Efficacy In Preclinical Models Research Articles

Generating MVA-Vector Vaccine Candidates and Testing Them in Animal Models.

Modified Vaccinia Virus Ankara (MVA) is a highly attenuated and replication-deficient vaccinia virus developed through serial passages in chicken embryo fibroblasts (CEF). MVA is increasingly used in biomedicine for vaccine development in preclinical and clinical studies in humans. Major benefits of MVA include a well-established record in clinical safety, long-standing experience in genetic engineering of the virus, a large data set demonstrating efficacy in preclinical models with the capacity to induce both protective antigen-specific antibody and cellular immune responses, and the availability of virus production under Good Manufacturing Practice (GMP) suitable for industrial scale amplification. In this chapter, we describe established state-of-the-art protocols for generating, amplifying, and purifying recombinant MVA viruses, including possible vector viruses for further investigations as well as clinical evaluation.

Tight junction regulation, intestinal permeability, and mucosal immunity in gastrointestinal health and disease.

The contributions of intestinal barrier loss, that is, increased permeability, to multiple disorders, including inflammatory bowel disease (IBD), have been a topic of speculation for many years, and the literature is replete with conclusions based on correlation and speculation. The goal of this article is to critically review recent advances in mechanistic understanding of barrier regulation and the evidence for and against contributions of intestinal barrier loss to disease pathogenesis. It is now recognized that intestinal permeability reflects the combined effects of two distinct routes across tight junctions, which form selectively permeable seals between adjacent epithelial cells, and mucosal damage that leads to nonselective barrier loss. These are referred to as pore and leak pathways across the tight junction and an unrestricted pathway at sites of damage. Despite advances in phenotypic and mechanistic characterization of three distinct permeability pathways, development of experimental agents that specifically target these pathways, and remarkable efficacy in preclinical models, pathway-targeted therapies have not been tested in human subjects. After decades of speculation, therapeutic interventions that target the intestinal barrier are nearly within reach. More widespread use of available tools and development of new tools that discriminate between pore, leak, and unrestricted pathway permeabilities and underlying regulatory mechanisms will be essential to understanding the local and systemic consequences of intestinal barrier loss.

Preclinical Evaluation of MK-8189: A Novel Phosphodiesterase 10A Inhibitor for the Treatment of Schizophrenia.

MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A is a cyclic nucleotide phosphodiesterase enzyme highly expressed in medium spiny neurons of the striatum. MK-8189 exhibits sub-nanomolar potency on the PDE10A enzyme and has excellent pharmaceutical properties. Oral administration of MK-8189 significantly increased cGMP and pGluR1 in rat striatal tissues. Activation of the dopamine D1 direct and D2 indirect pathways was demonstrated by detecting significant elevation of mRNA encoding substance P (Sub P) and enkephalin (ENK) after MK-8189 administration. The PDE10A tracer [3H]MK-8193 was used determine the PDE10A enzyme occupancy (EO) required for efficacy in behavioral models. In the rat conditioned avoidance responding assay, MK-8189 significantly decreased avoidance behavior at PDE10A EO greater than ~48%. MK-8189 significantly reversed an MK-801-induced deficit in pre-pulse inhibition at PDE10A EO of ~47% and higher. Target engagement of MK-8189 in rhesus monkeys was examined with [11C]MK-8193 in PET studies and plasma concentrations of 127nM MK-8189 yielded ~50% EO in the striatum. The impact of MK-8189 on cognitive symptoms was evaluated using the objective retrieval task in rhesus monkeys. MK-8189 significantly attenuated a ketamine-induced deficit in object retrieval performance at exposure that yielded ~29% PDE10A EO. These findings demonstrate the robust impact of MK-8189 on striatal signaling and efficacy in preclinical models of symptoms associated with schizophrenia. Data from these studies were used to establish the relationship between preclinical efficacy, plasma exposures, and PDE10A EO to guide dose selection of MK-8189 in clinical studies. Significance Statement We describe the primary pharmacology of MK-8189 a PDE10A inhibitor under evaluation for the treatment of schizophrenia. We report efficacy in preclinical models that have been used to characterize other PDE10A inhibitors and atypical antipsychotics. The PDE10A occupancy achieved by MK-8189 in behavioral studies was used to support dose selection in clinical trials. This work provides evidence to support exploration of higher levels of PDE10A occupancy in clinical trials to determine if this translates to improved efficacy in patients.

Design, Synthesis, and Biological Evaluation of a Series of Spiro Analogues as Novel HPK1 Inhibitors.

Hematopoietic progenitor kinase 1 (HPK1) negatively affects T cell activation and proliferation and is a promising target for immunotherapy. Although HPK1 inhibitors have shown promising efficacy in preclinical models, none have been approved for clinical use. One significant challenge in developing an HPK1 inhibitor is the difficulty in designing a potent inhibitor with good kinase selectivity and pharmacokinetic properties. Here, we report a series of spiro HPK1 inhibitors with good potency and selectivity. Specifically, compound 16 exhibited potent HPK1 inhibition (IC50 = 2.67 nM), adequate selectivity toward the MAP4K family (>100-fold), and good selectivity against selected kinases (>300-fold). Compound 16 demonstrated moderate in vivo clearance and reasonable oral exposure in mice and rats. Notably, compound 16 possessed good antitumor efficacy in the CT26 murine colon cancer and a synergistic effect when combined with anti-PD-1. These exciting preclinical results support the continued development of this class of HPK1 inhibitors.

First-in-Human Phase I Clinical Trial of the Adenosine A1R/A3R Agonist AST-004 in Healthy Subjects.

AST-004 is a small-molecule adenosine A1/A3 receptor agonist that has exhibited significant cerebroprotective efficacy in preclinical models of acute ischemic stroke and traumatic brain injury. The primary objectives of this clinical phase I first-in-human study were to evaluate the safety and tolerability profile of single ascending intravenous doses in healthy subjects. The secondary objectives were to characterize the single-dose pharmacokinetic profiles in plasma, cerebrospinal fluid (CSF), and urine. In part 1 of the study, AST-004 was administered in ascending dose cohorts of 5, 25, 50, 75, and 100 mg, with 6 subjects in each cohort receiving the study drug and 2 receiving placebo. In part 2, all 12 subjects received a 100 mg IV infusion of the study drug followed by a single CSF collection per subject via lumbar puncture at 20, 40, or 60 minutes after infusion. A total of 42 subjects received AST-004, with no severe or serious adverse events observed. Twelve of these subjects experienced a treatment-emergent adverse event, the most frequent across groups being headache. In part 2, pharmacokinetic analyses confirmed that AST-004 was distributed in the CSF, with the CSF-to-plasma ratio increasing over the 3 timepoints sampled. The mean half-life was 1.1 to 1.4 hours for doses of 25 to 100 mg, and the geometric mean maximum plasma concentration obtained in the highest dosing cohort (100 mg) was 2232±428 ng/mL. AST-004 was safe and well-tolerated at plasma concentrations 3 to 8× higher than those associated with significant efficacy in astrocyte's preclinical primate stroke efficacy studies, with CSF concentrations highest at the 60-minute collection timepoint, the last timepoint tested. This study supports additional clinical investigations, including evaluation of an extended infusion to support the phase 2 program in stroke and traumatic brain injury.

The psychedelic drug DOI reduces heroin motivation by targeting 5-HT2A receptors in a heroin and alcohol co-use model

There has been a recent renewed interest in the potential use of psychedelic drugs as therapeutics for certain neuropsychiatric disorders, including substance use disorders. The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) has demonstrated therapeutic efficacy in preclinical models of opioid use disorder (OUD). Alcohol is commonly co-used in individuals with OUD, but preclinical models that recapitulate this comorbidity are lacking. We developed a polydrug model wherein male and female rats were allowed to self-administer intravenous heroin and oral alcohol (or saccharin control solution) over weeks of behavioral training, and then we conducted a series of progressive ratio tests to assess the animals' motivational state for heroin and alcohol. In this model, motivation for heroin is higher than alcohol, and DOI (0.4 mg/kg) administered prior to testing significantly reduced heroin motivation measured as the animals’ break point, or maximum effort the animal is willing to expend to obtain a single infusion of heroin. The 5-HT2A receptor antagonist MDL 100,907 (0.3 mg/kg), but not the 5-HT2C receptor antagonist SB-242084 (0.5 mg/kg), blocked the therapeutic effect of DOI on heroin motivation. No significant effects on alcohol break points were observed, nor did MDL 100,907 or SB-242084 have any effect on break points on their own. These data support the view that psychedelic drugs like DOI may have therapeutic effects on opioid use in individuals with OUD and comorbid alcohol use, by acting as a 5-HT2A receptor agonist.

Mitochondrial Dysfunction in Systemic Lupus Erythematosus: Insights and Therapeutic Potential.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by the presence of various serum autoantibodies and multi-system effects, predominantly affecting young female patients. The pathogenesis of SLE involves a combination of genetic factors, environmental triggers, and pathogen invasions that disrupt immune cell activation, leading to the release of autoantibodies and chronic inflammation. Mitochondria, as the primary cellular powerhouses, play a crucial role in SLE development through their control of energy generation, reactive oxygen species (ROS) production, and cellular apoptotic pathways. Dysregulation of mitochondrial structure and function can contribute to the immune dysregulation, oxidative stress, and inflammation seen in SLE. Recent research has highlighted the impact of mitochondrial dysfunction on various immune cells involved in SLE pathogenesis, such as T-lymphocytes, B-lymphocytes, neutrophils, and plasmacytoid dendritic cells. Mitochondrial dysfunction in these immune cells leads to increased ROS production, disrupted mitophagy, and alterations in energy metabolism, contributing to immune dysregulation and inflammation. Moreover, genetic variations in mitochondrial DNA (mtDNA) and abnormalities in mitochondrial dynamics have been linked to the pathogenesis of SLE, exacerbating oxidative stress and immune abnormalities. Targeting mitochondrial function has emerged as a promising therapeutic approach for SLE. Drugs such as sirolimus, N-acetylcysteine, coenzyme Q10, and metformin have shown potential in restoring mitochondrial homeostasis, reducing oxidative stress, and modulating immune responses in SLE. These agents have demonstrated efficacy in preclinical models and clinical studies by improving disease activity, reducing autoantibody titers, and ameliorating organ damage in SLE patients. In conclusion, this review underscores the critical role of mitochondria in the pathogenesis of SLE and the potential of targeting mitochondrial dysfunction as a novel therapeutic strategy for improving outcomes in SLE patients. Further investigation into the mechanisms underlying mitochondrial involvement in SLE and the development of targeted mitochondrial therapies hold promise for advancing SLE treatment and enhancing patient care.

Advancing Clinical Response Against Glioblastoma: Evaluating SHP1705 CRY2 Activator Efficacy in Preclinical Models and Safety in Phase I Trials.

It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are uniquely essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity. We analyzed buffy coats isolated from Phase 1 clinical trial subjects' blood to assess any changes to circadian, housekeeping, and blood transcriptome-based biomarkers following SHP1705 treatment. We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employed in vitro and in vivo methods to test the efficacy of SHP1705 against patient-derived GSCs and xenografts in comparison to earlier CRY activator scaffolds. Additionally, we applied a novel-REV-ERB agonist SR29065, which inhibits BMAL1 transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells. SHP1705 is safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published CRY activators. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with the novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs). These demonstrate the efficacy of SHP1705 against GSCs, which pose for GBM patient outcomes. They highlight the potential of novel circadian clock compounds in targeting GBM as single agents or in combination with each other or current standard-of-care. SHP1705 is a novel CRY2 activator that has shown success in Phase 1 safety trialsSHP1705 has a significantly improved efficacy against GSCs and GBM PDX tumorsNovel REV-ERB agonist SR29065 and SHP1705 display synergistic effects against GSCs. CRY2 is decreased in GBM tissues compared to CRY1 suggesting that promoting CRY2 activity will be an efficacious GBM treatment paradigm. SHP1705, a CRY2 activator that has shown success in Phase 1 safety trials, has significantly improved preclinical efficacy. Novel REV-ERB agonist SR29065 displays synergistic effects against diverse GBM cells.

The Potential of Indole Alkaloids in Bone Health and Osteoporosis Management

Indole alkaloids, a class of plant-derived nitrogen-containing compounds, have emerged as promising candidates for osteoporosis treatment. Their favorable biocompatibility profile demonstrated efficacy in preclinical models, and low reported toxicity make them attractive alternatives to existing therapies. This review focuses on the therapeutic potential of specific indole alkaloids, including vindoline, rutaecarpine, harmine, and its derivatives, in promoting bone health and managing osteoporosis.

Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade

Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-β triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.

ENDOLUNG trial. A phase 1/2 study of the Akt/mTOR inhibitor and autophagy inducer Ibrilatazar (ABTL0812) in combination with paclitaxel/carboplatin in patients with advanced/recurrent endometrial cancer

BackgroundCarboplatin and paclitaxel (CP) have been the standard of care for advanced/recurrent endometrial cancer (EC) for many years. However, this chemotherapy combination shows limited efficacy and recurrences often occur in less than 12 months. ABTL0812 is a novel drug that selectively kill cancer cells by cytotoxic autophagy and has shown anticancer efficacy in preclinical models of EC in combination with CP.MethodsENDOLUNG was an open-label, phase 1/2 clinical trial designed to determine the safety and efficacy of Ibrilatazar (ABTL0812) with CP in patients with advanced/recurrent EC and non-irradiable stage III and IV squamous non-small cell lung cancer (sq-NSCLC). The phase 1 part consisted of a 3 + 3 de-escalation design followed by an expansion cohort with 12 patients. The primary endpoint was safety. ABTL0812 starting dose was 1300 mg tid combined with carboplatin at area under the curve (AUC) 5 and paclitaxel at 175 mg/m2 both administered every 21 days for up to 8 cycles. The phase 2 part included a total of 51 patients. The primary endpoint was overall response rate (ORR) and the secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS).ResultsDuring the phase 1 only one dose limiting toxicity (DLT), a grade 4 neutropenia, was observed in 1 out of 6 patients, thus no de-escalation was applied. One additional DLT, a grade 3 febrile neutropenia, was observed in the expansion cohort, thus the recommended phase 2 dose (RP2D) for ABTL0812 was established at 1300 mg tid. Most frequent hematological adverse events (AE) of the combination were neutropenia (52.9%), anemia (37.3%) and thrombocytopenia (19.6%). Nausea (66.7%), asthenia (66.7%), diarrhea (54.9%) and vomiting (54.9%) were the most frequent non-hematological adverse events (AEs). The combination of ABTL0812 plus CP showed an ORR of 65.8% (13.2% complete response and 52.6% partial response) with a median DOR of 7.4 months (95% CI: 6.3–10.8 months). Median PFS was 9.8 months (95% CI: 6.6–10.6) and median OS 23.6 months (95% CI 6.4-ND). Pharmacokinetic parameters were compatible with target engagement observed in preclinical studies, and blood pharmacodynamic biomarkers indicated sustained target regulation during, at least, 28 days after starting the treatment.ConclusionsThis study suggests that the combination of ABTL0812 with CP is safe and feasible with an encouraging activity in patients with advanced/recurrent EC. Our data warrant further confirmation in prospective randomized trials.Trial registrationEU Clinical Trial Register, EudraCT number 2016-001352-21 and National Clinical Trials Number, NCT03366480. Registration on 19 September 2016.

Chronic liver disease and fibrosis: A review of emerging biomarkers and therapeutic targets

Chronic liver disease (CLD) and fibrosis represent a significant global health burden, driven by a range of etiologies including viral hepatitis, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD). These conditions often progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC), underscoring the urgent need for effective diagnostic and therapeutic strategies. Emerging biomarkers and therapeutic targets offer promising avenues for early diagnosis and intervention in CLD and fibrosis. Biomarkers are crucial for the early detection and monitoring of CLD and fibrosis, allowing for timely therapeutic intervention. Serum biomarkers such as liver enzymes (ALT, AST), bilirubin, and platelet count have traditionally been used, but they lack specificity and sensitivity. Recent advances have identified novel biomarkers with improved diagnostic performance. For instance, serum levels of fibrosis markers like hyaluronic acid, procollagen type III N-terminal peptide (P3NP), and tissue inhibitor of metalloproteinases-1 (TIMP-1) have shown potential in assessing liver fibrosis. Additionally, non-invasive imaging techniques such as transient elastography and magnetic resonance elastography provide quantitative measures of liver stiffness, correlating with fibrosis stage. The pathogenesis of liver fibrosis involves complex interactions between hepatocytes, hepatic stellate cells (HSCs), and the extracellular matrix (ECM). HSCs play a central role in fibrogenesis by transforming into myofibroblasts that secrete collagen and other ECM components. Targeting the activation and proliferation of HSCs has emerged as a promising therapeutic strategy. Small molecule inhibitors, such as those targeting the PDGF and TGF-? signaling pathways, have shown efficacy in preclinical models. Furthermore, antifibrotic agents like simtuzumab, an anti-LOXL2 monoclonal antibody, are being evaluated in clinical trials for their potential to halt or reverse fibrosis progression. Another promising approach involves the modulation of the gut-liver axis. Dysbiosis and increased intestinal permeability contribute to liver inflammation and fibrosis. Probiotics, prebiotics, and fecal microbiota transplantation (FMT) are being explored for their potential to restore gut homeostasis and mitigate liver injury. Additionally, the role of the immune system in fibrosis has gained attention, with immune checkpoint inhibitors and anti-inflammatory agents being investigated for their ability to modulate immune responses and reduce fibrosis. Keywords: Chronic Liver Disease, Fibrosis, Biomarkers, Therapeutic Targets.

Development of NR0B2 as a therapeutic target for the re-education of tumor associated myeloid cells

Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of Tregs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of Treg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.

Immunogenicity of Extracellular Vesicles.

Extracellular vesicles (EVs) are promising next-generation therapeutics and drug delivery systems due to demonstrated safety and efficacy in preclinical models and early-stage clinical trials. There is an urgent need to address the immunogenicity of EVs (beyond the apparent lack of immunotoxicity) to advance clinical development. To date, few studies have assessed unintended immunological recognition of EVs. An in-depth understanding of EV-induced immunogenicity and clearance is necessary to develop effective therapeutic strategies, including approaches to mitigate immunological recognition when undesired. This article summarizes various factors involved in the potential immunogenicity of EVs and strategies to reduce immunological recognition for improved therapeutic benefit.

IMMU-10. DEVELOPING NOVEL CHIMERIC ANTIGEN RECEPTOR THERAPIES FOR PAEDIATRIC HIGH GRADE GLIOMA

Abstract Paediatric high-grade gliomas (pHGG), particularly Diffuse Midline Glioma (DMG), present a formidable challenge in oncology. Due to the aggressive biology and location of pHGGs the implementation of adult treatment modalities (surgery, chemotherapy, and radiotherapy) is severely limited resulting in pHGG remaining a terminal disease. Thus, there is a pressing and urgent unmet clinical need for the development of innovative therapeutics. We will demonstrate the identification of cell surface targets using mass spectrometry proteomics. We have developed novel binders and engineered them into second-generation CAR T cells. We will present pre-clinical in vivo intracranial mouse models examining the efficacy of novel CAR T cell therapies. We have recently reported effective CART cell targeting of HER2 in DMG, and presently we will also demonstrate superior efficacy of additional CAR T cell targeting, both in vitro and in vivo in preclinical PDX models of DMG. We will present new data that CAR T cells targeting EphA3 show curative efficacy in pre-clinical models of DMG. Recognising that single targeting CAR T cells are unlikely to provide long-term clinical benefit, we will also present our combination approaches using CAR T cells targeting antigens such as GD2, EGFR, HER2, EphA3, CD276 and CD63. We are expanding our research to other CAR T combination strategies focusing on immune-modulating drugs such as checkpoint inhibitors or co-stimulatory agonists. We are committed to advancing CAR T cell therapies for pHGG patients and their families with an aim to aid in the development of much-needed new therapeutic options.

A phase 1, first-in-human, open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of TT125-802 in patients with advanced solid tumors.

TPS3171 Background: TT125-802 is a selective, potent, orally bioavailable small molecule inhibitor of the bromodomain of CBP and p300, two highly homologues lysine acetyltransferases. CBP/p300 act as transcriptional co-activators with multiple domains and functions, including well-documented roles in cell cycle regulation and several critical tumorigenic pathways (1-3). TT125-802 has shown mono-therapy efficacy in preclinical models of castration-resistant prostate cancer, KRAS-mutated colorectal and non-small cell lung cancer (4,5). Furthermore, TT125-802 is capable to interfere with transcriptional resistance mechanisms limiting targeted therapies (6) which will be explored clinically upon determination of a safe, well-tolerated, and biologically active single-agent dose. Methods: This study aims to establish the safety, tolerability, and pharmacokinetic profile of TT125-802. The maximum tolerated dose/recommended dose for expansion (MTD/RDE) of repeat daily dosing for TT125-802 monotherapy will be determined in subjects with advanced solid tumors in a sequential escalating cohorts design, (1 cycle = 21 days) using the Bayesian Logistics Regression Model (BLRM) with sentinel patients (2-day window for first patient enrolled in each cohort). Cohorts will consist of 3 to 6 subjects who will be followed over a dose-limiting toxicity (DLT) period of at least 21 days. TT125-802 will be administered orally once daily; additional schedules may be evaluated. Dose escalation is planned to follow two-fold increments. It may be adapted upon dose level revision and guided by pharmacokinetic analysis. Additional subjects (up to 6) may be enrolled in at least two monotherapy cohorts deemed safe and tolerable to optimize the recommended phase 2 dose (RP2D). Up to a total of 20 additional subjects may be enrolled. Translational/pharmacodynamic endpoints: Exploratory endpoints will provide proof-of-principle and early biomarker data for CBP/p300 inhibition. These analyses will include: 1. Single-cell gene expression evaluation of peripheral blood mononuclear cells (PBMCs) at multiple time points, 2. anagen hair bulb bulk RNAseq analysis, and 3. paired tumor biopsies will be analyzed with single-cell RNA sequencing. Together, these investigations are expected to support optimal dose determination. Additionally, circulating tumor DNA might be evaluated to define molecular responses. Outlook: The recommended phase 2 dose will be used further to explore the efficacy of TT125-802 as monotherapy. TT125-802 will be evaluated with targeted therapies (for example, KRASG12C/D, BRAF, EGFR, etc., inhibitors) to exploit the blocking of transcriptional escape mechanisms driven by CBP/p300. 1. Iyer, 2007. 2. Dutta, 2016. 3. Attar, 2017. 4. AACR2023 posters #6268. 5. AACR poster #3907. 6. AACR2023 poster #3907. Clinical trial information: 2022-500849-24-00 .

A phase Ib/IIa study of DX1002, a novel drug in patients with pretreated advanced hepatocellular carcinoma: Efficacy and safety analysis.

3122 Background: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. DX1002 is a novel, specific, small-molecule, tubulin inhibitors, that targets the beta subunit of tubulin in tumor vascular endothelial cells. It has been designed to destroy tumor blood vessels which has been demonstrated in preclinical efficacy models. The objectives of this trial were to assess safety, tolerability and preliminary efficacy of DX1002 in patients (pts) with pre-treated advanced HCC or gastric cancer. Here, we present the results from the HCC subpart. Methods: This is a prospective, single-arm open-label multi-center phase Ib/IIa trial (CTR2400080296) to investigate DX1002 in patients with pre-treated advanced HCC or gastric cancer. Patients received DX1002 600 mg orally once daily, continuously in 28-day cycles until progressive disease or intolerable toxicity. Primary endpoints were safety and objective response rate (ORR); other endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), pharmacokinetics and safety. Results: From Jun-2021 to Jan-2024, 40 patients with advanced HCC were enrolled. The median age was 54 (36-71) years. As of 31-Jan-2024, of the 40 pts, 4 pts (10.0%) showed PR and 15 (37.5%) had SD. ORR was 21.1% and DCR was 47.5%. The median PFS was 3.55 (95% CI 2.89-8.31) months and median OS was 13.4 (95% CI 11.0-NA) months. Any-grade TRAEs occurred in 75% pts (30/40), with 22.5% Grade 3 (9/40). The most common TRAEs were Aspartate aminotransferase increased (22.5%), total bilirubin increased (20%), albuminuria (20%), Hypoalbuminemia (15%) and gamma-glutamyl transferase increased (15%). Four patients (10%) discontinued DX1002 due to TRAEs. No death-related cases occurred. Conclusions: Initial data shows DX1002 demonstrated manageable safety profile and promising anti-tumor potential in pre-treated advanced hepatocellular carcinoma. Further exploration of DX1002 in HCC is warranted. Clinical trial information: ChiCTR2400080296.

Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical models of osteosarcoma.

T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control.

Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties.

Recent research with classic psychedelics suggests significant therapeutic potential, particularly for neuropsychiatric disorders. A mediating influence behind symptom resolution is thought to be the personal insight - at times, bordering on the mystical - one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of 'non-psychedelic/subjective psychedelics', or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence - both clinical and preclinical - surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question.

A novel SLC3A2-targeting antibody-drug conjugate exerts potent antitumor efficacy in head and neck squamous cell cancer

The development of innovative therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) is a critical medical requirement. Antibody-drug conjugates (ADC) targeting tumor-specific surface antigens have demonstrated clinical effectiveness in treating hematologic and solid malignancies. Our investigation revealed high expression levels of SLC3A2 in HNSCC tissue and cell lines. This study aimed to develop a novel anti-SLC3A2 ADC and assess its antitumor effects on HNSCC both in vitro and in vivo. This study developed a potent anti-SLC3A2 ADC (19G4-MMAE) and systematically investigated its drug delivery potential and antitumor efficacy in preclinical models. This study revealed that 19G4-MMAE exhibited specific binding to SLC3A2 and effectively targeted lysosomes. Moreover, 19G4-MMAE induced a significant accumulation of reactive oxygen species (ROS) and apoptosis in SLC3A2-positive HNSCC cells. The compound demonstrated potent antitumor effects derived from MMAE against SLC3A2-expressing HNSCC in preclinical models, displaying a favorable safety profile. These findings suggest that targeting SLC3A2 with an anti-SLC3A2 ADC could be a promising therapeutic approach for treating HNSCC patients.