Multiple Clinical Trials Research Articles

Outcomes for adults with KMT2A-r acute myeloid leukemia treated with venetoclax plus azacitidine (Ven/Aza) or intensive chemotherapy (IC): A single-center retrospective study.

e18537 Background: KMT2A-rearranged acute myeloid leukemia (KMT2A-r AML) is known for adverse outcomes due to aggressive disease presentation and high relapse rates. Oral menin inhibitors are being studied in combination with frontline chemotherapy regimens. However, baseline data regarding outcomes for KMT2A-r AML treated with Ven/Aza is limited. Here, we conducted a study to assess outcomes in newly diagnosed KMT2A-r AML treated with Ven/Aza or IC. Methods: We retrospectively analyzed outcomes for adults with KMT2A-r AML who received Ven/Aza or IC as their first therapy. Phenotype was assessed by Hematopathology by morphologic review and flow cytometry. A monocytic phenotype was defined by >20% monocytic differentiation within the blast population on morphology and expression of at least 2 of the following: CD14, CD64, CD11b, and CD11c. Responses were recorded based on 2022 ELN criteria. Statistical analyses were performed on R v4.4.2. Results: This study included 34 pts with KMT2A-r AML, with 50% receiving Ven/Aza (n = 17) and 50% receiving IC (n = 17). The median age was 46 (19-78) years (y), with the IC cohort being relatively younger (41 vs 57y for Ven/Aza; p = 0.01). 76% of pts had de novo AML, while 24% had therapy-related AML (t-AML). Most pts (79%) had a monocytic phenotype. The composite complete remission (CRc) rate was 35% in pts who received Aza/Ven and 82% in pts who received IC (p=0.005). Among the entire cohort, the median overall survival (mOS) was 17 months (mo) (95% CI 8.4 mo, NR), and the median event-free survival (mEFS) was 5.2 mo (3.7 mo, NR). The mOS was 8.8 mo (3.5 mo, NR) in pts treated with Ven/Aza and 37 mo (9.3 mo, NR) in pts treated with IC (p=0.27). The mEFS was 3.8 mo (2.0 mo, NR) in pts treated with Ven/Aza and 37 mo (4.6 mo, NR) in pts treated with IC (p=0.072). In multivariate analyses, Allo-HSCT was associated with a reduced risk of relapse (HR 0.09 (95% CI 0.03–0.33, p < 0.001)) and decreased risk of death (HR 0.17 (95% CI 0.05–0.52, p < 0.001)). t-AML was associated with an increased risk of death with a HR of 3.03 (95% CI 1.16–7.95, p = 0.02). Conclusions: Our results demonstrate that KMT2A-r is associated with a monocytic phenotype and highlights poor outcomes in KMT2A-r AML when treated with Ven/Aza as frontline therapy. Allo-HSCT independently improves the likelihood for long term survival. Whether the addition of a menin inhibitor to frontline chemotherapy will improve outcomes is being assessed in multiple clinical trials. Characteristics and responses for KMT2A-r AML. Variables Ven/AzaN = 17 IC 1 N = 17 P-value Median age, yrs 57 41 0.01 t-AML, n (%) 6 (35) 2 (12) 0.2 Monocytic phenotype, n (%) 12 (71) 15 (88) 0.4 Response, n (%)- CR- CRi- No response- UnknownCRc (CR + CRi) 5 (33)1 (6.7)9 (60)26 (35) 13 (81)1 (6.3)2 (13)114 (82) 0.007 0.005 1 IC regimens included 7+3 (n=13), 7+3 with midostaurin (n=1), FLAG-Ida+Ven (n=3).

Composite Confirmed Disability Worsening/Progression Is a Useful Clinical Endpoint for Multiple Sclerosis Clinical Trials.

Sensitive and meaningful disability worsening measures remain an unmet medical need in multiple sclerosis (MS). Composite confirmed disability worsening/progression (cCDW/cCDP) combines the Expanded Disability Status Scale (EDSS) with performance tests of ambulation and dexterity (Timed 25-Foot Walk Test [T25FWT] and Nine-Hole Peg Test [9HPT]). We assessed the relation of changes in these measures to understand the utility of cCDW/cCDP as an endpoint for MS trials. Clinical trials measuring all components of cCDW were selected for the analysis of (i) individual patient-level data from Roche-sponsored MS studies to characterize the association between performance-test changes and subsequent EDSS changes and (ii) population-level data from published studies reporting treatment effects on EDSS and either cCDP or T25FWT or 9HPT events to examine the relationship between treatment effects on T25FWT and EDSS events. Analysis (i): 6 Roche-sponsored Phase III trials comprising 4,979 patients with relapsing-remitting MS (RRMS; n = 1,225), relapsing MS (RMS; n = 1,656), progressive MS (PMS; n = 922), and primary progressive MS (PPMS; n = 1,171), with a data cutoff of November 2022, were included in the individual patient analyses. For all trials, T25FWT events were associated with increased risk of subsequent EDSS events (hazard ratios [HRs], p values: 2.11-5.20, 0.07-<0.001); similar associations were found for 9HPT events with HRs for later EDSS events ranging from 1.47 to 2.66 (p values from 0.24-<0.001). For patients without EDSS events in the first 96 study weeks, T25FWT or 9HPT events in the first 96 study weeks were associated with increased risk of subsequent EDSS events (HRs, p values: T25FWT 1.74-3.26, 0.01-<0.001; 9HPT 1.45-3.08, 0.45-<0.001). Patients with T25FWT or 9HPT events were more likely to experience a ≥8-point change from baseline at the final visit in the 29-item Multiple Sclerosis Impact Scale physical subscale (risk ratios, p values: T25FWT 1.45-2.17, 0.004-<0.001; 9HPT 1.26-1.87, 0.15-0.03). Analysis (ii): In the 9 studies included, treatment effects on T25FWT events were predictive of treatment effects on EDSS events (Spearman correlation [95% CI] = 0.82 [0.34-0.96], p = 0.005). In this post hoc analysis, worsening on T25FWT or 9HPT was a harbinger of EDSS worsening and treatment effects on T25FWT correlated with those on EDSS. These results establish the predictive validity and clinical relevance of performance-test worsening, thus supporting use of cCDW/cCDP as a primary outcome for progression in MS trials. ClinicalTrials.gov Identifiers: NCT01247324 (OPERA I); first submitted November 23, 2010; first patient enrolled: August 31, 2011; available at clinicaltrials.gov/study/NCT01247324. NCT01412333 (OPERA II); first submitted August 8, 2011; first patient enrolled: September 20, 2011; available at clinicaltrials.gov/study/NCT01412333. NCT03085810 (ENSEMBLE); first submitted March 16, 2017; first patient enrolled: March 27, 2017; available at clinicaltrials.gov/study/NCT03085810. NCT01194570 (ORATORIO); first submitted August 28, 2010; first patient enrolled: March 3, 2011; available at clinicaltrials.gov/study/NCT01194570. NCT03523858 (CONSONANCE); first submitted April 16, 2018; first patient enrolled: May 28, 2018; available at clinicaltrials.gov/study/NCT03523858. NCT00087529 (OLYMPUS); first submitted July 9, 2004; first patient enrolled: July 9, 2004; available at clinicaltrials.gov/study/NCT00087529.

Inhibitory pattern recognition receptors: lessons from LAIR1.

Many inhibitory receptors that regulate immune cell function recognize a limited number of specific ligands. However, a subgroup of so-called inhibitory pattern recognition receptors (iPRRs) can bind a much larger array of ligands of structural similarity. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) is one such iPRR that is expressed by most immune cells and recognizes a common structural pattern present in collagens and collagen domain-containing proteins. LAIR1 signalling regulates diverse immune cell populations and is currently the focus of multiple clinical trials for the treatment of cancer. We here review the current literature on LAIR1, as a prototypic example of how inhibitory PRRs contribute to immune balance and of how these receptors are regulated. We discuss the function of LAIR1 in homeostasis, infection, inflammation and cancer, and consider the advantages and potential pitfalls of targeting this receptor in human disease.

Precision Medicine for Pediatric Glioma and NF1-Associated Tumors: The Role of Small Molecule Inhibitors.

Pediatric gliomas encompass the most common brain tumor in children and are subdivided into pediatric low-grade gliomas (pLGGs) and pediatric high-grade gliomas (pHGGs). The era of molecular diagnosis has shifted the treatment paradigms and management of these patients. RAS/MAPK pathway alterations serve as the driver in the majority of pLGGs, a subset of pHGG and NF1-related plexiform neurofibromas (PNs). The role of small molecule inhibitors in the treatment of these tumors has evolved in the past decade, facilitated through multiple clinical trials and moving into earlier stages of treatment. Although these developments hold promise, questions remain regarding targeted therapy, the long-term toxicities, the duration of treatment and the potential effects on the natural history of the tumor behavior.

P36 - Comparative evaluation of three analytical approaches for pooled data from multiple clinical trials - Application to estimate the impact of post-resection adjuvant chemotherapy in rectal cancer

P36 - Comparative evaluation of three analytical approaches for pooled data from multiple clinical trials - Application to estimate the impact of post-resection adjuvant chemotherapy in rectal cancer

Practical approach to the patient with hypercholesterolemia in Spain. SEMERGEN position statement

Hypercholesterolemia, specifically the increase in the set of lipoproteins containing apolipoproteinB and, in particular, low-density lipoprotein cholesterol (LDL-C), together with the decrease in high-density lipoprotein cholesterol (HDL-C) constitute the etiopathogenic basis of atherosclerotic vascular disease. Multiple clinical trials have shown that lowering LDL-C by lipid-lowering therapy is associated with a significant decrease in the risk of vascular complications. Thus, LDL-C is the main therapeutic target in patients with dyslipidemia. Unfortunately, current LDL-C control figures are still very low, partly due to insufficient intensification of lipid-lowering therapy, but also due to the need for new tools to achieve these goals. This paper reviews the different lipid-lowering treatment options, including the latest available therapies, and provides a practical approach to achieving LDL-C control goals in patients with hypercholesterolemia, as well as in different patient subgroups.

Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence.

Multiscale characterization of ultrasmall fluorescent core-shell silica nanoparticles in cartilage and synovial joints reveals rapid cartilage penetration and sustained joint residence.

Refining Outcome Measures in Multiple Sclerosis Clinical Trials: A Call to Action

Refining Outcome Measures in Multiple Sclerosis Clinical Trials: A Call to Action

Contemporary risk models for transcatheter aortic valve replacement: A narrative review.

Contemporary risk models for transcatheter aortic valve replacement: A narrative review.

Gene therapy for hemophilia- From basic science to first approvals of "one-and-done" therapies.

Gene therapy for hemophilia- From basic science to first approvals of "one-and-done" therapies.

Perivascular Niche-Resident Alveolar Macrophages Promote Interstitial Pneumonitis Related to Trastuzumab Deruxtecan Treatment.

Trastuzumab deruxtecan (T-DXd) is a transformative HER2-targeting antibody-drug conjugate (ADC) for treating breast cancer. Unfortunately, T-DXd has also been implicated in causing fatal interstitial lung disease (ILD) in multiple clinical trials. A better understanding of the mechanistic basis of these ADC-induced adverse effects could enable development of strategies to prevent or treat T-DXd-related ILD. In this study, we determined that T-DXd-induced ILD represents an off-target adverse event rather than an on-target off-tumor adverse event. To further investigate this phenomenon, an immunocompetent murine model that recapitulates T-DXd-induced ILD events was developed, facilitating in-depth mechanistic studies. Single-cell RNA sequencing in this model implicated alveolar macrophages (AM) as the primary cell type impacted by T-DXd in the lung microenvironment. Intravital microscopy further revealed that AMs resident in perivascular niches directly engulfed blood-circulating T-DXd via Fc-FcγR engagement. This Fc-FcγR interaction with T-DXd triggered a phenotypic shift in AMs from an immunosuppressive to a pro-ILD state, characterized by inflammation and immune activation, mediated through the SPP1 pathways. Finally, mitigating nonspecific T-DXd uptake in the lung by preconditioning perivascular AMs with IgG1 or the parental antibody of T-DXd significantly reduced unintended ADC absorption. These findings elucidate a mechanism by which T-DXd ignites the lung immune microenvironment and underscore the importance of off-target endocytosis by innate immune cells in the development of ADC-related toxicities. Significance: Preconditioning the perivascular niche can prevent lung inflammation induced by antibody-drug conjugate phagocytosis by alveolar macrophages and subsequent SPP1high macrophage differentiation, providing a clinically viable strategy for mitigating interstitial lung disease.

Application and Mechanism of GLP-1 Receptor Agonists in the Treatment of Obesity Complicated with Type 2 Diabetes Mellitus

Obesity and type 2 diabetes mellitus (T2DM) are the main metabolic diseases in the world, and they are closely related in pathogenesis. Obesity can induce insulin resistance and chronic inflammation, while T2DM is often accompanied by abnormal distribution of body fat, which further aggravates metabolic disorder. Traditional treatment methods have some problems, such as hypoglycemia risk, weight gain and limited long-term curative effect. Therefore, the development of new hypoglycemic and weight-reducing drugs has become a clinical demand. GLP-1 receptor agonists (GLP-1 RAs), as a new generation of hypoglycemic drugs, has become a breakthrough in the treatment of obesity complicated with T2DM with its unique glucose-dependent hypoglycemic mechanism, significant weight loss effect and potential cardiovascular protection. By activating GLP-1 receptors, GLP-1 RAs enhance insulin secretion, suppress glucagon release, delay gastric emptying, and inhibit appetite, thereby improving glycemic control and reducing energy intake. Multiple clinical trials have confirmed that GLP-1 RAs can significantly lower glycated hemoglobin (HbA1c) levels, reduce body weight by 5%-15%, and decrease the risk of cardiovascular events by 13%-26%. However, their mechanism of action has not been fully elucidated, and differences in efficacy and long-term safety still require further investigation. This article reviews the current application of GLP-1 RAs in the treatment of obesity combined with T2DM, explores their multi-faceted mechanisms of action in glycemic control, weight loss, and cardiovascular protection, and analyzes their efficacy and safety based on the latest clinical research data to provide a reference for rational clinical use.

Patent Ductus Arteriosus in Preterm Infants.

Despite extensive research in basic science and in clinical settings with thousands of infants over decades, uncertainty and controversy persist regarding the significance, assessment, and management of the patent ductus arteriosus (PDA) in preterm infants, resulting in substantial variability in clinical approach. This clinical report aims to succinctly review the available evidence to guide evaluation and treatment of preterm infants with prolonged ductal patency. Delayed closure of the PDA is common in preterm infants, particularly at more extreme immaturity. Echocardiography is essential for confirming the presence of a PDA and assessing hemodynamic significance. Medical closure of a PDA using ibuprofen or acetaminophen is an option for a hemodynamically significant PDA (hsPDA). Recent data from multiple clinical trials indicate the lack of benefits of prophylactic or early (<2weeks of age) medical closure of PDA as compared with expectant management, and they are, therefore, not recommended. There are insufficient data to support firm recommendations on management of infants with an hsPDA beyond 2weeks of age as relative benefits and risks of expectant management with close monitoring, attempted pharmacologic closure, or procedural (transcatheter/surgical) closure have not been adequately defined. Many clinicians attempt medical closure of an hsPDA beyond 2weeks of age. If the hsPDA persists despite medical therapy (or if medical therapy is contraindicated), such infants may be considered for either transcatheter closure or surgical ligation. In recent years, surgical closure of the PDA has become less frequent, and transcatheter closure is more common in many centers. Although there are known adverse effects of an hsPDA, there is a lack of evidence to guide management, necessitating equipoise regarding treatment options and timing and a need for trials that can expand the available body of evidence, especially regarding long-term cardiopulmonary and neurodevelopmental outcomes.

Model-Informed Immunogenicity Assessment of Nivolumab as Monotherapy and in Combination with Ipilimumab.

Immunogenicity to biotherapeutics can lead to antidrug antibodies (ADAs) that have potential to alter pharmacokinetics (PK), efficacy, and safety. Here we provide an extensive model-informed immunogenicity assessments of nivolumab monotherapy and in combination with ipilimumab across multiple clinical trials. ADA was evaluated as both a binary and semiquantitative covariate, incorporating ADA titers to account for intensity over time. Data from 28 clinical trials, including 7,820 subjects with 2,770 ADA titer measurements, were analyzed using population pharmacokinetic (popPK) modeling. Nivolumab ADA incidence rate was higher for combination therapy (~ 32%) compared to monotherapy (~ 16%). ADA increased nivolumab clearance (CL) by 20-80% depending on titer. Nivolumab ADA impact on efficacy and safety was evaluated in melanoma and non-small cell lung cancer (NSCLC) patients. Despite the occurrence of nivolumab ADA being associated with lower nivolumab exposures, objective response rates (ORR) were similar in ADA-positive and negative patients, and ADA titer was not a significant predictor of response. An overall survival (OS) landmark analysis at 3months suggested similar OS for NSCLC but lower OS for melanoma for ADA-positive vs negative patients mainly due to the imbalanced patient baseline characteristics. Propensity score matching and multivariable Cox Proportional-Hazards analysis indicated no ADA impact on OS. Additionally, there were no associations between ADA and acute hypersensitivities or immune mediated safety events. This model-based approach underscores the importance of accounting for ADA dynamics in clinical development and supports no significant association between ADA presence and clinical efficacy or safety, even with higher ADA incidence in combination therapy.

Abstract 3184: Development of novel anti-mesothelin CAR-T cells for the treatment of solid tumors

Abstract Introduction: Mesothelin (MSLN) is overexpressed in many human solid tumors and absent from most healthy tissues. Despite multiple clinical trials, little success has been achieved by MSLN CARs. Shed MSLN accumulates in patient sera and tumor draining fluids, potentially blocking MSLN CAR function (1, 2). Alpaca-derived VHHs are an attractive option for CAR design that offer exquisite epitope targeting and the potential to circumvent the challenges of cleaved and shed MSLN. Methods: Eight alpaca-derived VHHs targeting the MSLN membrane-proximal region were incorporated into a second-generation CD28-CD3ζ CAR framework. A previously developed scFv-based MSLN CAR with either CD28 or 4-1BB co-stimulation was used as comparison. MSLN CAR-T cells from healthy donors were tested in vitro for CAR surface expression, overnight killing and real-time consecutive tumor re-challenge. Cytokine production by CAR-T cells was measured after overnight co-culture with MSLN+ tumor cells. In vivo CAR-T cell function was evaluated in an AsPC1 pancreatic tumor NSG mouse xenograft model. Persistence of CAR-T cells in vivo was investigated by measuring T cells in peripheral blood (PB) and at tumor site. Additionally, shed MSLN in plasma samples was quantified by ELISA. We also tested the effect of soluble MSLN on the potency of CAR-T cells as analyzed by spiking MSLN into in vitro killing assays, modeling in vivo conditions. Results: VHH CAR D0492 and scFv CAR D0405 were selected for their high surface expression, in vitro cytotoxicity and expansion. In vitro, scFv-based CARs with a CD28 co-stimulatory domain demonstrated higher anti-tumor activity, in comparison to 4-1BB. CAR-T cell production of TNFα, IL2 and IFNγ in response to MSLN+ A431 tumor cells was consistently stronger in CD28 CARs. The VHH CAR showed moderate cytokine release without target stimulation, assumed to be via self-association on the T cell surface. In vivo, tumor-bearing mice treated with MSLN CAR-T cells each delayed tumor progression without adverse effects on body weight. In contrast to in vitro studies, the scFv-based 4-1BB CAR D0181 showed the highest expansion and persistence in PB. IHC staining of tumor samples demonstrated the presence of T cells within tumors in mice treated with anti-MSLN CARs. Shed MSLN plasma concentration in vivo at the end of study take down (TD) correlated with tumor size. Importantly, spiking with equivalent or greater MSLN concentrations did not impede CAR-T cell activity in an in vitro cytotoxicity assay. Conclusions: A series of novel MSLN CARs demonstrated potent in vitro and in vivo anti-tumor activity, were well-tolerated and insensitive to inhibition by soluble MSLN. Second generation scFv-based CARs with 4-1BB co-stimulation demonstrated greater CAR expansion in vivo. VHH CARs demonstrated equivalent in vivo tumor control to scFv, highlighting the importance in both formats to targeting MSLN membrane-proximal domains. Citation Format: Sayyed Hamid Zarkesh Esfahani, Kun Luo, Michael Wagner, Ngoc Tran, Brittany Steimle, Rimas Orentas, Peirong Hu, Dina Schneider. Development of novel anti-mesothelin CAR-T cells for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3184.

Abstract 6061: Dual PD-L1 blockade and VEGF-A neutralization with the bispecific antibody BNT327/PM8002 shows potent antitumor activity in preclinical models

Abstract The combined blockade of the PD-1/PD-L1 checkpoint and VEGF-A driven angiogenesis has been shown to reduce immune suppression in the tumor microenvironment, to enhance antitumor immune responses, and exhibit improved antitumor activity compared to each individual treatment. BNT327 (also known as PM8002) is an investigational bispecific antibody (bsAb) composed of a bivalent Fc-silenced anti-VEGF-A IgG1 antibody fused at its C-terminus to two humanized anti-PD-L1 single-domain VHH antibodies. By simultaneously targeting PD-L1 and VEGF-A, BNT327 is designed to combine the two complementary functions of amplifying pre-existing immune responses and anti-angiogenesis. Here, we report preclinical studies characterizing the functional activity of BNT327 in vitro and antitumor activity in vivo. BNT327 bound with high affinity (i.e., nanomolar or subnanomolar KD) to recombinant human PD-L1 and VEGF-A, as shown by biolayer interferometry. In cell-based bioluminescent reporter assays, BNT327 inhibited PD-L1/PD-1 signaling and VEGF-A/VEGFR2 signaling with subnanomolar EC50 values. In mixed lymphocyte reaction assays using human PBMCs and allogeneic monocyte-derived dendritic cells, BNT327 and the parental anti-PD-L1 VHH dose-dependently increased IL-2 and IFN-γ secretion. Furthermore, BNT327 dose-dependently enhanced CD8+ T-cell mediated tumor-cell killing in an antigen-specific cytotoxicity assay in vitro, with the effects being comparable to those of PD-L1 blockade by atezolizumab. In vivo, a BNT327 surrogate bsAb targeting human PD-L1 and mouse VEGF-A exhibited dose-dependent antitumor activity in human PD-L1 knock-in mice bearing syngeneic human PD-L1-expressing CT26 tumors. Tumor growth inhibition was superior to individual treatments with PD-L1 blockade (parental anti-PD-L1 or atezolizumab) or with anti-VEGF-A. Furthermore, BNT327 showed antitumor activity in several xenograft models, including A375 melanoma cells, NCI-H1975 lung carcinoma cells, LoVo colon carcinoma cells, and MDA-MB-231 breast carcinoma cells. Antitumor activity was dose-dependent where tested, and superior to single PD-1 (pembrolizumab) or PD-L1 (atezolizumab) checkpoint inhibitor treatment. In conclusion, BNT327 inhibits PD-1/PD-L1 signaling and VEGF-A/VEGFR2 signaling in vitro and shows potent antitumor activity in vivo both in syngeneic and xenograft models. The safety and efficacy of BNT327 as a monotherapy or in combination is being investigated in multiple clinical trials in patients with solid tumors, including Phase II and Phase III trials investigating the combination with chemotherapeutic agents in triple-negative breast cancer and lung cancer. Citation Format: Xiaoniu Miao, Yifeng Xu, Shaogang Peng, Weifeng Huang, Junying Chen, Maren Köhne, Andrea Imle, Alexander Muik, Özlem Türeci, Ugur Sahin, Andy Tsun, Yi Luo. Dual PD-L1 blockade and VEGF-A neutralization with the bispecific antibody BNT327/PM8002 shows potent antitumor activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6061.

Abstract 447: Preclinical development and characterization of IACS-16559, a dual bromodomain inhibitor of CBP/EP300, and its potential in AML subtypes

Abstract Paralogs CBP and EP300 are transcriptional co-regulators, with a mechanism of action involving regulation of chromatin accessibility, direct acetylation of master transcriptional factors and bridging enhancers to activated promoters. They possess both reader and writer of the histone code due to the bromodomain and histone acetyltransferase domain, respectively. Aberrant transcription in cancer can occur at multiple stages, contributing to proliferation, therapeutic resistance, and escape from induced cell death, making it a good target for therapeutic intervention. Clinical validation of bromodomain inhibition of paralogs CBP and EP300 is undergoing in multiple clinical trials, including both hematological diseases and solid tumors, using EP31670, CCS1477 and TT125-802, while selective CBP or EP300 inhibition is being explored preclinically. We recently developed a dual bromodomain inhibitor for CBP and EP300, IACS-16559 with selectivity over BRD4, pharmacokinetic properties showing low clearances, high oral exposures and predicted QD dosing in human. IACS-16559 toxicity profile in rats and dogs was in line with previous reports for dual CBP/EP300 bromodomain inhibition. Repeat dose studies in rats and dogs of IACS-16559 was tolerated, with dose-dependent changes affecting bone marrow and lymphoid tissues, testes, GI tract at high doses. All the toxicology findings were reversable once the drug treatment is discontinued, and the animals allowed to recover. Given the potential for anticancer activity mediated by dual CBP/EP300 inhibition, we evaluated the response in selected subtypes of AML, both in vitro and in vivo. Single agent inhibition prolongs survival of the mice bearing orthotopic leukemia xenografts driven by several alterations, such as AML1-ETO, MLL-AF9, NPM1c, RUNX1mut. Mechanistically, CBP/EP300 dual inhibition caused disruption of the MYC and MYB oncogenic network in multiple models, required for the AML proliferation. Interestingly, the combination of IACS-16559 and MLL-Menin inhibition demonstrated synergistic effects in vivo with the OCI-AML3 (NPM1c) model, significantly prolonging the survival of experimental animals. However, in contrast, long-term treatment in the MLL-AF9 (MOLM14) model resulted in antagonistic effects. These findings underscore the complexities of combinatorial therapeutic development and emphasize the critical need for careful selection of robust therapeutic combinations and consideration of the genetic background in the target disease. Citation Format: Ciro Zanca, Michael Soth, Ajay Saw, Uttara Saran, Guang Gao, Jason Gay, Ningping Feng, Christopher Bristow, Joseph Marszalek, Kunal Rai, Virginia Giuliani, Tim Heffernan. Preclinical development and characterization of IACS-16559, a dual bromodomain inhibitor of CBP/EP300, and its potential in AML subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 447.

Abstract 6511: Immunocompetent large animal model of mesenchymal glioblastoma achieved through somatic gene editing technology

Glioblastoma multiforme (GBM) is the most common primary brain tumor. GBM tumors are invasive and highly proliferative, with less than 3% of patients surviving five years from initial diagnosis. Current standard of care treatment consists of surgical resection, radiation, and chemotherapy, and despite this aggressive treatment, nearly all patients succumb to disease recurrence. GBM tumors have heterogeneity, high mutation rates, infiltrating growth, and a complicated tumor-immune microenvironment making treatments difficult and complex. Additionally, therapies must cross the blood brain barrier, a significant problem preventing therapeutic efficacy. Novel drugs, promising therapeutic targets, and new targeting strategies frequently fail in late Phase 2 and Phase 3 clinical trials due to lack of efficacy. The therapies often show effectiveness in a subset of patients, but fail in the majority, leading to clinical trial failure. Because GBM clinical trials are not enrolled based on patient specific biomarkers or genetic subtypes, precision medicine approaches have faced an uphill battle for a patient population that is too small for multiple concurrent clinical trials and a disease with a severe lack of predictive preclinical models. GBM tumors fall into three subtypes, mesenchymal, classical and proneural, each with distinct genetic profiles. Variations in progression and survival and differences in therapeutic response suggest that each subtype should be treated with a regimen unique to that subtype. Roughly 30-50% of GBMs are characterized as mesenchymal, the most common and aggressive subtype. In this study, we demonstrate the development of a large animal (mini pig), immunocompetent model of mesenchymal GBM, using stereotactic delivery of gene editing reagents. 50% of injected animals rapidly develop reproducible tumors that genetically and immunologically resemble human tumors, making this an ideal preclinical model for therapeutic development and biomarker identification. Importantly, tumors can be detected within weeks of injection through a simple, cost-effective blood-based assay. Cell lines developed from these tumors show temozolomide sensitivity and provide an opportunity for high throughput drug screening prior to animal trials. Therillume is utilizing these animals to identify, develop, and validate novel drugs, prognostic and diagnostic biomarkers, therapeutic devices, and effective drug delivery strategies. In particular, Therillume has focused on identifying targeted therapies that previously failed in clinical trials, despite showing efficacy in a subset of patients, and validating the safety and efficacy of these therapies in animals that have a companion biomarker that predicts therapeutic efficacy, in hopes of developing new strategies for clinical trials that will enable biomarker-driven therapeutic development and success. Citation Format: Nicholas Koes, Mandy Taisto, Barbara R. Tschida, Daniel F. Carlson, Maryam Aftabizadeh, H Nayanga Thirimanne, Eric C. Holland, Massimo D'Apuzzo, Christine E. Brown, Adrienne L. Watson. Immunocompetent large animal model of mesenchymal glioblastoma achieved through somatic gene editing technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6511.

Abstract 3688: Correlation between natural killer cell sensitivity and epithelial mesenchymal transition morphology: A cell morphology based screening for NK cell susceptible tumor cells

Abstract Natural killer (NK) cell-based immunotherapy has demonstrated promising anti-tumor efficacy and safety in multiple early clinical trials against hematological and solid tumors. However, intrinsic NK resistance in tumors has resulted in a variable response to adoptively transferred NK cells. To enhance the treatment efficacy, a personalized approach must be adopted. Current methods for screening NK cell sensitive tumors using transcriptomic or proteomic techniques can be costly and often biased by the limited markers detected. Studies showed that cancer cells undergoing the process of epithelial mesenchymal transition (EMT) increase their vulnerability to NK mediated cytotoxicity. We hypothesize that by utilizing image-based analysis to quantify EM morphology change we can correlate EMT morphology with NK cell sensitivity. To analyze EM morphology, we trained a machine learning model based on cell morphological features using the A549 cell line treated with transforming growth factor-β (TGF- β), which depicts various cell morphology across the EMT spectrum. We optimized an organelle specific and live cell compatible staining panel that targets the nucleus, nucleic acid, cell membrane, and F-actin, which does not rely on antigen presentation. The images were processed via a Cell Painting cell segmentation and feature extraction pipeline. In parallel, we conducted a NK cell cytotoxicity assay on cells undergoing the same treatments and confirmed the EMT status via transcriptomic analysis. Our machine learning model successfully identified the EM status of A549 cells treated with TGF- β for different durations (0, 24, 48, and 72 hours) by assigning each cancer cell a quantitative EM score (zero be most epithelial and one be most mesenchymal). We identified a correlative trend between higher EM scores and increased NK cell sensitivity. The same trend was observed when we evaluated the workflow on various non-small lung cancer (NSCLC) cell lines, including two in-house patient derived CTC cell lines. In conclusion, we have established a quantitative measurement for EM status in NSCLC cancer cell lines and observed a correlation between EM score and NK cell sensitivity. We will extend this work by transferring our EM score model to process clinic patient tumor samples, paving the way for developing a rapid screening method for personalized NK cell therapy. Citation Format: Yin Zou, Harrison Ball, Yuru Chen, Nithya Ramnath, Venkateshwar Keshamouni, Sunitha Nagrath. Correlation between natural killer cell sensitivity and epithelial mesenchymal transition morphology: A cell morphology based screening for NK cell susceptible tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3688.

Tailoring MAPK Pathways: New Therapeutic Avenues for Treating Alzheimer's Disease.

Alzheimer's disease (AD) is irreversible, progressive, and refractory in nature and is managed very poorly clinically due to very limited treatment outcomes. Unfortunately, most of the multiple clinical trials involving AD patients were unsuccessful in improving the disease prognosis. At the cellular level, many signaling pathways have been proposed to be involved in the sterile/refractory behavior of degenerating neurons in AD. Due to the involvement of p38MAPK in the pathogenesis of Alzheimer's disease, numerous investigations have attempted to determine the beneficial effects of MAPK targeting on memory, inflammatory programming of the brain, and synaptic plasticity. In view of this, various clinical trials involving several MAPK inhibitors (with good safety profiles and few side effects) have yielded positive results in AD patients, suggesting that MAPK targeting may be effective for reducing the pathogenesis of AD, but due to selectivity, dosing, and patient stratification, this aspect still needs further development. In view of their selectivity and off-target effects, only a few MAPK inhibitors have been employed in clinical trials against AD, indicating the scope of their development in this area. Therefore, this study focused on MAPK-based interventions as an upcoming and innovative approach for alleviating AD, with a special emphasis on clinical studies.