Financial Incentives and Treatment Outcomes in Adolescents With Severe Obesity: A Randomized Clinical Trial.

Importance: Adolescent severe obesity is usually not effectively treated with traditional lifestyle modification therapy. Meal replacement therapy (MRT) shows short-term efficacy for body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) reduction in adolescents, and financial incentives (FIs) may be an appropriate adjunct intervention to enhance long-term efficacy. Objective: To evaluate the effect of MRT plus FIs vs MRT alone on BMI, body fat, and cardiometabolic risk factors in adolescents with severe obesity. Design, Setting, and Participants: This was a randomized clinical trial of MRT plus FIs vs MRT alone at a large academic health center in the Midwest conducted from 2018 to 2022. Participants were adolescents (ages 13-17 y) with severe obesity (≥120% of the 95th BMI percentile based on sex and age or ≥35 BMI, whichever was lower) who were unaware of the FI component of the trial until they were randomized to MRT plus FIs or until the end of the trial. Study staff members collecting clinical measures were blinded to treatment condition. Data were analyzed from March 2022 to February 2024. Interventions: MRT included provision of preportioned, calorie-controlled meals (~1200 kcals/d). In the MRT plus FI group, incentives were provided based on reduction in body weight from baseline. Main Outcomes and Measures: The primary end point was mean BMI percentage change from randomization to 52 weeks. Secondary end points included total body fat and cardiometabolic risk factors: blood pressure, triglyceride to high-density lipoprotein ratio, heart rate variability, and arterial stiffness. Cost-effectiveness was additionally evaluated. Safety was assessed through monthly adverse event monitoring and frequent assessment of unhealthy weight-control behaviors. Results: Among 126 adolescents with severe obesity (73 female [57.9%]; mean [SD] age, 15.3 [1.2] years), 63 participants received MRT plus FIs and 63 participants received only MRT. At 52 weeks, the mean BMI reduction was greater by -5.9 percentage points (95% CI, -9.9 to -1.9 percentage points; P = .004) in the MRT plus FI compared with the MRT group. The MRT plus FI group had a greater reduction in mean total body fat mass by -4.8 kg (95% CI, -9.1 to -0.6 kg; P = .03) and was cost-effective (incremental cost-effectiveness ratio, $39 178 per quality-adjusted life year) compared with MRT alone. There were no significant differences in cardiometabolic risk factors or unhealthy weight-control behaviors between groups. Conclusions and Relevance: In this study, adding FIs to MRT resulted in greater reductions in BMI and total body fat in adolescents with severe obesity without increased unhealthy weight-control behaviors. FIs were cost-effective and possibly promoted adherence to health behaviors. Trial Registration: ClinicalTrials.gov Identifier: NCT03137433.

A high-density microfluidic bioreactor for the automated manufacturing of CAR T cells.

The manufacturing of autologous chimaeric antigen receptor (CAR) T cells largely relies either on fed-batch and manual processes that often lack environmental monitoring and control or on bioreactors that cannot be easily scaled out to meet patient demands. Here we show that human primary T cells can be activated, transduced and expanded to high densities in a 2 ml automated closed-system microfluidic bioreactor to produce viable anti-CD19 CAR T cells (specifically, more than 60 million CAR T cells from donor cells derived from patients with lymphoma and more than 200 million CAR T cells from healthy donors). The in vitro secretion of cytokines, the short-term cytotoxic activity and the long-term persistence and proliferation of the cell products, as well as their in vivo anti-leukaemic activity, were comparable to those of T cells produced in a gas-permeable well. The manufacturing-process intensification enabled by the miniaturized perfusable bioreactor may facilitate the analysis of the growth and metabolic states of CAR T cells during ex vivo culture, the high-throughput optimization of cell-manufacturing processes and the scale out of cell-therapy manufacturing.

Endoscopic Surveillance of Intestinal Metaplasia of the Esophagogastric Junction: A Decision Modeling Analysis.

INTRODUCTION: The incidence of esophagogastric junction adenocarcinoma (EGJAC) has been rising. Intestinal metaplasia of the esophagogastric junction (EGJIM) is a common finding in gastroesophageal reflux (irregular Z-line) and may represent an early step in the development of EGJAC in the West. Worldwide, EGJIM may represent progression along the Correa cascade triggered by Helicobacter pylori . We sought to evaluate the cost-effectiveness of endoscopic surveillance of EGJIM. METHODS: We developed a decision analytic model to compare endoscopic surveillance strategies for 50-year-old patients after diagnosis of non-dysplastic EGJIM: (i) no surveillance (standard of care), (ii) endoscopy every 3 years, (iii) endoscopy every 5 years, or (iv) 1-time endoscopy at 3 years. We modeled 4 progression scenarios to reflect uncertainty: A (0.01% annual cancer incidence), B (0.05%), C (0.12%), and D (0.22%). RESULTS: Cost-effectiveness of endoscopic surveillance depended on the progression rate of EGJIM to cancer. At the lowest progression rate (scenario A, 0.01%), no surveillance strategies were cost-effective. In moderate progression scenarios, 1-time surveillance at 3 years was cost-effective, at $30,989 and $16,526 per quality-adjusted life year for scenarios B (0.05%) and C (0.12%), respectively. For scenario D (0.22%), surveillance every 5 years was cost-effective at $77,695 per quality-adjusted life year. DISCUSSION: Endoscopic surveillance is costly and can cause harm; however, low-intensity longitudinal surveillance (every 5 years) is cost-effective in populations with higher EGJAC incidence. No surveillance or 1-time endoscopic surveillance of patients with EGJIM was cost-effective in low-incidence populations. Future studies to better understand the natural history of EGJIM, identify risk factors of progression, and inform appropriate surveillance strategies are required.

Current perspectives on resistance to chimeric antigen receptor T-cell therapy and strategies to improve efficacy in B-cell lymphoma.

Although chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with chemo-refractory B-cell lymphoma, a significant portion is refractory or relapse. Resistance is a major barrier to improving treatment efficacy and long-term survival in CAR T-cell therapy, and clinicians have very limited tools to discriminate a priori patients who will or will not respond to treatment. While CD19-negative relapses due to loss of target antigen is well described, it accounts for only about 30% of cases with treatment failure. Recent efforts have shed light on mechanisms of CD19-positive relapse due to tumor intrinsic resistance, T-cell quality/manufacturing, or CAR T-cell exhaustion mediated by hostile tumor microenvironment. Here, we review the latest updates of preclinical and clinical trials to investigate the mechanisms of resistance and relapse post CAR T-cell therapy in B cell lymphoma and discuss novel treatment strategies to overcome resistance as well as advances that are useful for a CAR T therapist to optimize and personalize CAR T-cell therapy.

Cost-Effectiveness of Liquid Biopsy for Colorectal Cancer Screening in Patients Who Are Unscreened.

Importance: Despite recommendations for universal screening, adherence to colorectal cancer screening in the US is approximately 60%. Liquid biopsy tests are in development for cancer early detection, but it is unclear whether they are cost-effective for colorectal cancer screening. Objective: To estimate the cost-effectiveness of liquid biopsy for colorectal cancer screening in the US. Design, Setting, and Participants: In this economic evaluation, a Markov model was developed to compare no screening and 5 colorectal cancer screening strategies: colonoscopy, liquid biopsy, liquid biopsy following nonadherence to colonoscopy, stool DNA, and fecal immunochemical test. Adherence to first-line screening with colonoscopy, stool DNA, or fecal immunochemical test was assumed to be 60.6%, and adherence for liquid biopsy was assumed to be 100%. For colonoscopy, stool DNA, and fecal immunochemical test, patients who did not adhere to testing were not offered other screening. In colonoscopy-liquid biopsy hybrid, liquid biopsy was second-line screening for those who deferred colonoscopy. Scenario analyses were performed to include the possibility of polyp detection for liquid biopsy. Exposures: No screening, colonoscopy, fecal immunochemical test, stool DNA, liquid biopsy, and colonoscopy-liquid biopsy hybrid screening. Main Outcomes and Measures: Model outcomes included life expectancy, total cost, and incremental cost-effectiveness ratios. A strategy was considered cost-effective if it had an incremental cost-effectiveness ratio less than the US willingness-to-pay threshold of $100 000 per life-year gained. Results: This study used a simulated cohort of patients aged 45 years with average risk of colorectal cancer. In the base case, colonoscopy was the preferred, or cost-effective, strategy with an incremental cost-effectiveness ratio of $28 071 per life-year gained. Colonoscopy-liquid biopsy hybrid had the greatest gain in life-years gained but had an incremental cost-effectiveness ratio of $377 538. Colonoscopy-liquid biopsy hybrid had a greater gain in life-years if liquid biopsy could detect polyps but remained too costly. Conclusions and Relevance: In this economic evaluation of liquid biopsy for colorectal cancer screening, colonoscopy was a cost-effective strategy for colorectal cancer screening in the general population, and the inclusion of liquid biopsy as a first- or second-line screening strategy was not cost-effective at its current cost and screening performance. Liquid biopsy tests for colorectal cancer screening may become cost-effective if their cost is substantially lowered.

Quantifying the potential benefits of early detection for pancreatic cancer through a counterfactual simulation modeling analysis.

The benefits of cancer early detection depend on various factors, including cancer type, screening method performance, stage at diagnosis, and subsequent treatment. Although numerous studies have evaluated the effectiveness of screening interventions for identifying cancer at earlier stages, there is no quantitative analysis that studies the optimal early detection time interval that results in the greatest mortality benefit; such data could serve as a target and benchmark for cancer early detection strategies. In this study, we focus on pancreatic ductal adenocarcinoma (PDAC), a cancer known for its lack of early symptoms. Consequently, it is most often detected at late stages when the 5-year survival rate is only 3%. We developed a PDAC population model that simulates an individual patient's age and stage at diagnosis, while replicating overall US cancer incidence and mortality rates. The model includes "cancer sojourn time," serving as a proxy for the speed of cancer progression, with shorter times indicating rapid progression and longer times indicating slower progression. In our PDAC model, our hypothesis was that earlier cancer detection, potentially through a hypothetical screening intervention in the counterfactual analysis, would yield reduced mortality as compared to a no-screening group. We found that the benefits of early detection, such as increased life-years gained, are greater when the sojourn time is shorter, reaching their maximum when identification is made 4-6 years prior to clinical diagnosis (e.g., when a symptomatic diagnosis is made). However, when early detection occurs even earlier, for example 6-10 years prior to clinical diagnosis, the benefits significantly diminish for shorter sojourn time cancers, and level off for longer sojourn time cancers. Our study clarifies the potential benefits of PDAC early detection that explicitly incorporates individual patient heterogeneity in cancer progression and identifies quantitative benchmarks for future interventions.

Cost-Effectiveness of Pharmacotherapy for the Treatment of Obesity in Adolescents.

Importance: Antiobesity pharmacotherapy is recommended for adolescents ages 12 years and older with obesity. Several medications have been approved by the US Food and Drug Administration for adolescent use, but the most cost-effective medication remains unclear. Objective: To estimate the cost-effectiveness of lifestyle counseling alone and as adjunct to liraglutide, mid-dose phentermine and topiramate (7.5 mg phentermine and 46 mg topiramate), top-dose phentermine and topiramate (15 mg phentermine and 92 mg topiramate), or semaglutide among adolescent patients with obesity. Design, Setting, and Participants: This economic evaluation used a microsimulation model to project health and cost outcomes of lifestyle counseling alone and adjunct to liraglutide, mid-dose phentermine and topiramate, top-dose phentermine and topiramate, or semaglutide over 13 months, 2 years, and 5 years among a hypothetical cohort of 100 000 adolescents with obesity, defined as an initial body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 37. Model inputs were derived from clinical trials, published literature, and national sources. Data were analyzed from April 2022 to July 2023. Exposures: Lifestyle counseling alone and as adjunct to liraglutide, mid-dose phentermine and topiramate, top-dose phentermine and topiramate, or semaglutide. Main Outcomes and Measures: The main outcome was quality-adjusted life years (QALYs), costs (2022 US dollars), and incremental cost-effectiveness ratios (ICERs), with future costs and QALYs discounted 3.0% annually. A strategy was considered cost-effective if the ICER was less than $100 000 per QALY gained. The preferred strategy was determined as the strategy with the greatest increase in QALYs while being cost-effective. One-way and probabilistic sensitivity analyses were used to assess parameter uncertainty. Results: The model simulated 100 000 adolescents at age 15 with an initial BMI of 37, of whom 58 000 (58%) were female. At 13 months and 2 years, lifestyle counseling was estimated to be the preferred strategy. At 5 years, top-dose phentermine and topiramate was projected to be the preferred strategy with an ICER of $56 876 per QALY gained vs lifestyle counseling. Semaglutide was projected to yield the most QALYs, but with an unfavorable ICER of $1.1 million per QALY gained compared with top-dose phentermine and topiramate. Model results were most sensitive to utility of weight reduction and weight loss of lifestyle counseling and top-dose phentermine and topiramate. Conclusions and Relevance: In this economic evaluation of pharmacotherapy for adolescents with obesity, top-dose phentermine and topiramate as adjunct to lifestyle counseling was estimated to be cost-effective after 5 years. Long-term clinical trials in adolescents are needed to fully evaluate the outcomes of pharmacotherapy, especially into adulthood.

Evolving therapeutic landscape of diffuse large B-cell lymphoma: challenges and aspirations.

Diffuse large B-cell lymphoma (DLBCL) represents the commonest subtype of non-Hodgkin lymphoma and encompasses a group of diverse disease entities, each harboring unique molecular and clinico-pathological features. The understanding of the molecular landscape of DLBCL has improved significantly over the past decade, highlighting unique genomic subtypes with implications on targeted therapy. At the same time, several new treatment modalities have been recently approved both in the frontline and relapsed settings, ending a dearth of negative clinical trials that plagued the past decade. Despite that, in the real-world setting, issues like drug accessibility, reimbursement policies, physician and patient preference, as well as questions regarding optimal sequencing of treatment options present difficulties and challenges in day-to-day oncology practice. Here, we review the recent advances in the therapeutic armamentarium of DLBCL and discuss implications on the practice landscape, with a particular emphasis on the context of the healthcare system in Singapore.

Hysterectomy Trends and Risk of Vaginal Cuff Dehiscence: An Update by Mode of Surgery.

STUDY OBJECTIVE: To analyze hysterectomy trends and vaginal cuff dehiscence (VCD) rates by mode of surgery at a tertiary care medical center and to describe characteristics of VCD cases. DESIGN: Observational retrospective cohort study. SETTING: Large academic hospital and affiliated community hospital. PATIENTS: 4722 patients who underwent hysterectomy at Columbia University Irving Medical Center between January 2010 and August 2021. INTERVENTIONS: Current Procedural Terminology and International Classification of Diseases codes identified hysterectomies and VCD cases. Hysterectomy trends and VCD rates were calculated by mode of surgery. Relative risks of VCD for each mode were compared with total abdominal hysterectomy (TAH). Clinical characteristics of VCDs were reviewed. MEASUREMENTS AND MAIN RESULTS: There were 4059 total hysterectomies. Laparoscopic hysterectomies, including total laparoscopic hysterectomies (TLHs), laparoscopic-assisted vaginal hysterectomies, and robot-assisted TLHs (RA-TLHs), increased from 41.9% in 2010 to 65.9% in 2021 (p <.001). RA-TLH increased from 5.7% in 2010 to 40.2% in 2021. Supracervical hysterectomies followed similar trends and were excluded from VCD analysis. There were 15 VCDs (overall rate 0.37%). VCD was highest after RA-TLH (0.66%), followed by TLH (0.32%) and TAH (0.27%), with no VCDs after laparoscopic-assisted vaginal hysterectomy or total vaginal hysterectomy. Compared with TAH, the relative risk for VCD after RA-TLH was 2.44 (95% confidence interval 0.66-9.00) and after TLH was 1.18 (95% confidence interval 0.24-5.83), which were not statistically significant. The mean time to dehiscence was 39 days (range 8-145 days). The most common trigger event was coitus (41%). CONCLUSION: VCD rates were low (<1%) for all modes of hysterectomy, and rates after robotic and laparoscopic hysterectomy were much lower than previously reported. Although VCD rates trended higher after robotic and laparoscopic hysterectomy compared with abdominal hysterectomy, the difference was not significant. It is difficult to determine whether this finding represents true lack of difference vs a lack of power to detect a significant difference given the rarity of VCD.

A Review of CAR-T Therapy in Pediatric and Young Adult B-Lineage Acute Leukemia: Clinical Perspectives in Singapore.

Approximately 10-15% of pediatric B-cell acute lymphoblastic leukemia (B-ALL) are high risk at diagnosis or relapsed/ refractory. Prior to the availability of chimeric antigen receptor T-cell (CAR-T) in Singapore and the region, the treatment options for these paediatric and young adults are conventional salvage chemotherapy or chemo-immunotherapy regimens as a bridge to allogeneic total body irradiation-based hematopoietic stem cell transplantation (allo-HSCT). This results in significant acute and long-term toxicities, with suboptimal survival outcomes. Finding a curative salvage therapy with fewer long-term toxicities would translate to improved quality-adjusted life years in these children and young adults. In this review, we focus on the burden of relapsed/refractory pediatric B-ALL, the limitations of current strategies, the emerging paradigms for the role of CAR-T in r/r B-ALL, our local perspectives on the health economics and future direction of CAR-T therapies in pediatric patients.

Conjunctival T Cell Profile in Allogeneic Hematopoietic Stem Cell Transplant Patients after Instilling Topical Cyclosporine-A 0.1% Cationic Emulsion.

INTRODUCTION: To profile conjunctival T cell populations in allogeneic hematopoietic stem cell transplant (HSCT) patients after instillation of daily topical cyclosporine-A (CsA) 0.1% cationic emulsion (Ikervis), and to evaluate patients' tolerance to these eye drops. METHODS: Nineteen participants were prescribed Ikervis prophylaxis once daily to both eyes from 3-5 weeks pre-HSCT to 12 months post-HSCT. The outcome measure was conjunctival T cell proportions from flow cytometry after impression cytology. Covariates included visual acuity, intraocular pressure, slit lamp and fundal examination, dry eye (SPEED) and quality of life questionnaires, non-invasive keratograph tear break-up time (NIKBUT), conjunctival redness, meibography, lipid thickness, Schirmer test, tear cytokines, fluorescein staining, tear osmolarity, and meibomian gland expressibility. RESULTS: The conjunctival T cell analysis showed either stable or decreased proportions of conjunctival CD4 T cells at the last visit from baseline in compliant patients. CD4 proportions were increased in non-compliant patients and in the single patient who developed ocular graft-versus-host disease (GVHD). All patients were tolerant to Ikervis but 6/19 were not compliant. In the majority of patients, vision did not affect activities of daily living. Pre- and post-HSCT up to the last study visit, there was no statistically significant change in clinical covariates. Only one participant developed ocular GVHD at 9 months post-HSCT. CONCLUSION: Superficial conjunctival T cell profile reflects compliance to daily topical Ikervis eye drops and clinical ocular surface parameters in allogenic HSCT patients. Tolerance is comparable to other formulations of topical CsA in the first 12 months. GOV IDENTIFIER: NCT04636918. URL: https://clinicaltrials.gov/ct2/show/NCT04636918?cond=ocular+Graft+Versus+Host+Disease&cntry=SG&draw=2&rank=2 .

Favorable outcomes of COVID-19 in vaccinated hematopoietic stem cell transplant recipients: A single-center experience.

INTRODUCTION: A high incidence of mortality and severe COVID-19 infection was reported in hematopoietic stem cell transplant (HSCT) recipients during the early phases of the COVID-19 pandemic; however, outcomes with subsequent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, such as the omicron variant, have yet to be reported. Additionally, rollout of COVID-19 vaccinations in subsequent pandemic waves may modify COVID-19 disease severity and mortality in this immunocompromised population. We describe COVID-19 outcomes among a highly vaccinated population of HSCT recipients at a single center during successive waves of community transmission arising from the SARS-CoV-2 delta and omicron variants. METHODS: We retrospectively reviewed medical records of all HSCT recipients at our institution who tested positive for SARS-CoV-2 from May 2021 to May 2022. Descriptive statistics were reported; the chi-square test was utilized to identify factors associated with 90-day all-cause mortality and severity of COVID-19 infection. RESULTS: Over the 1-year study period, 77 HSCT recipients at our center contracted COVID-19 (43 allogenic; 34 autologous). Twenty-six (33.8%) patients were infected with the SARS-CoV-2 delta variant, while 51 (66.2%) had the SARS-CoV-2 omicron variant. Thirty-nine (50.6%) patients required hospitalization. More than 80% had received prior COVID-19 vaccination (57.1% with two doses, 27.3% with three doses). The majority (90.9%) had mild disease; only one (1.3%) patient required mechanical ventilation. Active hematological disease at time of COVID-19 infection was associated with increased odds of mortality [odds ratio (OR) = 6.90, 95% confidence interval (CI) = 1.20-40]. The 90-day all-cause mortality was 7.8% (six patients). Infection with the omicron variant (vs. delta) was associated with less severe illness (OR = 0.05, 95% CI = 0.01-0.47) and decreased odds of mortality (OR = 0.08, 95% CI = 0.01-0.76). Being on immunosuppression (OR = 5.10, 95% CI = 1.10-23.60) and being unvaccinated at disease onset (OR = 14.76, 95% CI = 2.89-75.4) were associated with greater severity of COVID-19 infection. CONCLUSION: We observed favorable outcomes with COVID-19 infection in a cohort of vaccinated HSCT patients. The SARS-CoV-2 omicron variant was associated with both less severe illness and decreased odds of mortality. As COVID-19 moves toward endemicity, early access to treatment and encouraging vaccination uptake is crucial in mitigating the challenge of COVID-19 management among HSCT recipients. Surveillance and assessment of clinical outcomes with new SARS-CoV-2 variants also remains important in this immunocompromised population.

Yield of Repeat Endoscopy for Barrett's Esophagus After Normal Index Endoscopy.

INTRODUCTION: Guidelines suggest 1-time screening with esophagogastroduodenoscopy (EGD) for Barrett's esophagus (BE) in individuals at an increased risk of esophageal adenocarcinoma (EAC). We aimed to estimate the yield of repeat EGD performed at prolonged intervals after a normal index EGD. METHODS: We conducted a national retrospective analysis within the U S Veterans Health Administration, identifying patients with a normal index EGD between 2003 and 2009 who subsequently had a repeat EGD. We tabulated the proportion with a new diagnosis of BE, EAC, or esophagogastric junction adenocarcinoma (EGJAC) and conducted manual chart review of a sample. We fitted logistic regression models for the odds of a new diagnosis of BE/EAC/EGJAC. RESULTS: We identified 71,216 individuals who had a repeat EGD between 1 and 16 years after an index EGD without billing or cancer registry codes for BE/EAC/EGJAC. Of them, 4,088 had a new billing or cancer registry code for BE/EAC/EGJAC after the repeat EGD. On manual review of a stratified sample, most did not truly have new BE/EAC/EGJAC. A longer duration between EGD was associated with greater odds of a new diagnosis (adjusted odds ratio [aOR] for each 5 years 1.31; 95% confidence interval [CI] 1.19-1.44), particularly among those who were younger during the index EGD (ages 19-29 years: aOR 3.92; 95% CI 1.24-12.4; ages 60-69 years: aOR 1.19; 95% CI 1.01-1.40). DISCUSSION: The yield of repeat EGD for BE/EAC/EGJAC seems to increase with time after a normal index EGD, particularly for younger individuals. Prospective studies are warranted to confirm these findings.

Activated B cells suppress T-cell function through metabolic competition.

BACKGROUND: B cells play a pivotal role in regulating the immune response. The induction of B cell-mediated immunosuppressive function requires B cell activating signals. However, the mechanisms by which activated B cells mediate T-cell suppression are not fully understood. METHODS: We investigated the potential contribution of metabolic activity of activated B cells to T-cell suppression by performing in vitro experiments and by analyzing clinical samples using mass cytometry and single-cell RNA sequencing. RESULTS: Here we show that following activation, B cells acquire an immunoregulatory phenotype and promote T-cell suppression by metabolic competition. Activated B cells induced hypoxia in T cells in a cell-cell contact dependent manner by consuming more oxygen via an increase in their oxidative phosphorylation (OXPHOS). Moreover, activated B cells deprived T cells of glucose and produced lactic acid through their high glycolytic activity. Activated B cells thus inhibited the mammalian target of rapamycin pathway in T cells, resulting in suppression of T-cell cytokine production and proliferation. Finally, we confirmed the presence of tumor-associated B cells with high glycolytic and OXPHOS activities in patients with melanoma, associated with poor response to immune checkpoint blockade therapy. CONCLUSIONS: We have revealed for the first time the immunomodulatory effects of the metabolic activity of activated B cells and their possible role in suppressing antitumor T-cell responses. These findings add novel insights into immunometabolism and have important implications for cancer immunotherapy.

Artificial Cell Membrane Polymersome-Based Intranasal Beta Spike Formulation as a Second Generation Covid-19 Vaccine.

Current parenteral coronavirus disease 2019 (Covid-19) vaccines inadequately protect against infection of the upper respiratory tract. Additionally, antibodies generated by wild type (WT) spike-based vaccines poorly neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. To address the need for a second-generation vaccine, we have initiated a preclinical program to produce and evaluate a potential candidate. Our vaccine consists of recombinant Beta spike protein coadministered with synthetic CpG adjuvant. Both components are encapsulated within artificial cell membrane (ACM) polymersomes, synthetic nanovesicles efficiently internalized by antigen presenting cells, including dendritic cells, enabling targeted delivery of cargo for enhanced immune responses. ACM vaccine is immunogenic in C57BL/6 mice and Golden Syrian hamsters, evoking high serum IgG and neutralizing responses. Compared to an ACM-WT spike vaccine that generates predominantly WT-neutralizing antibodies, the ACM-Beta spike vaccine induces antibodies that neutralize WT and Beta viruses equally. Intramuscular (IM)-immunized hamsters are strongly protected from weight loss and other clinical symptoms after the Beta challenge but show delayed viral clearance in the upper airway. With intranasal (IN) immunization, however, neutralizing antibodies are generated in the upper airway concomitant with rapid and potent reduction of viral load. Moreover, antibodies are cross-neutralizing and show good activity against Omicron. Safety is evaluated in New Zealand white rabbits in a repeated dose toxicological study under Good Laboratory Practice (GLP) conditions. Three doses, IM or IN, at two-week intervals do not induce an adverse effect or systemic toxicity. Cumulatively, these results support the application for a Phase 1 clinical trial of ACM-polymersome-based Covid-19 vaccine (ClinicalTrials.gov identifier: NCT05385991).

A unique hub-and-spoke model to optimize patient management in lymphoma using novel CAR-T cell therapy in Southeast and South Asia.

Novel therapeutic options for cancer offer hope for patients and their families, particularly when the cancer has not responded to established treatment regimens. The CAR-T cell therapeutic approach has changed the treatment paradigm for relapsed or refractory lymphoma, extending the capacity of the patient's own T cells to detect and eliminate cancer cells through genetic modification of T-cell surface receptors. The process of establishing treatment centers and developing clinical expertize in this novel treatment strategy is complex. Time, resources, and a commitment to focusing health budgets on a new area are required. Currently, Singapore is the only country in southeast and south Asia with market authorization of the CAR-T product, tisagenlecleucel. Availability of CAR-T treatment across international borders provides patients in neighboring countries with choice in therapeutic options. This paper describes the unique hub-and-spoke cross-border collaboration developed between Singapore and its neighbors to provide access to CAR-T cell therapy for patients with relapsed or refractory lymphoma. To date in 2022, four patients have been included in the CAR-T treatment cross-border collaboration. Their stay in Singapore has been at least 2 months' duration, including the pre-treatment evaluation, apheresis, CAR-T cell infusion and post-treatment monitoring. Patient support from referring and treating physicians, critical to the success of the undertaking, is characterized by early communication, patient selection, multi-disciplinary care, post-treatment monitoring, and attention to detail. The patient journey and the development and implementation of this unique collaboration are discussed.

A unique hub-and-spoke model to optimize patient management in lymphoma using novel chimeric antigen receptor-T cell therapy in Southeast and South Asia.

Novel therapeutic options for cancer offer hope for patients and their families, particularly when the cancer has not responded to established treatment regimens. The chimeric antigen receptor (CAR)-T cell therapeutic approach has changed the treatment paradigm for relapsed or refractory lymphoma, extending the capacity of the patient's own T cells to detect and eliminate cancer cells through genetic modification of T-cell surface receptors. The process of establishing treatment centers and developing clinical expertize in this novel treatment strategy is complex. Time, resources, and a commitment to focusing health budgets on a new area are required. Currently, Singapore is the only country in southeast and south Asia with market authorization of the CAR-T product, tisagenlecleucel. Availability of CAR-T treatment across international borders provides patients in neighboring countries with choice in therapeutic options. This paper describes the unique hub-and-spoke cross-border collaboration developed between Singapore and its neighbors to provide access to CAR-T cell therapy for patients with relapsed or refractory lymphoma. To date in 2022, four patients have been included in the CAR-T treatment cross-border collaboration. Their stay in Singapore has been about 2 months' duration, including the pre-treatment evaluation, apheresis, CAR-T cell infusion and post-treatment monitoring. Patient support from referring and treating physicians, critical to the success of the undertaking, is characterized by early communication, patient selection, multi-disciplinary care, post-treatment monitoring, and attention to detail. The patient journey and the development and implementation of this unique collaboration are discussed.

CAR T Cell Therapy in Hematological Malignancies: Implications of the Tumor Microenvironment and Biomarkers on Efficacy and Toxicity.

Chimeric antigen receptor (CAR) T cell therapy has ushered in a new era in cancer treatment. Remarkable outcomes have been demonstrated in patients with previously untreatable relapsed/refractory hematological malignancies. However, optimizing efficacy and reducing the risk of toxicities have posed major challenges, limiting the success of this therapy. The tumor microenvironment (TME) plays an important role in CAR T cell therapy's effectiveness and the risk of toxicities. Increasing research studies have also identified various biomarkers that can predict its effectiveness and risk of toxicities. In this review, we discuss the various aspects of the TME and biomarkers that have been implicated thus far and discuss the role of creating scoring systems that can aid in further refining clinical applications of CAR T cell therapy and establishing a safe and efficacious personalised medicine for individuals.