Lack Of Clinical Efficacy Research Articles

Ex Vivo Drug Evaluation Using Human Ocular Cells: A Contribution to Drug Discovery

The field of therapeutics is fundamentally and heavily dependent on drug discovery. The record number of new agents being developed probably conceals how ardent the task is [1]. Drug discovery is indeed a long, costly, and high-risk process that takes over 10-15 years with an average cost of over $1-2 billion for a new drug to be approved for clinical use [2]. What is astonishing is the failure rate of candidate drugs. By most accounts over 90% of drug candidates fail to be approved for clinical use. Lack of clinical efficacy and poor drug-like properties along with unmanageable toxicity are among the frequent reasons for their failure. The transition between basic and clinical science, known colloquially and the “valley of death”, is where most promising discoveries meet their demise [3]. Multiple efforts have been made to overcome this difficult situation that adversely affects modern therapeutics [2].

Abstract 4230: Patient-derived tumoroid platforms with progressing tumor microenvironment representability reveals efficacy and resistance patterns in pre-clinical HSP90i regimen testing for improved clinical insights

Abstract Introduction: Drug candidates advance to phase I clinical trial after rigorous optimization at preclinical stage and yet nine out of ten drug candidates fail during clinical trials and approval stage. Lack of clinical efficacy is a major contributor (~ 50%) towards this 90% of the failure at clinical trials. Tremendous efforts are being taken to demonstrate drug efficacy in preclinical studies by mitigating the biological discrepancy of molecular target between human disease and the model used for the validation. Herein this study, we aim to showcase therapeutic responses of heat-shock protein 90 (HSP90) inhibitor regimens (HSP90i only and HSP90i + Doxorubicin combination) against three-dimensional (3D), patient-derived tumoroid (PDT) model platforms with progressing tumor microenvironment (TME) representability by incorporating supplementary TME structure, immunity, and oxygenation. Revelations on efficacy and resistance patterns of such drug treatments on increasingly complex models is aimed at providing unique insights to tumor and drug-drug interplay. Methods: Human Uterine Adenosarcoma PDT models were prepared across three COMPASS (Custom Organoid Modeling Platform for Accurate SolutionS) platforms: 1) COMPASS 1a - Non-scaffold 2) COMPASS 3b - Scaffold + Immune cells and 3) COMPASS 3d - Scaffold + Immune cells + Oxygenation. The various platforms were tested against two regimens A) HSP90i only [50 nM and 100 nM] and B) HSP90i [50 nM and 100 nM] + Doxorubicin [50 nM]. Tumor size and volume assessment were carried out on Days 3 and 7 post-treatment -with statistical done via one-way ANOVA, followed by student’s t test for significance (p<0.05, n=3). Results: While a simpler platform COMPASS 1a showcased the therapeutic efficacy of monotherapeutic HSP90i [at 100 nM] (p<0.05), progressively complex models (COMPASS 3b and COMPASS 3d) have otherwise indicated the lack of significant tumor volume changes. On the other hand, current findings on combination therapies of HSP90i and Doxorubicin have revealed persistent therapeutic resistance (even suggestive of patterns of increasing tumor growth) on COMPASS 1a, necessitating further comparisons on the more complex models. Conclusion: Our results demonstrate the need to test drugs in context of TME and oxygenation to help stratify patients to develop better clinical trials based on patient tumor characteristics of vascularization and immunogenicity. We plan to test several different drug modalities and cancer types for these parameters to demonstrate the need and effectiveness of testing prior to taking the drugs to the clinic. Citation Format: Huckie Del Mundo, Damieanus O. Ochola, Bhuvanesh Dave, Preethi Samuel. Patient-derived tumoroid platforms with progressing tumor microenvironment representability reveals efficacy and resistance patterns in pre-clinical HSP90i regimen testing for improved clinical insights [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 4230.

Anti-prostate cancer metabolites from the soil-derived Aspergillus neoniveus.

Prostate cancer (PCa) ranks as one of the most commonly diagnosed malignancies worldwide. Toxicity, lack of clinical efficacy, and development of resistance phenotypes are the main challenges in the control of prostate malignancies. Notably, castration-resistance prostate cancer (CRPCa) is a highly aggressive and metastatic phenotype of the disease with a poor prognosis and very limited therapeutic options. Herein, we report the isolation and genotypic identification of a soil-derived fungus Aspergillus neoniveus using the PCR-based internal transcribed spacer (ITS) region amplification approach. HPLC/MS investigation of the metabolic profile of the ethyl acetate extract from the fungal biomass revealed tentative identification of forty-five compounds belonging to various chemical classes including γ-butyrolactones, alkaloids, phenolics, and quinoids. Furthermore, the chromatographic purification of microbial extract enabled the identification of nervonic acid methyl ester (1) for the first time from endophytic fungi, as well as acetyl aszonalenin (2), and butyrolactone II (3) for the first time from A. neoniveus. The chemical frameworks of the isolated compounds were identified via extensive spectral analysis including 1 and 2D NMR and MS. The X-ray crystal structure and absolute configuration of acetyl aszonalenin (2) were also determined. Additionally, screening of in vitro anticancer activity of the fungal extract revealed its potential antiproliferative and anti-migratory activities against five different prostate cancer cells (PC3, PC-3M, DU-145, CWR-R1ca, and 22Rv1), including different cells with the castration-resistance phenotype. Moreover, the isolated metabolites significantly inhibited the proliferation, migration, and colonization of human prostate cancer cells at low micromolar levels, thus providing credence for future investigation of these metabolites in relevant anti-prostate cancer animal models. Furthermore, computational target prediction tools identified the cannabinoid G-protein coupled receptors type 1 (CB1) as a potential biological target mediating, at least in part, the anticancer effects of acetylaszonalenin (2). Moreover, molecular modeling and docking studies revealed a favorable binding pose at the CB1 receptor orthosteric ligand pocket aided by multiple polar and hydrophobic interactions with critical amino acids. In conclusion, the Aspergillus neoniveus-derived prenylated indole alkaloid acetylaszonalenin has promising anticancer activity and is amenable to further hit-to-lead optimization for the control of prostate malignancies via modulating CB1 receptors

Annona cherimola Mill. Leaf Extracts Affect Melanoma Cells Growth and Progression.

Cancer represents one of the major causes of mortality worldwide; indeed, 19.3 million new cases and almost 10.0 million deaths were estimated last year. Among the different type of cancers, malignant melanoma represents the most aggressive and deadly skin cancer. Unfortunately, the long-term efficacy of melanoma treatments is limited by the lack of clinical efficacy, onset of side effects and resistance. The latter is a major obstacle for the success of the melanoma therapy; thus, the exploration of new potent and safer anticancer agents is of great importance. Recently, numerous plant species, used for therapeutic purposes and containing various non-toxic nutraceuticals have been widely studied. Herein, we investigated the antioxidant and anticancer properties on melanoma cells of the ethanolic, methanolic and aqueous Annona cherimola leaf extracts (ACE, ACM and ACW, respectively). The ethanolic extract showed higher anticancer activity, mostly against the malignant A2058 melanoma cell line (IC50 = 5.6 ± 0.8 ng/mL), together with a very low activity on the normal cells. It blocks the melanoma cells migration process, and induces a clear disorganization of cytoskeleton, triggering cell apoptosis. Finally, some bioactive compounds were identified in the studied extracts.

Study of the effect of RS1800629 TNF polymorphism on the course of age-related macular degeneration through the prism of ANTI-VEGF therapy

Annotation. Age-related macular degeneration (AMD) includes pathological changes in the deep layers of the retina, macula, and surrounding blood vessels, leading to loss of central vision. The wet form of nosology is the leading cause of irreversible blindness in developed countries among people over 60, where more than 30 million people suffer from the disease. The number of patients in the United States is expected to increase from 9.1 million in 2010 to 17.8 million in 2050. New therapeutic strategies and the development of new practical methods for identifying patients at high risk of treatment resistance are needed to reduce the prevalence of the disease. That is why the aim of the study was to shed light on the role of the rs1800629 polymorphism of the TNF gene as one of the prognostic factors in the effectiveness of treatment of the wet form of AMD. The study group consisted of 162 people diagnosed with a wet form of pathology, while the comparison group consisted of 105 people without a history of ophthalmic pathology. Optical coherence tomography of certain areas of the eye, including the retina, was used to confirm or rule out the diagnosis. To detect the polymorphism status of the TNF gene, the real-time polymerase chain reaction method was used on the BioRad CFX 96 thermocycler-amplifier, using “Litekh” (RF) reagent kits. Statistical processing of the results was performed by determining the Hardy-Weinberg equilibrium, Student’s and Wilcoxon’s criteria, logistic regression using OR values and 95% CI, and by subtracting RR and χ². The study found that the frequency of genotype distribution with mutant allele A was predominant among patients in the study group, and the G allele was determined predominantly in the control group and was associated with better results of anti-VEGF therapy. The results of OCT confirmed this information, because among carriers of genotypes GG and GA (p<0.05) visual acuity improved even after the first injection of the drug in most areas, while among carriers of homozygous genotype AA was not sufficient probability of biological effects, efficiency in the presence of this genotype was reduced (p<0,05). The results of treatment were most representative in the areas of OCT 4, OCT 8 and macula (OCT 3) – among carriers of allele A in the OCT 4 zone, the chance of resistance to treatment was 3.1 times (OR=3.1; 95% SI 1,686 - 5.7) higher than in carriers of the G allele, and in the zone of OCT 8 in patients from the study group the risk of ineffectiveness of therapy was 2.81 times (OR=2.81; 95% CI 1.56 - 5.059) higher than in the corresponding zone of the G allele carriers. This suggests a lack of clinical efficacy in individuals carrying the mutant A allele, and the need to identify the status of polymorphisms for prognostic assessment of treatment efficacy.

MO1023: Effects of Bortezomib on Complement Fixation and IGM Reactivity in Late Abmr — Results of A Randomized Controlled Trial (The Borteject Trial)

Abstract BACKGROUND AND AIMS Late antibody-mediated rejection (ABMR) is a cardinal cause of kidney allograft failure. Currently, there is no proven effective treatment for this type of rejection. In a recent randomized controlled trial, we have reported no meaningful effect of plasma cell-directed treatment using the proteasome inhibitor bortezomib on the clinical course of late ABMR (BORTEJECT trial; ClinicalTrials.gov, NCT01873157; Eskandary et al. J Am Soc Nephrol, 2018; 29: 591). Treatment had also no significant effect on IgG type donor-specific antibody (DSA) patterns, possibly due to rapid reconstitution of the allospecific plasma cell repertoire. To further dissect the impact of bortezomib on donor-specific B cell alloimmunity, we here sought to investigate whether and to what extent bortezomib impacts the dynamics of specific alloreactivity patterns, in particular, the course of IgM type DSA and complement-activating capability of detected DSA. METHOD The BORTEJECT trial was a randomized, placebo-controlled parallel group trial designed to investigate whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8 and 11) were able to halt the progression of IgG-DSA-positive late ABMR. A total of 44 recipients were randomly assigned to receive bortezomib (n = 21) or placebo (n = 23). In the present re-analysis of biobanked serum samples obtained in the context of the trial, we applied modified single antigen bead assays to assess IgM-DSA and, in addition, complement (C1q) binding. To estimate antibody/complement binding, levels of mean fluorescence intensity (MFI) were recorded. IgM DSA was defined in relation to donor/recipient HLA typing, independently of IgG reactivity patterns. RESULTS At baseline, the complement-fixing capability of the immunodominant IgG DSA did not differ between groups. Thirty of 44 patients had detectable IgM DSA at baseline, and we observed a considerable overlap of IgG and IgM DSA specificities (22/30) without group differences. IgM DSA levels were also similar between groups. Bortezomib treatment did not affect the complement-fixing capability of IgG DSA over time. Similarly, there was no effect on the course of IgM-DSA. There were also no significant differences between groups when analysing percentage changes. CONCLUSION A limited course of bortezomib as a sole treatment strategy may not be sufficient to impact on DSA levels, including the evolution of IgM type DSA and the complement-binding capability of detected alloreactivity patterns. Our study results, which may mirror the lack of clinical efficacy, reinforce the need for the development of innovative new strategies to effectively target plasma cells and halt the progression of ABMR.

Gold Nanoparticles as a Drug Delivery Vehicle System Against ErbB2+ Breast Cancer

Breast cancer is the most common and second leading cause of cancer related death among women. Currently, chemotherapy treatments involving heat shock protein 90 (Hsp90) inhibitors (17‐AAG) are not FDA approved due to their lack of clinical efficacy. Hsp90 inhibitors decrease binding and stabilization of clients that aid in tumor formation and growth. ErbB2, a Hsp90 client, is overexpressed in ErbB2+ breast cancers and promotes tumor progression. Cul5 is downregulated in ErbB2+ breast cancer cells making them resistant to chemotherapy treatments involving Hsp90 inhibitors. Cul5 is required for degradation of ErbB2 in response to Hsp90 inhibitors. Hsp90 inhibitors are not efficacious alone and require Cul5 for effective antitumor response. I have synthesized gold nanoparticles coated with anti‐ErbB2 antibody, 17‐AAG, and Cul5 DNA as an intracellular drug delivery mechanism. This targeted drug delivery vehicle has been evaluated in a cell culture model of drug resistance. We have constructed a breast cancer cell line in the past that is resistant to the HSP90 inhibitor 17‐AAG and we used this model system to evaluate Cul5 expression. Our hypothesis is that gold nanoparticles coated with Cul5 DNA, 17‐AAG, and anti‐ErbB2 antibodies will increase the sensitivity and specificity of Cul5 deficient ErbB2+ breast cancer cells to 17‐AAG. This has been achieved through comparing payload efficacy of differently sized gold nanoparticles and evaluating targeting of anti‐ErbB2 antibodies to ErbB2+ breast cancer cells. Specifically targeting and making breast cancer cells susceptible to Hsp90 inhibitors will be a milestone in improving therapeutic treatment for those diagnosed.

Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial.

Simple SummaryPrimary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and translational research augmented our understanding of the pathogenesis and pathophysiology of different subtypes of CTCL, enabling the identification of novel therapeutic drug targets. In this study, the primary focus is on bimiralisib gel 2%, a dual pan-class PI3K/mTOR inhibitor, and its potential to inhibit the PI3K/AKT/mTOR signaling pathway as a novel therapeutic target in CTCL.Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm2 on 400 cm2, with a mean Cavg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean Cavg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.

DC-Derived Exosomes for Cancer Immunotherapy

Simple SummaryDendritic cells (DCs)-based cancer vaccines have not succeeded in generating significant clinical responses despite their capacity to induce host anti-tumor CD8 T cell immunity, and one major hurdle is tumor-mediated immunosuppression. Exosomes are nano-sized inert membrane vesicles derived from the endocytic pathway that play a critical role in intercellular communication. DC-derived exosomes (DCexos) additionally carried MHC class I/II (MHCI/II) often complexed with antigens and co-stimulatory molecules, thus capable of priming antigen-specific CD4 and CD8 T cells. Indeed, vaccines with DCexos have been shown to exhibit better anti-tumor efficacy in eradicating tumors compared to DC vaccines in pre-clinical models. Coupled with their resistance to tumor immunosuppression, DCexo-based cancer vaccines have been heralded as the superior alternative cell-free therapeutic vaccines over DC vaccines, and have now been tested in multiple clinical trials. In this review, current studies of DCexo cancer vaccines as well as potential future directions will be discussed.As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy.

Low-Dose IL-2 for Treating Moderate to Severe Alopecia Areata: A 52-Week Multicenter Prospective Placebo-Controlled Study Assessing its Impact on T Regulatory Cell and NK Cell Populations

Low-Dose IL-2 for Treating Moderate to Severe Alopecia Areata: A 52-Week Multicenter Prospective Placebo-Controlled Study Assessing its Impact on T Regulatory Cell and NK Cell Populations

Immunogenicity of Inactivated Varicella Zoster Vaccine in Autologous Hematopoietic Stem Cell Transplant Recipients and Patients With Solid or Hematologic Cancer.

BackgroundIn phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZVIN) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZVIN immunogenicity from these studies.MethodsPatients were randomized to ZVIN or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling.ResultsEstimated geometric mean fold rise ratios (ZVIN/placebo) by gpELISA and IFN-y ELISPOT ~28 days post–dose 4 were 2.02 (95% confidence interval [CI], 1.53–2.67) and 5.41 (95% CI, 3.60–8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79–1.98) and 2.10 (95% CI, 1.69–2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81–3.05) in patients with HM.ConclusionsZVIN immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZVIN immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations.Clinical trial registrationNCT01229267, NCT01254630.

The Targeted Impact of Flavones on Obesity-Induced Inflammation and the Potential Synergistic Role in Cancer and the Gut Microbiota.

Obesity is an inflammatory disease that is approaching pandemic levels, affecting nearly 30% of the world’s total population. Obesity increases the risk of diabetes, cardiovascular disorders, and cancer, consequentially impacting the quality of life and imposing a serious socioeconomic burden. Hence, reducing obesity and related life-threatening conditions has become a paramount health challenge. The chronic systemic inflammation characteristic of obesity promotes adipose tissue remodeling and metabolic changes. Macrophages, the major culprits in obesity-induced inflammation, contribute to sustaining a dysregulated immune function, which creates a vicious adipocyte–macrophage crosstalk, leading to insulin resistance and metabolic disorders. Therefore, targeting regulatory inflammatory pathways has attracted great attention to overcome obesity and its related conditions. However, the lack of clinical efficacy and the undesirable side-effects of available therapeutic options for obesity provide compelling reasons for the need to identify additional approaches for the prevention and treatment of obesity-induced inflammation. Plant-based active metabolites or nutraceuticals and diets with an increased content of these compounds are emerging as subjects of intense scientific investigation, due to their ability to ameliorate inflammatory conditions and offer safe and cost-effective opportunities to improve health. Flavones are a class of flavonoids with anti-obesogenic, anti-inflammatory and anti-carcinogenic properties. Preclinical studies have laid foundations by establishing the potential role of flavones in suppressing adipogenesis, inducing browning, modulating immune responses in the adipose tissues, and hindering obesity-induced inflammation. Nonetheless, the understanding of the molecular mechanisms responsible for the anti-obesogenic activity of flavones remains scarce and requires further investigations. This review recapitulates the molecular aspects of obesity-induced inflammation and the crosstalk between adipocytes and macrophages, while focusing on the current evidence on the health benefits of flavones against obesity and chronic inflammation, which has been positively correlated with an enhanced cancer incidence. We conclude the review by highlighting the areas of research warranting a deeper investigation, with an emphasis on flavones and their potential impact on the crosstalk between adipocytes, the immune system, the gut microbiome, and their role in the regulation of obesity.

Development Of Quantitative Förster Resonance Energy Transfer (QFRET) Based High Throughput (HTS) Screening For PD-1/PD-L1 Immune-Checkpoint Assay

Author(s): Xaypraseuth, Amanda; Madahar, Vipul; Liao, Jiayu | Abstract: Programmed cell death protein 1 (PD-1) and programmed cell death 1 - ligand 1 (PD-L1) are immune-checkpoint proteins that play an important part in cancer immunity. PD-1 is a protein on the surface of cells that down-regulates the immune system1 while PD-L1 is a protein on some normal and cancer cells. The interaction of these proteins play a major role in tumor immune escape, inhibiting T lymphocyte proliferation and survival functions. To combat this issue, targeting these immune checkpoint proteins with monoclonal antibodies (mAbs) has become the turning point in cancer treatment. However, limitations were found using mAbs such as the cost of administration, its high molecular weight, and its lack of clinical efficacy. Recently, researchers are investigating small molecule inhibitors to target the PD-1/PD-L1 mechanism instead. With CA-170 as the only small-molecule modulator in clinical trials targeting PD-1, it is essential to research options that can contribute to cancer treatments. This study provides a novel, rapid assessment for PD-1/PD-L1 interaction with the use of FRET- based kinetic analysis. PD-1/PD-L1 binding will be quantified by fluorescence using donor and acceptor pairs, CyPet and Ypet, which were bound to PD-L1 and PD-1, respectively. From this study, we calculated a Kd value of 0.31±0.13 and developed an HTS assay with a Z’ value g 0.7, values that validate the robustness and efficacy of this assay. With the development of this type of screening, it will be easy to contribute to small molecule inhibitor discovery and the growing field of cancer immunotherapy.

Ventilation following established ARDS: a preclinical model framework to improve predictive power

BackgroundDespite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily...

Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study

BackgroundWith proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML). Patients and MethodsThe primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795). ResultsDose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML. ConclusionFurther investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.

IgG4-associated sclerosing cholangitis: a diagnosis that may change the course of events (review of the literature and a clinical case)

Immunoglobulin G4-associated sclerosing cholangitis (IgG4-SC) can mimic primary sclerosing cholangitis, cholangiocarcinoma, and pancreatic adenocarcinoma. Its proper diagnosis allows for an adequate therapy and an improvement of the outcomes. The article presents a short literature review with an emphasis on the challenging diagnostic and therapeutic aspects, illustrated by a clinical case. The diagnosis of IgG4-SC is based on a combination of biochemical, radiological and histological signs and symptoms, including elevated levels of serum IgG4, intra- and extrahepatic biliary strictures detected by magnetic resonance cholangiography, and multifocal IgG4-lymphoplasmic infiltrations, sclerosing fibrosis of the bile ducts, seen at morphological assessment. Glucocorticoids (GCS) are the first line agents to achieve remission in patients with IgG4-SC. Most patients respond well to the systemic GCS. However, about 20% of patients (mostly those with extensive sclerotic intra- and/or extrahepatic abnormalities and signs of advanced disease / cirrhosis) show an insufficient or no response from the beginning of the treatment. The clinical case illustrates that timely verification of the IgG4-SC diagnosis may have an important prognostic value. The case history of a 62-year old female patient confirms the difficulties of the early diagnosis of the disease: for a relatively long time, the patient had the diagnosis of primary sclerosing cholangitis. Delay with GCS prescription (the treatment was initiated only at the stage of liver cirrhosis) had led to the lack of clinical efficacy and development of complications, such as relapsing cholangitis with advanced biliary strictures. In patients with suspected primary sclerosing cholangitis, timely differential diagnosis with IgG4-SC is relevant, because early GCS administration can slow the progression of the disease.

Rivaroxaban-Associated Intraparenchymal Hemorrhage Managed with 4-Factor Prothrombin Complex Concentrate

Background: Rivaroxaban is a Xa inhibitor and one of the direct acting oral anticoagulants (DOAC) that currently does not have evidence-based guidelines for its reversal. Prothrombin complex concentrate (PCC) has been recommended as a potential reversal agent for life-threatening bleeds. With no direct antidote and its widespread usage, the attempt to manage life-threatening hemorrhages with procoagulant drugs will continue to rise. Case report :A 55-year-old male on rivaroxaban and clopidogrel presented to another facility with ataxia, confusion, and lateralizing weakness. Computed tomography (CT) scan of the brain showed a large intraparenchymal hemorrhage. He was intubated, given mannitol and nicardipine, and transferred to our tertiary care facility. His coagulation studies upon arrival were normal. He was given 50 units/kg of PCC in an attempt to reverse rivaroxaban and one unit of platelets for clopidogrel reversal. A repeat CT 18 h later showed extension of the bleed. Neurosurgical intervention was not done, and 4 days into his stay, a right cephalic vein thrombosis was found. During his hospital stay, the patient developed encephalopathy and required a tracheostomy tube and gastrostomy tube. A CT on day 36 showed stabilization of the bleeds, and on day 42, he was transferred to a skilled nursing facility. Why should an emergency physician be aware of this? Novel oral anticoagulants are becoming ever popular due to their ease in management and lack of required monitoring when compared to conventional therapy. But, they are still associated with hemorrhages, which is their most common complication. Due to the lack of antidotes and reversal agents for DOACs, prothrombotic agents are being frequently utilized in the setting of life-threatening hemorrhages. While various case reports have been published on the usage of varying dosages of PCC to treat rivaroxaban-associated bleeds, no strong evidence exists to its clinical efficacy. Our case adds to the growing body of evidence showing a lack of clinical efficacy in the reversal of the anticoagulation effects of oral factor Xa inhibitors in addition to a complication in utilizing this potential reversal agent (J Crit Care 33:252–6, 2016; J Thromb Heamost 12:1428–1436, 2014; World Neurosurg 84(6)1956–1961, 2015)

EU decision-making for marketing authorization of advanced therapy medicinal products: a case study

A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.

Immune checkpoint inhibition in elderly non-small cell lung cancer patients.

137 Background: Age-related changes in the immune system are dynamic and complex. Use of anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer (NSCLC), with median patient age of 71, has rapidly become standard of care. Understanding how senescent remodeling of the immune system may affect outcomes with anti-PD-1/PD-L1 therapy is poorly understood. Although trends in phase III clinical trials of anti-PD-1/PD-L1 therapy suggest a potential lack of clinical efficacy in patients ≥ 75 years of age, the proportion of treated patients in this age range was low. The use and outcomes of these agents in this population treated in clinical practice has not been reported. Methods: The Johns Hopkins Upper Aerodigestive Diseases Malignancies and Immunotherapy Database was queried for all patients treated with anti-PD-1/PD-L1 agents as part of a clinical trial or as standard of care, from 2007 to 2017. Patients ≥ 75 years old were assessed for demographic, response, toxicity and survival data as of September 2017. Results: Of the 275 patients in our database, 144 NSCLC patients had received an anti-PD-1/PD-L1 agent alone or in combination with another immune checkpoint inhibitor (52%). Of those 144 patients, 20 patients were ≥ 75 years of age at time of anti-PD-1/PD-L1 therapy initiation (14%), with a median age of 81 years (range: 75-90). Of those 20 patients, 19 received anti-PD1 monotherapy (95%); 1 patient received combination anti-PD-1 with an anti-KIR. 14 of the 20 patients (70%) received therapy in second line or beyond; 6 received anti-PD-1 monotherapy as first line therapy. No significant difference in median survival for 1st line or ≥2nd line group was seen (12.7m vs 15.3m; p = 0.92). A median of 5.5 doses were administered (range 1-24). Reasons for off therapy included: progressive NSCLC (9; 45%), consent withdrawal (1; 5%) and adverse events (6; 30%) with 4 patients who remain on therapy (20%). Conclusions: Anti-PD-1/PD-L1 therapy is now standard of care in NSCLC, a malignancy of the elderly. Translational evaluation of how immune system senescent remodeling affects outcome and toxicity is needed. Further analysis of immunologic and genomic data will be presented and compared to the overall population in our database at the time of presentation.

Pharmacokinetics of doripenem in plasma and epithelial lining fluid (ELF): comparison of two dosage regimens

PurposeIn 2014, FDA released a warning for prescription of doripenem for ventilator-associated bacterial pneumonia due to unsatisfactory clinical cure rates. The present study explores if the observed lack of efficacy might be explained by insufficient target site pharmacokinetics in intensive care patients after two different infusion schemes.MethodsPlasma and bronchoalveolar lavage sampling was performed in 16 intubated patients with pneumonia receiving doripenem either as 1-h or as 4-h infusion. Doripenem concentrations were measured at steady state in plasma over 8 h, bronchoalvoelar lavage was performed in each patient once either after 0 h, 2 h, 4 h or 6 h.ResultsIn plasma, mean values of Cmax, Tmax and AUC0–8 were 16.87 mg/L, 0.69 h and 52.98 mg/L×h after 1 h of infusion, and 12.94 mg/L, 3.21 h and 70.64 mg/L×h after 4 h of infusion, respectively. While the later tmax in plasma was with delay mirrored in the lung, for ELF, much lower concentrations were observed (Cmax, Tmax and AUC0–8 after 1-h infusion of 4.6 mg/L, 2 h and 15.3 mg/L×h and after 4-h infusion 6.9 mg/L, 4 h and 14.8 mg/L×h).ConclusionThe difference in plasma pharmacokinetics after 1-h and 4-h infusion reflects in the concentration versus time profile in the lung, but concentration at the target site was not only considerably lower but also subject to high inter-individual variability. We hypothesise that insufficient concentrations at the target site might have contributed to the previously described lack of clinical efficacy and confirmed the demand for assessment of target site pharmacokinetics in larger patient collectives.