCG vaccine-mediated control of mycobacterial growth observed. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.

An observational study identifying highly tuberculosis-exposed, HIV-1-positive but persistently TB, tuberculin and IGRA negative persons with M. tuberculosis specific antibodies in Cape Town, South Africa.

BACKGROUND: Mycobacterium tuberculosis (Mtb) infection is inferred from positive results of T-cell immune conversion assays measuring Mtb-specific interferon gamma production or tuberculin skin test (TST) reactivity. Certain exposed individuals do not display T-cell immune conversion in these assays and do not develop TB. Here we report a hitherto unknown form of this phenotype: HIV-1-positive persistently TB, tuberculin and IGRA negative (HITTIN). METHODS: A community-based case-control design was used to systematically screen and identify adults living with HIV (HIV+), aged 35-60 years, who met stringent study criteria, and then longitudinally followed up for repeat IGRA and TST testing. Participants had no history of TB despite living in TB hyper-endemic environments in Cape Town, South Africa with a provincial incidence of 681/100,000. Mtb-specific antibodies were measured using ELISA and Luminex. FINDINGS: We identified 48/286 (17%) individuals who tested persistently negative for Mtb-specific T-cell immunoreactivity (three negative Quantiferon results and one TST = 0mm) over 206±154 days on average. Of these, 97·2% had documented CD4 counts<200 prior to antiretroviral therapy (ART). They had received ART for 7·0±3·0 years with a latest CD4 count of 505·8±191·4 cells/mm3. All HITTIN sent for further antibody testing (n=38) displayed  Mtb-specific antibody titres. INTERPRETATION: Immune reconstituted HIV+ persons can be persistently non-immunoreactive to TST and interferon-γ T-cell responses to Mtb, yet develop species-specific antibody responses. Exposure is evidenced by Mtb-specific antibody titres. Our identification of HIV+ individuals displaying a persisting lack of response to TST and IGRA T-cell immune conversion paves the way for future studies to investigate this phenotype in the context of HIV-infection that so far have received only scant attention.

Differential localizations of protein phosphatase 1 isoforms determine their physiological function in the heart.

Protein phosphatase 1 isoforms α, ß, and γ (PP1α, PP1ß, and PP1γ) are highly homologous in the catalytic domains but have distinct subcellular localizations. In this study, we utilized both primary cell culture and knockout mice to investigate the isoform-specific roles of PP1s in the heart. In both neonatal and adult cardiac myocytes, PP1ß was mainly localized in the nucleus, compared to the predominant presence of PP1α and PP1γ in the cytoplasm. Adenovirus-mediated overexpression of PP1α led to decreased phosphorylation of phospholamban, which was not influenced by overexpression of either PP1ß or PP1γ. Interestingly, only cardiac-specific knockout of PP1ß resulted in increased HDAC7 phosphorylation, consistent with the predominant nuclear localization of PP1ß. Functionally, deletion of either PP1 isoform resulted in reduced fractional shortening in aging mice, however only PP1ß deletion resulted in interstitial fibrosis in mice as early as 3 weeks of age. Deletion of neither PP1 isoform had any effect on pathological cardiac hypertrophy induced by 2 weeks of pressure overload stimulation. Together, our data suggest that PP1 isoforms have differential localizations to regulate the phosphorylation of their specific substrates for the physiological function in the heart.

Antibodies and tuberculosis.

Tuberculosis (TB) remains a major public health problem internationally, causing 9.6 million new cases and 1.5 million deaths worldwide in 2014. The Bacillus Calmette-Guérin vaccine is the only licensed vaccine against TB, but its protective effect does not extend to controlling the development of infectious pulmonary disease in adults. The development of a more effective vaccine against TB is therefore a pressing need for global health. Although it is established that cell-mediated immunity is necessary for the control of latent infection, the presupposition that such immunity is sufficient for vaccine-induced protection has recently been challenged. A greater understanding of protective immunity against TB is required to guide future vaccine strategies against TB. In contrast to cell-mediated immunity, the human antibody response against M.tb is conventionally thought to exert little immune control over the course of infection. Humoral responses are prominent during active TB disease, and have even been postulated to contribute to immunopathology. However, there is evidence to suggest that specific antibodies may limit the dissemination of M.tb, and potentially also play a role in prevention of infection via mucosal immunity. Further, antibodies are now understood to confer protection against a range of intracellular pathogens by modulating immunity via Fc-receptor mediated phagocytosis. In this review, we will explore the evidence that antibody-mediated immunity could be reconsidered in the search for new vaccine strategies against TB.

The Macronutrients, Appetite, and Energy Intake.

Each of the macronutrients-carbohydrate, protein, and fat-has a unique set of properties that influences health, but all are a source of energy. The optimal balance of their contribution to the diet has been a long-standing matter of debate. Over the past half century, thinking has progressed regarding the mechanisms by which each macronutrient may contribute to energy balance. At the beginning of this period, metabolic signals that initiated eating events (i.e., determined eating frequency) were emphasized. This was followed by an orientation to gut endocrine signals that purportedly modulate the size of eating events (i.e., determined portion size). Most recently, research attention has been directed to the brain, where the reward signals elicited by the macronutrients are viewed as potentially problematic (e.g., contribute to disordered eating). At this point, the predictive power of the macronutrients for energy intake remains limited.

The Effects of Increased Protein Intake on Fullness: A Meta-Analysis and Its Limitations.

BACKGROUND: Higher protein intake has been implicated in weight management because of its appetitive properties. However, the effects of protein intake on appetitive sensations such as fullness have not been systematically assessed. Meta-analysis is a useful technique to evaluate evidence of an intervention's effect on testable outcomes, but it also has important limitations. OBJECTIVE: The primary aim of this study was to synthesize the available evidence on the effect of protein intake on fullness using a quantitative meta-analysis and a secondary directional analysis using the vote-counting procedure. A tertiary aim was to address limitations of meta-analyses as they pertain to findings from this meta-analysis. DESIGN: We searched multiple databases for interventional studies that evaluated the effect of increased protein intake on fullness ratings. Inclusion criteria for both analyses were as follows: healthy human participants, preload studies that utilized intact dietary protein, delivery of protein load orally, and studies reporting fullness as an outcome. For the meta-analysis, an additional criterion was that the studies also needed to report 2- to 4-hour area under the curve value for fullness. RESULTS: Five studies met all criteria for the meta-analysis. Twenty-eight studies met all criteria for the directional analysis. The meta-analysis indicated higher protein preloads have a greater effect on fullness than lower protein preloads (overall effect estimate: 2,435.74 mm.240 min, (95% CI 1,375.18 to 3,496.31 mm.240 min; P<0.0001). The directional analysis also revealed a positive effect on fullness with higher protein preloads (P<0.01). Many related scientifically rigorous studies were excluded from the analysis because analytical criteria required a narrowly focused research question. CONCLUSIONS: The present analyses show that higher protein preloads increase fullness ratings more than lower protein preloads under tightly defined conditions. Extrapolation of findings to common conditions outside the specified criteria of this analysis must be made cautiously, as must speculation about the influence of fullness sensations on ingestive behavior, body weight, and various health outcomes.