Poor Persistence Research Articles

Advances in CAR NK Cell Therapy for Targeting and Eradicating Circulating Tumor Cells: Challenges and Solutions for Aging Patients Mini Review

Chimeric Antigen Receptor (CAR) Natural Killer (NK) cells represent a promising advancement in cancer immunotherapy, particularly for targeting circulating tumor cells (CTCs) and preventing metastasis. This review examines the latest developments in CAR NK cell therapy, including diverse NK cell sources, genetic engineering techniques, and dual mechanisms of action. Targeting CTCs with CAR NK cells shows significant potential in aggressive cancers like triple-negative breast cancer (TNBC) and pancreatic cancer. The impact of aging on NK cell function, especially regarding cytotoxicity, cytokine secretion, and persistence, poses challenges for elderly patients, but strategies such as interleukin-15 and metabolic interventions offer potential solutions. The review also addresses current limitations, such as poor persistence in immunosuppressive microenvironments and low solid tumor infiltration, while proposing combination therapies to enhance effectiveness. Although still in earlier clinical stages compared to CAR T cells, CAR NK cells’ safety profile and MHC-independent recognition mechanisms make them a versatile therapeutic option. Future directions include optimizing NK cell persistence, improving infiltration, and developing age-adapted therapies for elderly patients. _________________________________________________________________________________________ Keywords: CAR NK cells, CAR T cells, Circulating tumor cells (CTCs), Cell Therapy, Aging

Factors Affecting Treatment Persistence in Japanese Patients with Psoriasis Prescribed Biologics: A Real-World Study Using an Insurance Claim Database.

Poor persistence to biologics can result in suboptimal health outcomes and increased economic burden for chronic conditions, including psoriasis (PsO). In Japan, studies evaluating factors responsible for biologic treatment persistence in patients with PsO are limited. We assessed biologic treatment persistence (median treatment duration and overall treatment survival) and associated factors in patients with PsO in a real-world setting. This retrospective analysis of insurance claims records from the Japan Medical Data Center (JMDC) database included patients with PsO [International Classification of Diseases (ICD) code: L40.x] ≥ 18years of age who had received biologic treatment. Treatment persistence was analyzed using data from 2016 to 2020 by biologic class and by individual biologics (infliximab, adalimumab, ustekinumab, guselkumab, secukinumab, ixekizumab, and brodalumab) in bio-naïve (who initiate first biologic at index) and bio-experienced patients. Kaplan-Meier survival (treatment persistence), and multivariate Cox proportional hazard regression (predictive factors) analyses were used. Overall, 1528 patients with PsO were included (mean age 47.4years). Infliximab had the longest median treatment duration (33.6months), while brodalumab had the shortest (9.7months) among biologics evaluated. Of the biologics evaluated, 1-year treatment survival was highest with guselkumab (83%), and lowest with brodalumab (45%). Bio-experienced patients showed slightly longer median treatment duration than bio-naïve patients (22.8 versus 18.1months). Factors predictive of treatment persistence were sex [male; hazard ratio (HR) 0.84, p = 0.016] and specific PsO diagnostic codes, such as L40.0 (PsO vulgaris; HR 0.69; p = 0.006), L40.1 (generalized pustular PsO; HR 0.75; p = 0.034), and L40.9 (PsO unspecified; HR 0.72; p = 0.001). Meanwhile, age and Charlson Comorbidity Index score were significantly associated with adalimumab and infliximab treatment persistence, respectively. Among biologics evaluated, infliximab had the longest median treatment duration, and guselkumab had the highest 1-year treatment survival. Sex and specific PsO diagnostic codes influenced overall treatment persistence. These findings could inform long-term treatment plans for PsO in real-world clinical settings.

A review of the potential impacts of coastal mosquito control programs on Australian Stingless Bees (Apidae, Meliponini)-likely exposure pathways and lessons learned from studies on honey bees.

The impact of the programmatic use of larvicides for mosquito control on native stingless bees (e.g., Apidae, Meliponini) is a growing concern in Australia due to heightened conservation awareness and the growth of hobbyist stingless bee keeping. In Australia, the two most widely used mosquito larvicides are the bacterium Bacillus thuringiensis var. israelensis (Bti) and the insect hormone mimic methoprene (as S-methoprene). Each has a unique mode of action that could present a risk to stingless bees and other pollinators. Herein, we review the potential impacts of these larvicides on native Australian bees and conclude that their influence is mitigated by their low recommended field rates, poor environmental persistence, and the seasonal and intermittent nature of mosquito control applications. Moreover, evidence suggests that stingless bees may display a high physiological tolerance to Bti similar to that observed in honey bees (Apis mellifera), whose interactions with B. thuringiensis-based biopesticides are widely reported. In summary, neither Bti or methoprene is likely to pose a significant risk to the health of stingless bees or their nests. However, current knowledge is limited by regulatory testing requirements that only require the use of honey bees as toxicological models. To bridge this gap, we suggest that regulatory testing is expanded to include stingless bees and other nontarget insects. This is imperative for improving our understanding of the potential risks that these and other pesticides may pose to native pollinator conservation.

Use of heart failure medical therapy before and after a cancer diagnosis: A longitudinal study.

We aim to evaluate change in the use of prognostic guideline-directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non-cancer controls, including renin-angiotensin-system inhibitors (RASIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non-cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR=1.51, 95% CI=1.35-1.68; beta-blockers: OR=1.22, 95% CI=1.08-1.37; MRAs: OR=1.31, 95% CI=1.08-1.59) and poor persistence (RASIs: OR=2.04, 95% CI=1.75-2.37; beta-blockers: OR=1.35, 95% CI=1.12-1.63; MRAs: OR=1.49, 95% CI=1.16-1.93), and higher risks for dose down-titration for RASIs (OR=1.69, 95% CI=1.40-2.04) and beta-blockers (OR=1.31, 95% CI=1.05-1.62). Cancer diagnosis was not associated with treatment initiation or dose up-titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF.

DIPG-15. NOVEL CNS SENSING SYNNOTCH-CAR T CELLS FOR TARGETING DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline glioma (DMG), including Diffuse intrinsic pontine glioma (DIPG), is an aggressive brain tumor in children with limited treatment options. Recent developments of phase 1 clinical trials have shown early promise for chimeric antigen receptor (CAR) T cells in patients with DMG/DIPG. However, several barriers such as the absence of tumor-specific antigens, restricted trafficking to the tumor site, and poor persistence hinder the full therapeutic potential of CAR T cell therapy in DMG/DIPG. METHODS To safely target the glioma-associated antigens (GAAs) without attacking nomal tissues expressing the same antigens, we adopted a novel synthetic Notch (synNotch) receptor system and engineered T cell circuits employing a “prime-and-kill” strategy. In this system, a synNotch receptor recognizing the priming antigen, Brevican (BCAN), exclusively expressed on cells in the central nervous system (CNS) but not on non-CNS cells, locally induces the expression of a tandem CAR against GAAs, ephrin type A receptor (EphA2) and interleukin-13 receptor a2 (IL13Ra2), there by homogenously eliminating DMG/DIPG cells. RESULTS The α-BCAN synNotch⋄α-EphA2/IL-13Rα2 CAR (B-SYNC) T cells efficiently killed DMG/DIPG (BT-245, SF8628, SU-DIPGXIII, and SU-DIPGXVII) cells in vitro in the presence of priming cells (K562 cells expressing BCAN). Moreover, a single intravenous infusion of B-SYNC T cells significantly (P< 0.001) prolonged the survival of immunodeficient mice bearing aggressive, orthotopic SF8628 DIPG xenografts and completely eradicated the tumor in more than 50% (4/7) of mice. Strikingly, we observed excellent homing, priming, activation, and persistence of B-SYNC T cells in the brain stem of mice bearing SF8628 xenografts. In contrast, constitutively active α-EphA2/IL-13Rα2 CAR T cells or untransduced T cells demonstrated a failure to migrate to the brain stem and improve the survival of mice. CONCLUSIONS Collectively, our findings strongly support the development of clinical trials evaluating the efficacy of B-SYNC T cells in DMG/DIPG patients.

Subcutaneous biodegradable scaffolds for restimulating the antitumour activity of pre-administered CAR-T cells.

The efficacy of adoptive T-cell therapies based on chimaeric antigen receptors (CARs) is limited by the poor proliferation and persistence of the engineered T cells. Here we show that a subcutaneously injected biodegradable scaffold that facilitates the infiltration and egress of specific T-cell subpopulations, which forms a microenvironment mimicking features of physiological T-cell activation, enhances the antitumour activity of pre-administered CAR-T cells. CAR-T-cell expansion, differentiation and cytotoxicity were driven by the scaffold's incorporation of co-stimulatory bound ligands and soluble molecules, and depended on the types of co-stimulatory molecules and the context in which they were presented. In mice with aggressive lymphoma, a single, local injection of the scaffold following non-curative CAR-T-cell dosing led to more persistent memory-like T cells and extended animal survival. Injectable biomaterials with optimized ligand presentation may boost the therapeutic performance of CAR-T-cell therapies.

Fully equipped CARs to address tumor heterogeneity, enhance safety, and improve the functionality of cellular immunotherapies.

Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin

Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells

The antitumor efficacy of adoptively transferred T cells is limited by their poor persistence, in part due to exhaustion, but the underlying mechanisms and potential interventions remain underexplored. Here, we show that targeting histone demethylase LSD1 by chemical inhibitors reshapes the epigenome of in vitro activated and expanded CD8+ T cells, and potentiates their antitumor efficacy. Upon T cell receptor activation and IL-2 signaling, a timely and transient inhibition of LSD1 suffices to improve the memory phenotype of mouse CD8+ T cells, associated with a better ability to produce multiple cytokines, resist exhaustion, and persist in both antigen-dependent and -independent manners after adoptive transfer. Consequently, OT1 cells primed with LSD1 inhibitors demonstrate an enhanced antitumor effect in OVA-expressing solid tumor models implanted in female mice, both as a standalone treatment and in combination with PD-1 blockade. Moreover, priming with LSD1 inhibitors promotes polyfunctionality of human CD8+ T cells, and increases the persistence and antitumor efficacy of human CD19-CAR T cells in both leukemia and solid tumor models. Thus, pharmacological inhibition of LSD1 could be exploited to improve adoptive T cell therapy.

Real-world persistence and adherence to glucagon-like peptide-1 receptor agonists among obese commercially insured adults without diabetes.

In 2014, the US Food and Drug Administration approved the first glucagon-like peptide-1 (GLP-1) receptor agonist product, liraglutide injection, for obesity treatment. Many GLP-1 obesity treatment clinical trials report significant weight loss and medication adherence at more than 85%. Little is known about the real-world GLP-1 obesity treatment adherence, persistence, and switch rates. To measure GLP-1 therapy persistence, adherence, and switch rates in a real-world cohort of members without diabetes using these drugs for obesity treatment. Integrated pharmacy and medical claims data from 16.5 million average monthly commercially insured membership were used to identify obese members without diabetes newly initiating GLP-1 therapy between January 1, 2021, and December 31, 2021. Members were required to be continuously enrolled 1-year before and after the GLP-1 therapy start date and aged 19 years of age or older. Persistence was measured as no greater than or equal to 60-day gap with allowance for GLP-1 switching. Adherence was measured as the proportion of days covered (PDC) and members with a PDC greater than or equal to 80% were considered adherent. GLP-1 product switching was also assessed descriptively. 4,066 commercially insured obese members without diabetes that newly initiated GLP-1 therapy met all study criteria. The mean age was 46 years, and 81% were female. Overall, GLP-1 persistence was 46.3% at 180 days and 32.3% at 1 year. The highest and lowest persistence rates at 1 year were observed for semaglutide (Ozempic) at 47.1% and liraglutide (Saxenda) 19.2%, respectively. Average PDC during the 1-year assessment was 51.0% with 27.2% adherent to therapy and 11.1% switched GLP-1 drugs. This GLP-1 weight loss treatment real-world analysis, among obese individuals without diabetes, found poor 1-year persistence and adherence and low rates of switching between products. These findings will aid in assessing products cost-effectiveness, understanding obesity care management program needs, forecasting future GLP-1 use and cost trends, and negotiating GLP-1 pharmaceutical manufacturer value-based purchasing agreements.

Overexpressing Bcl-2 enhances murine chimeric antigen receptor T cell therapy against solid tumor.

Chimeric antigen receptor T (CART) cell therapy has demonstrated promising potential in the treatment of hematologic malignancies. However, its application to solid tumors is limited due to the restrictive nature of the tumor microenvironment, resulting in functional failure and poor persistence of CART cells. Overexpression of Bcl-2 in human CART cells (hCART) has been found to significantly enhance their anti-apoptotic effects both in vitro and in vivo. Nevertheless, the evaluation of hCART cells in preclinical studies has predominantly relied on immunodeficient mice xenograft tumor models, making it challenging to assess the impact of hCART cells on normal tissues and the immune system. We established a murine CART (mCART) that overexpresses Bcl-2 and targets the epidermal growth factor receptor variant III (EGFRvIII), named EGFRvIII·mCART-Bcl2. It demonstrated superior proliferation, cytotoxicity, and anti-apoptotic capabilities in vitro. In an immunocompetent mouse model of abdominal metastasis of colorectal cancer, EGFRvIII·mCART-Bcl2 exhibited improved survival of CART in the abdomen, increased tumor clearance, and significantly prolonged overall mouse survival. In summary, our study provides evidence that the introduction of Bcl-2 into mCART cells can enhance their therapeutic efficacy against solid tumors while ensuring safety.

Chemokine‐Based Injectable Navigation System for Enhancing CAR‐T Cell Therapy Against Solid Tumors

AbstractChimeric antigen receptor (CAR)‐T cell therapy has demonstrated poor efficacy for solid tumors. The low number and poor functional persistence of CAR‐T cells in tumors are the main limiting factors. Here a Chemokine‐based Injectable platform for enhancing adoptive T cells’ Efficacy (CITE) is presented. CITE consists of peritumorally‐injected immunogel co‐loading chemotactic CXCL9 particles with PD‐1 antibody (aPD1) and intravenously‐infused tumor‐penetrating peptide iRGD. Immunogel formed drug depots and allowed sustained release of cargo peritumorally while iRGD facilitated tumor infiltration of gel‐released drugs, thus remarkably increasing the amount of CXCL9 and aPD1 in the tumor. CITE induced an effective chemotactic gradient to promote the tumor‐specific migration of CAR‐T cells and boosted the function of infiltrated T cells by blocking immunosuppression via a two‐in‐one approach. Consequently, CITE yielded a 218‐fold increase in the intratumoral number of transferred T cells and substantially improved the efficacies of transferred T cell receptor (TCR)‐T cells and CAR‐T cells in multiple syngeneic tumor models, including immunologically “cold” tumors, in immunocompetent mice. More importantly, CITE enhanced systemic antitumor immunity and elicited immune memory, enabling CITE to treat multimodal, metastatic, and recurrent tumors. CITE is broadly applicable to adoptive cell therapies involving CAR‐T or TCR‐T cells.

FOXO1 is a master regulator of memory programming in CAR T cells

A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2–6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.

Adherence and Persistence to Basal Insulin Among People with Type2 Diabetes in Europe: A Systematic Literature Review and Meta-analysis.

Diabetes is associated with a number of complications, particularly if glycaemic targets are not achieved. Glycaemic control is highly linked to treatment persistence and adherence. To understand the burden of poor persistence and adherence, this systematic literature review identified existing evidence regarding basal insulin adherence/non-adherence and persistence/non-persistence among people with diabetes in Western Europe (defined as the UK, France, Spain, Switzerland, the Netherlands, Ireland, Austria, Portugal, Denmark, Norway, Sweden, Finland, Italy, Germany, Iceland and Belgium). Eligible studies were systematically identified from two databases, Medline and Embase (published between 2012 and June 2022). Conference abstracts from ISPOR and EASD were manually included. Identified studies were screened by two independent reviewers in a two-step blinded process. The eligibility of studies was decided on the basis of pre-established criteria. A proportional meta-analysis and comparative narrative analyses were conducted to analyse the included studies. Twelve studies were identified. Proportions of adherence/non-adherence and persistence/non-persistence varied across studies. Pooled rates of non-persistence at 6, 12 and 18months were 20.3% (95%CI 13.8; 27.8), 33.8% (95%CI 24.1; 44.3) and 36.5% (95%CI 33.6; 39.4), respectively. In the literature, the proportion of adherent people ranged from 41% to 64% (using the outcome measure medication possession ratio (MPR) > 80%), with a pooled rate of 55.6% (95%CI 45.3; 65.6), suggesting that approximately 44% of people with type2 diabetes (T2D) are non-adherent. The results highlight that almost half of patients with T2D in Western Europe have poor adherence to insulin therapy and, at 18months, one in three patients do not persist on treatment. These findings call for new basal insulin therapies and diabetes management strategies that can improve treatment persistence and adherence among people with T2D.

Abstract 6326: Targeting PRDM1 to enhance CAR T cell efficacy against diffuse large B cell lymphoma (DLBCL)

Abstract CAR T cell therapy has shown remarkable success in treating patients with relapsed or refractory (r/r) DLBCL, but a majority (&amp;gt;60%) will experience disease progression. A key failure mechanism is the rapid terminal differentiation and exhaustion of CAR T cells, driven by persistent antigen exposure in vitro during manufacturing and in vivo in the DLBCL environment, which culminates in poor persistence and short-term effector functions. Recent studies have identified the transcriptional repressor PR/SET domain 1 (PRDM1) as a key regulator that drives differentiation of T cells toward these unwanted fates. Further, single cell transcriptomic profiling of r/r DLBCL biopsies has revealed PRDM1 enrichment in a cluster of exhausted-like CD8+ CAR T cells. These observations indicate that targeting PRDM1 could prevent or delay terminal differentiation/exhaustion in CAR T cells, thereby enhancing their persistence for lasting anti-tumor activity. Using CRISPR/Cas9 targeting, we have demonstrated that PRDM1-deficient CAR T cells exhibit enhanced proliferative capacity, memory characteristics, and resilience against exhaustion upon repeated stimulation. Moreover, genetic ablation of PRDM1 also promoted the in vivo expansion and persistence of CAR T cells, which led to significantly improved survival of lymphoma-bearing mice. Mechanistically, loss of PRDM1 leads to de-repression of PPARGC1A (PGC1α), a master regulator of mitochondrial biogenesis and antioxidant activity. This confers elevated tolerance to oxidative damage in CAR T cells lacking PRDM1, which showed increased capacity to buffer oxidative stress induced by mitochondrial uncouplers and constant stimulation. These findings suggest that PRDM1 loss may improve CAR T cell fitness through PGC1α upregulation and mitochondrial activation. From a translational perspective, we assessed the potential synergistic effects of PGC1α agonist, bezafibrate, with CAR T cells. Dual therapy with bezafibrate and CAR T cells mediated more robust expansion and anti-tumor immunity of CAR T cells without causing discernible adverse events. Importantly, bezafibrate alone had no direct tumoricidal effects, which indicates that bezafibrate suppressed tumor growth through modulating CAR T cell functions. Moving forward, we will uncover the previously uncharted role of PRDM1 in orchestrating the mitochondrial and metabolic activity of CAR T cells. Building upon a correlation between PRDM1 expression and CAR T cell dysfunction, we aim to pioneer the use of PRDM1 and/or its target genes as novel biomarkers for predicting clinical responses of r/r DLBCL patients to CAR T cell therapy. Our endeavors will shed light on the long-standing conundrum of CAR T cell dysfunction and offer solutions that may be applicable for improving T cell-based therapy against cancer in general. Citation Format: Sidney Wang, Lishi Xie, Xiufen Chen, Alan Cooper, Joanna Chorazeczewski, Justin Kline. Targeting PRDM1 to enhance CAR T cell efficacy against diffuse large B cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6326.

Abstract 18: The polyamine-hypusine axis is a promising avenue to improve T-cell metabolism and persistence for adoptive cell therapy

Abstract There are significant barriers to the application of Adoptive Cell Therapy (ACT) to many cancer types. One of these barriers is a result of poor metabolic fitness of T cells, leading to poor proliferation, persistence, and dampened anti-tumor function. Leveraging T-cell metabolism to improve their function is becoming increasingly important to make significant strides in immunotherapy. Stat5a has been shown to be a master regulator of energy and metabolism in T cells, highlighting it as a promising avenue to improve T-cell metabolism for ACT. We have established that the expression of Constitutively Active Signal Transducer and Activator of Transcription 5A (CASTAT5) on tumor-specific CD4+ T cells improves their persistence, polyfunctionality, and anti-tumor effects in a mouse model. This study further examines Stat5a and its downstream metabolic targets in the context of ACT. We carried out scRNAseq analysis and found that Stat5a directly interacts with genes involved in polyamine metabolism. More specifically, Stat5a activation increases the expression of ornithine decarboxylase (Odc1), spermidine synthase (Srm), deoxyhypusine synthase (Dhps), and deoxyhypusine hydroxylase (Dohh) in a subset of CD4+ T cells expressing CASTAT5. Cleavage Under Targets and Tagmentation (Cut&amp;Tag) analysis of histone H3K27ac also demonstrated increased H3K27ac at promoter and enhancer regions of polyamine pathway genes in CASTAT5 compared to control CD4+ T cells. To further examine the function of Stat5a, the murine pro-B cell line, Ba/F3, is being used as a model to study Stat5a-mediated signaling. We have found that upon withdrawal of IL-3 from Ba/F3 cells, Stat5a activation is significantly downregulated. Our scRNA-seq-based metabolic flux estimation showed a significant reduction in metabolic fluxes and related genes, including polyamines, following IL-3 withdrawal. Correspondingly, Stat5a ChIP-Seq and Cut&amp;Tag analyses of H3K27ac revealed Stat5a binding to active enhancer regions in the presence of IL-3 that are lost following its withdrawal. Untargeted metabolomics confirmed the marked Stat5a-mediated reduction in metabolite abundance after IL-3 deprivation, in a time-dependent manner. The polyamine-hypusine axis revealed in our studies is a promising avenue to improve T-cell function. This axis has been shown to regulate T-cell function, and potentially modulate mitochondrial respiration and T-cell activation. Hence, our studies have identified polyamine supplementation and gene modulation as promising strategies to improve the metabolism of Adoptive T cells in a Stat5a-mediated manner. Further studies will evaluate the effectiveness of this avenue in improving T-cell function, improving their efficacy for ACT, and improving patient outcomes. Citation Format: Mercy Kehinde-Ige, Ogacheko Okoko, Gang Zhou, Huidong Shi. The polyamine-hypusine axis is a promising avenue to improve T-cell metabolism and persistence for adoptive cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 18.

Impact of Glucagon-Like Peptide1 Agonist Deprescription in Type2 Diabetes in a Real-World Setting: A Propensity Score Matched Cohort Study.

Glucagon-like peptide1 receptor agonists (GLP-1) elicit substantial reductions in glycemia and body weight in people with type2 diabetes (T2D) and obesity, but existing data suggest the therapy must be continued indefinitely to maintain clinical improvements. Given the high cost and poor real-world persistence of GLP-1, an effective therapy that enables deprescription with sustained clinical improvements would be beneficial. Thus, the purpose of this real-world study was to assess the effect of GLP-1 deprescription on glycemia and body weight following co-therapy with carbohydrate restricted nutrition therapy (CRNT) supported via telemedicine in a continuous remote care model. A retrospective, propensity score matched cohort study among patients with T2D at a telemedicine clinic was conducted. Patients in whom GLP-1 were deprescribed (DeRx; n = 154) were matched 1:1 with patients in whom GLP-1 were continued (Rx). HbA1c and body weight at enrollment in clinic (pre-CRNT), at date of deprescription or index date (derx/ID), and at 6 and 12months (m) post-derx/ID were utilized in this study. No regression in weight was observed following deprescription with > 70% maintaining ≥ 5% weight loss 12m post-derx/ID. HbA1c rose 6m and 12m post-derx/ID in both DeRx and Rx cohorts, but most patients maintained HbA1c < 6.5%. HbA1c and body weight measured 6m and 12m following derx/ID did not significantly differ between cohorts and were improved at derx/ID and at follow-up intervals compared to pre-CRNT. These results demonstrate the potential for an alternate therapy, such as CRNT supported via telemedicine, to enable maintenance of weight loss and glycemia below therapeutic targets following discontinuation of GLP-1 therapy.

Revolutionizing cancer treatment: enhancing CAR-T cell therapy with CRISPR/Cas9 gene editing technology.

CAR-T cell therapy, a novel immunotherapy, has made significant breakthroughs in clinical practice, particularly in treating B-cell-associated leukemia and lymphoma. However, it still faces challenges such as poor persistence, limited proliferation capacity, high manufacturing costs, and suboptimal efficacy. CRISPR/Cas system, an efficient and simple method for precise gene editing, offers new possibilities for optimizing CAR-T cells. It can increase the function of CAR-T cells and reduce manufacturing costs. The combination of CRISPR/Cas9 technology and CAR-T cell therapy may promote the development of this therapy and provide more effective and personalized treatment for cancer patients. Meanwhile, the safety issues surrounding the application of this technology in CAR-T cells require further research and evaluation. Future research should focus on improving the accuracy and safety of CRISPR/Cas9 technology to facilitate the better development and application of CAR-T cell therapy. This review focuses on the application of CRISPR/Cas9 technology in CAR-T cell therapy, including eliminating the inhibitory effect of immune checkpoints, enhancing the ability of CAR-T cells to resist exhaustion, assisting in the construction of universal CAR-T cells, reducing the manufacturing costs of CAR-T cells, and the security problems faced. The objective is to show the revolutionary role of CRISPR/Cas9 technology in CAR-T cell therapy for researchers.

Herbage and sheep production from simple, diverse, and legume pastures established in an agrivoltaic production system

AbstractAgrivoltaic systems combine solar energy and agriculture, promoting dual land use. Although grazing sheep in these systems is common, research on intentionally designed pastures to increase production is lacking. This study seeks to compare the herbage growth and lamb production in simple, diverse, and legume pastures in an agrivoltaic system over 2 years in Oregon. Annual herbage production in diverse pastures (4583 kg DM ha−1) was comparable to simple pastures (4457 kg DM ha−1), but higher than legume pastures (p &lt; .05; 4023 kg DM ha−1) for the 2020/2021 growing season. In the 2021/2022 growing season, diverse pastures had a higher yield (4660 kg DM ha−1, p &lt; .05) than simple pastures (4052 kg DM ha−1), which were similar to legume pastures (3955 kg DM ha−1). Liveweight gain (LWG; g head−1 d−1) tended (p = .06) to be higher from lambs in diverse and legume pastures compared to simple pastures in spring 2021. Liveweight production (LWP; kg ha−1 d−1) of legume pasture were greater (P &lt; 0.05) than other pasture types, while simple pastures had the lowest LWP during this period. In summer 2021, LWG tended to be greater in lambs grazing diverse versus simple pastures. No difference was detected (all p &gt; .05) in LWG or LWP at any grazing period in 2022. Overall, efficiency of pasture production was greatly reduced by lower light availability in all pasture types. Diversification of pastures using forbs in agrivoltaics was a good strategy for greater herbage production, while the legume pastures had poor persistence.

Functional Analysis of Contextually Inappropriate Social Behavior in Children With Down Syndrome.

Children with Down syndrome often engage in contextually inappropriate social behavior, which researchers suggest may function to escape from difficult activities to preferred social interactions. Caregivers may reinforce the behavior, perceiving it only as evidence of the child's social strength, when, in fact, the pattern may also prevent or slow the development of critical skills. Unlike overt forms of challenging behavior, contextually inappropriate social behavior had never been subjected to experimental analysis. The purpose of the current study was to identify and demonstrate functional control of contextually inappropriate social behavior to caregiver-informed contingencies. We interviewed caregivers and subjected contextually inappropriate social behavior to functional analyses for nine young children with Down syndrome. We found sensitivity to the caregiver-informed contingencies for all nine participants with strong functional control and large effect sizes for most. Caregivers may not perceive contextually inappropriate social behavior as problematic, yet patterns of contextually inappropriate and other problem behaviors suggest decreased engagement and poor task persistence. Assessments that lead to intervention decisions may be more informative when they include questions about social topographies of behavior not typically considered as problematic. Once caregivers are aware of the pattern, they may be better prepared to intervene.