Therapeutic Clinical Trials Research Articles

Investigation of the Optimal Prime Boost Spacing Regimen for a Cancer Therapeutic Vaccine Targeting Human Papillomavirus.

Simple SummaryThe selection of a therapeutic vaccine schedule can influence the magnitude, efficacy, and durability of immune responses. This study aims to test different prime-boost intervals using a model vaccine in a well-established tumor model system to investigate how the timing of repetitive antigen exposure impacts the induction of effector and memory T cells. Identifying the vaccine schedule most likely to induce durable protective anti-tumor immunity will facilitate decisions made to balance the induction of highly cytotoxic effector T cells and the generation of long-term immunologic memory.Therapeutic vaccine studies should be designed to elicit durable, high magnitude, and efficacious T cell responses, all of which can be impacted by the choice of the vaccination schedule. Here, we compare different prime-boost intervals (PBI) in a human papillomavirus (HPV) model using a HPV16E7E6 Venezuelan equine encephalitis virus replicon particle (VRP) vaccination to address the optimal boosting schedule, quality of immune response, and overall in vivo efficacy. Six different vaccine regimens were tested with each group receiving booster vaccinations at different time intervals. Analysis of T-cell responses demonstrated a significant HPV16 E7 specific CD8+ T cell response with at minimum a one-week PBI between antigen re-exposure. Significant E7-specific in vivo cytotoxicity was also observed with longer PBIs. Additionally, longer PBIs led to an enhanced memory recall response to tumor challenge, which correlated with differential expansion of T cell memory subsets. Our findings imply that when using alphavirus vector platforms as a vaccination strategy, a one-week PBI is sufficient to induce high magnitude effector T cells with potent anti-tumor activity. However, longer PBIs lead to enhanced long-term protective anti-tumor immunity. These findings have implications for therapeutic vaccine clinical trials in which shorter intervals of prime-boost regimens may lead to suboptimal durable immune responses.

Clinical Assessment of Fetal Well-Being and Fetal Safety Indicators.

Delivering safe clinical trials of novel therapeutics is central to enable pregnant women and their babies to access medicines for better outcomes. This review describes clinical monitoring of fetal well‐being and safety. Current pregnancy surveillance includes regular antenatal checks of blood pressure and urine for signs of gestational hypertension. Fetal and placental development is assessed routinely using the first‐trimester “dating” and mid‐trimester “anomaly” ultrasound scans, but the detection of fetal anomalies can continue throughout pregnancy using targeted sonography or magnetic resonance imaging (MRI). Serial sonography can be used to assess fetal size, well‐being, and placental function. Carefully defined reproducible imaging parameters, such as the head circumference (HC), abdominal circumference (AC), and femur length (FL), are combined to calculate an estimate of the fetal weight. Doppler analysis of maternal uterine blood flow predicts placental insufficiency, which is associated with poor fetal growth. Fetal doppler analysis can indicate circulatory decompensation and fetal hypoxia, requiring delivery to be expedited. Novel ways to assess fetal well‐being and placental function using MRI, computerized cardiotocography (CTG), serum circulating fetoplacental proteins, and mRNA may improve the assessment of the safety and efficacy of maternal and fetal interventions. Progress has been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. A new system for improved safety monitoring for clinical trials in pregnancy, Maternal and Fetal Adverse Event Terminology (MFAET), describes 12 maternal and 18 fetal adverse event (AE) definitions and severity grading criteria developed through an international modified Delphi consensus process. This fills a vital gap in maternal and fetal translational medicine research.

Potential COVID -19 Therapeutics in Clinical Trials – A Brief Review

The severe acute respiratory syndrome coronavirus 2 (SARS – CoV2), the causative viral pathogen of the COVID-19 pandemic belongs to the family of Coronaviruses which are positive single stranded RNA viruses. The scientific fraternity has developed and developing various types of vaccines for prevention against COVID-19, such as inactivated virus vaccines, mRNA vaccines, replicating vector protein subunit vaccines, etc., Out of which ten vaccines namely Novovax, Covovax (protein subunit vaccines), Pfizer BNT16b2, Moderna mRNA 1273 (mRNA vaccines), Johnson & Johnson Ad26, Cov2.S, Astrazeneca AZD1222, Covishield (non-replicating viral vector vaccines), Covaxin, Sinopharm BBIBP-CorV, CoronoVac (inactivated vaccines) have been approved for clinical use by WHO. There is an urgent need for SARS-CoV2 specific therapeutics for the treatment of COVID-19 as there is the emergence of various variants such as Alpha, Beta, Gamma, Delta, Omicron, etc. The emergence of variants that possesses immune evading property and spike protein mutation have increased infectivity and more pathogenicity which impelled the need to develop various therapeutics for the treatment of COVID-19. This review compiles the information about potential antiviral candidates in preclinical trials intended for the treatment of COVID-19. The clinical development of such antivirals will be very crucial for the treatment of COVID-19 and also to curb the spread as the present scenario depends on the development of effective prophylactic vaccines.

Clinical Strategies Targeting the Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.

Simple SummaryTumors from pancreatic cancer contain many types of cells (such as immune cells and fibroblasts) in addition to the cancer cells. Using targeted drugs to disrupt interactions between these cells which can support cancer cell growth, invasion, and immune suppression has become an important area of exploration in the pancreatic cancer field. This review describes new drugs designed to modulate interactions between cancer cells and other cell types in the tumor and discusses the initial clinical trials testing these novel therapeutics in pancreatic cancer patients.Pancreatic cancer has a complex tumor microenvironment which engages in extensive crosstalk between cancer cells, cancer-associated fibroblasts, and immune cells. Many of these interactions contribute to tumor resistance to anti-cancer therapies. Here, new therapeutic strategies designed to modulate the cancer-associated fibroblast and immune compartments of pancreatic ductal adenocarcinomas are described and clinical trials of novel therapeutics are discussed. Continued advances in our understanding of the pancreatic cancer tumor microenvironment are generating stromal and immune-modulating therapeutics that may improve patient responses to anti-tumor treatment.

Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia.

High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)–lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.

Appropriate controls for digital therapeutic clinical trials: A narrative review of control conditions in clinical trials of digital therapeutics (DTx) deploying psychosocial, cognitive, or behavioral content.

Digital therapeutics (DTx) are software programs that treat a disease or condition. Increasingly, DTx are part of medical care, and in the US healthcare system they are regulated by the FDA as Software as a Medical Device (SaMD). Randomized controlled trials (RCT) remain a key evidence generation step for most DTx. However, developing a unified approach to the design of appropriate control conditions has been a challenge for two main reasons: (1) inheriting control condition definitions from pharmacotherapy and medical device RCT that may not directly apply, and (2) challenges in establishing control conditions for psychosocial interventions that build the core of many DTx. In our critical review we summarize different approaches to control conditions and patient blinding in RCT evaluating DTx with psychosocial, cognitive or behavioral content. We identify control condition choices, ranging from very minimal digital controls to more complex and stringent digital applications that contain aspects of "fake" therapy, general wellness content or games. Our review of RCTs reveals room for improvement in describing and naming control conditions more consistently. We further discuss challenges in defining placebo controls for DTx and ways in which control choices may have a therapeutic effect. While no one-size-fits-all control conditions and study designs will apply to all DTx, we propose points to consider for defining appropriate digital control conditions. At the same time, given the rapid iterative development and optimization of DTx, treatments with low risk profile may be evaluated with minimal digital controls followed by extensive real-world effectiveness trials.

Funding Sources of Therapeutic and Vaccine Clinical Trials for COVID-19 vs Non–COVID-19 Indications, 2020-2021

Effective COVID-19 vaccines and therapeutics reached the market within the first year of the pandemic. This rate of development and availability was an unprecedented achievement that required attention to numerous research and development, regulatory, and policy challenges. However, only limited evidence is currently available on the sources of funding for COVID-19 clinical trials. To compare the number and funding sources of clinical trials aimed at investigating therapeutics and vaccines for COVID-19 vs those for all non-COVID-19 indications. In this cross-sectional study, clinical trials in phase 1 to 3 that were registered to start between January 1, 2020, and August 31, 2021, were examined. All relevant data were collected from ClinicalTrials.gov. Number of clinical trials and their funding sources. A total of 1977 clinical trials that addressed COVID-19 therapeutics and vaccines were registered worldwide with starting dates from January 1, 2020, to August 31, 2021. This cohort represented 13.9% of all trials (N = 14 274) during the same period. Most of the COVID-19 therapeutic and vaccine clinical trials were funded by public sources (1144 [57.9%]), followed by industry (540 [27.3%]) and public-private partnerships (293 [14.8%]). Most of these studies focused on the development of anti-COVID-19 therapeutics (1680 [85.0%]) rather than vaccines (297 [15.0%]). The findings of this study suggest that publicly funded research and medical institutions played a leading role as funding sources for generating effective COVID-19 therapeutics and vaccines during the first 1.5 years of the pandemic and were most likely instrumental in their rapid development. It may be beneficial for the public sector to maintain the affordability and global access to these therapeutics and vaccines to ensure that they remain available for use worldwide.

Efficacies of two medicinal plants [Goma Guar Walmart (Cyamopsis tetragonolobus L.) and Cinnamon (Cinnamomum verum)] versus efficacy of allopathic treatment [Sil–Norboral (Glibenclamide 5 mg/Metformin 1000 mg + Janumet (Sitagliptin 50 mg/Metformin 850 mg)

The objective of this study was to statistically compare –using the One–Way Analysis of Variance and Dunnett's multiple comparisons test– the efficacy of Cyamopsis tetragonolobus L. and Cinnamomum verum versus the efficacy of the allopathic treatment Sil–Norboral (Glibenclamide 5 mg/Metformin 1000 mg) + Janumet (Sitagliptin 50 mg/Metformin 850 mg) as hypoglycemic agents in patients with type 2 diabetes mellitus who attend the "Dr. Agustin O'Horán" General Hospital for medical care. The epistemological approach is quantitative, probabilistic or positivistic. The study design corresponds to that of a therapeutic experimental epidemiological study (therapeutic clinical trial) with prospective temporality. Forty–eight patients with type 2 diabetes mellitus were studied. The 48 patients were randomly assigned to three groups: two experimental groups and one control group. Each group was made up of 16 patients. The first experimental group was given Cyamopsis tetragonolobus L. (twelve dry leaves of Cyamopsis tetragonolobus L. and 500 ml of hot water); pour the 500 ml of hot water into a container and add the twelve dry leaves of Cyamopsis tetragonolobus L.; take 250 ml in the morning and 250 ml at night); the second experimental group was given Cinnamomum verum (two g of dry leaves of Cinnamomum verum and 500 ml of hot water; pour the 500 ml of hot water into a container and add two g of dry leaves of Cinnamomum verum; take 250 ml in the morning and 250 ml at night); and the control group was given the Sil–Norboral allopathic treatment (Glibenclamide 5 mg/Metformin 1000 mg) + Janumet (Sitagliptin 50 mg/Metformin 850 mg). In ascending numerical order, the arithmetic means of the hematic glucose values ​​corresponded to the following treatments: Cyamopsis tetragonolobus L. (84.06 mg/100mL); Cinnamomum verum (88.63mg/100mL); and Sil–Norboral (Glibenclamide 5 mg/Metformin 1000 mg) + Janumet (Sitagliptin 50 mg/Metformin 850 mg) (122.25 mg/100mL). The One–Way Analysis of Variance reported a value of F= 56.03 with a value of p= 0.0000, which indicates a statistically significant difference between a pair or between more than one pair of arithmetic means. Dunnett's multiple comparisons test showed statistically significant differences between the treatment with the medicinal plant Cyamopsis tetragonolobus L. and the allopathic treatment Sil–Norboral + Janumet: p= 0000. Likewise, Dunnett's multiple comparisons test showed a statistically significant difference between the treatment with the medicinal plant Cinnamomum verum and the allopathic treatment Sil–Norboral + Janumet: p= 0.0000. It is concluded that Cyamopsis tetragonolobus L. is, from a numerical and not a statistical point of view, the best hypoglycemic agent for the treatment of type 2 diabetes mellitus.

Impact of travel distance on outcomes for clinical trial patients: the Kinghorn Cancer Centre experience.

Geographic isolation and travel distance to specialist care is a known social determinant of health and contributes to poorer oncology survival outcomes. To compare survival and toxicity outcomes for patients travelling long distances (>50 km) for treatment on clinical trials with local patients (<10 km and 10-50 km). We performed a retrospective cohort study based at the Kinghorn Cancer Centre, a comprehensive cancer care centre in metropolitan Sydney. We included adult patients with advanced solid-organ malignancies who were enrolled on therapeutic clinical trials between July 2015 and December 2017. Outcome measures included overall survival, progression-free survival, rates of grade 3-4 toxicity and unplanned hospital admissions for the duration of the clinical trial. We included 173 patients, of whom 27% lived within 10 km, 29% lived between 10 and 50 km and 44% lived further than 50 km. We did not identify significant differences between survival or toxicity outcomes between patients travelling long distances and local patients. All patients should be considered for clinical trial referral based on clinical parameters and preference, regardless of geographic proximity. In the meantime, improving access to clinical trials for rural and regional patients continues to be a priority.

Critical Decisions: A mixed-methods study investigating decision-making and disparities among diverse gynecologic cancer patients considering therapeutic clinical trial enrollment (014)

Objectives: Disparities in clinical trial enrollment are extensive and persistent. From 1994-2013, 83% of GOG trial participants were White, despite the similar willingness of participation among diverse groups. This limits study generalizability and marginalized patients’ access to novel therapeutics. This mixed-method study at an academic institution in a rural state included groups underrepresented in clinical trials, including American Indian and Hispanic, sexual and gender minority, and less well-educated patients. Institutional enrollment exceeds national numbers and reflects broader state demographics, allowing investigation of patients’ decision-making regarding clinical trial participation. Methods: We conducted surveys and in-depth qualitative interviews with 27 gynecologic cancer patients eligible for therapeutic clinical trials. Their gynecologic oncologists completed parallel surveys. Two investigators completed an iterative analysis of interviews, eliciting themes pertinent to decision-making, patient-provider relationships, and illness experiences. Surveys addressed shared decision-making, decisional conflict, and patient-centered care. We compared patient and provider survey data for participants who enrolled and those who did not, using Fisher’s exact tests. Conclusions: Concerns regarding social support and coping, exacerbated by experienced distress, unmet needs, and vulnerability, shape clinical trial enrollment in gynecologic cancer. Discussions of clinical trial disparities often focus on patient education, yet participants in this study expressed receiving sufficient information to make shared decisions with their providers. Those who remained unenrolled reported more apprehension regarding cancer diagnosis and treatment, making the additional uncertainty of clinical trials unmanageable. Reasons posited for such differences include coping styles, degree of social support, and perceptions that clinical trials may result in additional vulnerabilities for patients and their families. Therefore, for clinical trial participation to be feasible for vulnerable patients, interventions must provide significant social/economic support and recognize and manage patient distress related to isolation, treatment options, and coping. The next step includes developing tools to support historically marginalized patients, many of whom have experienced minority stress, to mitigate the uncertainty of clinical trial enrollment. Objectives: Disparities in clinical trial enrollment are extensive and persistent. From 1994-2013, 83% of GOG trial participants were White, despite the similar willingness of participation among diverse groups. This limits study generalizability and marginalized patients’ access to novel therapeutics. This mixed-method study at an academic institution in a rural state included groups underrepresented in clinical trials, including American Indian and Hispanic, sexual and gender minority, and less well-educated patients. Institutional enrollment exceeds national numbers and reflects broader state demographics, allowing investigation of patients’ decision-making regarding clinical trial participation. Methods: We conducted surveys and in-depth qualitative interviews with 27 gynecologic cancer patients eligible for therapeutic clinical trials. Their gynecologic oncologists completed parallel surveys. Two investigators completed an iterative analysis of interviews, eliciting themes pertinent to decision-making, patient-provider relationships, and illness experiences. Surveys addressed shared decision-making, decisional conflict, and patient-centered care. We compared patient and provider survey data for participants who enrolled and those who did not, using Fisher’s exact tests. Conclusions: Concerns regarding social support and coping, exacerbated by experienced distress, unmet needs, and vulnerability, shape clinical trial enrollment in gynecologic cancer. Discussions of clinical trial disparities often focus on patient education, yet participants in this study expressed receiving sufficient information to make shared decisions with their providers. Those who remained unenrolled reported more apprehension regarding cancer diagnosis and treatment, making the additional uncertainty of clinical trials unmanageable. Reasons posited for such differences include coping styles, degree of social support, and perceptions that clinical trials may result in additional vulnerabilities for patients and their families. Therefore, for clinical trial participation to be feasible for vulnerable patients, interventions must provide significant social/economic support and recognize and manage patient distress related to isolation, treatment options, and coping. The next step includes developing tools to support historically marginalized patients, many of whom have experienced minority stress, to mitigate the uncertainty of clinical trial enrollment.

Development of a novel patient-reported outcome measure to assess signs and symptoms of COVID-19

BackgroundGiven the urgent need for vaccines and treatments for coronavirus disease 2019 (COVID-19), the Symptoms of Infection with Coronavirus-19 (SIC), a comprehensive, patient-reported outcome (PRO) measure of signs and symptoms associated with COVID-19, was developed in full alignment with current US regulatory guidance to support evaluations of vaccines and treatments in development.MethodsAn initial version of the SIC was developed to address concepts identified through a targeted literature review and consultation with experts in infectious diseases and clinicians routinely managing COVID-19 in a hospital setting. A qualitative study was conducted in sites in the United States among 31 participants aged ≥ 18 years who were English-speaking and willing and able to provide informed consent and a self-reported history by telephone or online method. The measure was refined based on additional feedback from the clinicians and three iterative rounds of combined concept elicitation and cognitive debriefing interviews conducted with patients, caregivers, and healthy volunteers.ResultsAmong 39 scientific articles identified in the literature review, 35 COVID-19 signs and symptoms were reported and confirmed during interviews with clinicians, patients, and caregivers. Patients and healthy participants suggested changes for refining the draft SIC to ensure consistent interpretation and endorsed both the 24-h recall period and use of an 11-point numeric rating scale (NRS) for capturing change in symptom severity. The final version of the SIC captures the daily presence or absence of 30 symptoms and a rating of severity for 25 of the 30 symptoms using an NRS for those symptoms reported as present.ConclusionsThe SIC comprehensively addresses observations described in the literature, by clinicians, and by patients, and captures patients’ experiences with COVID-19 in a manner that minimizes complexity and facilitates completion for both patients and healthy volunteers. This measure is thus appropriate for use in clinical trials of both therapeutics and vaccines for COVID-19.

The Role of HDACs in the Response of Cancer Cells to Cellular Stress and the Potential for Therapeutic Intervention.

Throughout the process of carcinogenesis, cancer cells develop intricate networks to adapt to a variety of stressful conditions including DNA damage, nutrient deprivation, and hypoxia. These molecular networks encounter genomic instability and mutations coupled with changes in the gene expression programs due to genetic and epigenetic alterations. Histone deacetylases (HDACs) are important modulators of the epigenetic constitution of cancer cells. It has become increasingly known that HDACs have the capacity to regulate various cellular systems through the deacetylation of histone and bounteous nonhistone proteins that are rooted in complex pathways in cancer cells to evade death pathways and immune surveillance. Elucidation of the signaling pathways involved in the adaptive responses to cellular stress and the role of HDACs may lead to the development of novel therapeutic agents. In this article, we overview the dominant stress types including metabolic, oxidative, genotoxic, and proteotoxic stress imposed on cancer cells in the context of HDACs, which guide stress adaptation responses. Next, we expose a closer view on the therapeutic interventions and clinical trials that involve HDACs inhibitors, in addition to highlighting the impact of using HDAC inhibitors in combination with stress-inducing agents for the management of cancer and to overcome the resistance to current cancer therapy.

Complement drives circuit modulation in the adult brain.

Once widely considered an immune-privileged organ, the brain is now known to be intimately intertwined with immune-system activation. In particular, the complement system, an enzymatic cascade conferring innate immunity, has crucial functions for several neurodevelopmental and neuromigratory mechanisms. Recent advances have demonstrated the neurological importance of complement activation in the adult brain, whereby phagocytosis of weakened synapses biologically encodes "forgetting" of information through complement activation. Neurophysiologically, complement factors can also influence the brain's computational processes, increasing neuronal calcium influx and neurotransmitter release and altering synaptic strength. The complement system's effects on synaptic connectivity can also be observed in many pathological conditions including epilepsy, schizophrenia, and viral-induced cognitive deficits, where perturbations of complement-stimulated synaptic remodelling lead to severe dysfunction. In this review we provide an overview of current knowledge for complement in neurodevelopment, and examine recent evidence highlighting a critical physiological role of complement in the plasticity of the adult brain. This is especially relevant due to the explosion of complement-targeted therapeutics in clinical trials to treat neurological disorders.

Impact and treatment of exacerbations in adults with bronchiectasis.

Exacerbations have a negative impact on inflammatory diseases of the airways and, in patients with bronchiectasis, severe exacerbations are associated with increased morbidity and mortality. Exacerbations are also associated with a decline in quality of life and lung function, greater local and systemic inflammation and clinically more severe forms of the disease. As a consequence, the majority of therapeutic clinical trials carried out in patients with bronchiectasis are aimed at preventing exacerbations, but there is a scarcity of scientific evidence on the best treatment once they occur. All of these elements, combined with the great heterogeneity of bronchiectasis and the influence of geographical and microbiological factors on its clinical presentations and aetiologies, mean that the recommendations of therapeutic guidelines vary. An international group of experts has now reached agreement on the definition of exacerbation in bronchiectasis for the inclusion of patients in clinical trials, although its validity in clinical practice has yet to be demonstrated.

Sex differences in plasma p-tau181 associations with Alzheimer’s disease biomarkers, cognitive decline, and clinical progression

Studies have shown that women on the Alzheimer’s disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-β (Aβ) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aβ and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aβ positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

MicroRNA-Based Diagnosis and Therapy.

MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes involving a range of biological processes, contributing to numerous human disorders. With high stability in human fluids, miRNAs in the circulation are considered as promising biomarkers for diagnosis, as well as prognosis of disease. In addition, the translation of miRNA-based therapy from a research setting to clinical application has huge potential. The aim of the current review is to: (i) discuss how miRNAs traffic intracellularly and extracellularly; (ii) emphasize the role of circulating miRNAs as attractive potential biomarkers for diagnosis and prognosis; (iii) describe how circulating microRNA can be measured, emphasizing technical problems that may influence their relative levels; (iv) highlight some of the circulating miRNA panels available for clinical use; (v) discuss how miRNAs could be utilized as novel therapeutics, and finally (v) update those miRNA-based therapeutics clinical trials that could potentially lead to a breakthrough in the treatment of different human pathologies.

Abstract 1808: Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem cells

Abstract Mesenchymal stem cells (MSCs) are being investigated for several therapeutic applications, including cancer, inflammation, tissue repair, and transplantation because of their ability to home to injured and inflamed tissues. Despite the large number of preclinical studies investigating engineered MSCs as therapeutic agents and numerous clinical trials investigating MSCs for other therapeutic applications, there have only been a handful of clinical trials investigating MSCs for treating solid tumors, and none have progressed beyond Phase I/II. Inefficient tumor homing ability and a lack of understanding of fundamental mechanisms may contribute to the limited translational success of MSC-based therapies. We hypothesized that nanoengineering MSCs with anticancer drugs induces oxidative stress, and MSCs counteract this stress by activating Nrf2, which increases the expression of various antioxidant proteins, including CXCR4, a key mediator of MSC tumor homing. We performed global label-free, unbiased proteomics on nanoengineered MSCs using modified in-Stage technology. Our studies indicated that MSCs nanoengineered with paclitaxel underwent significant changes in the overall proteome compared to either untreated MSCs or MSCs loaded with blank nanoparticles. Analysis of molecular function profile revealed that loading paclitaxel in MSCs significantly enhanced the expression of proteins involved in the antioxidant and catalytic activity and protein binding. The biological process profile also showed a similar increase in defense response and an increase in metabolic processes. It was further found that MSCs nanoengineered with PTX lead to significant upregulation of nrf2, the master regulator of antioxidant responses, and CXCR4, a direct target of Nrf2 and a key mediator of tumor homing. Also, an increase in CXCR4 expression was directly proportional to paclitaxel loading in cells. These studies suggest nanoengineering of MSCs impacts their biology, which likely contributes to their improved tumor homing capacity in vivo. Citation Format: Drishti Sehgal, Susheel Kumar Nethi, Carmen Merali, Salim Merali, Jayanth Panyam, Swayam Prabha. Impact of nanoengineering on redox regulation and CXCR4-mediated homing of mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1808.

Abstract CT170: A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ)

Abstract Background: Ramucirumab is a monoclonal antibody that binds to the vascular endothelial growth factor receptor 2, increasing hypoxia in the tumor microenvironment. In advanced gastric cancer, single agent ramucirumab is well tolerated and improves overall survival (OS) compared to placebo although it is largely cytostatic with a response rate ≤3%. Preclinical in vitro and in vivo experiments reveal that hypoxia induces homologous recombination deficiency (HRD) in tumors, which may be exploited by the addition of inhibitors of poly (ADP-ribose) polymerase (PARPi). We thus designed NCI10066 for metastatic gastric cancer with the hypothesis that ramucirumab would sensitize tumors to the PARPi olaparib. Methods: NCI 10066 (NCT03008278) was a phase 1/2, multicenter, open-label clinical trial sponsored by the Cancer Therapy Evaluation Program. Eligible patients had histologically confirmed metastatic gastric or GEJ adenocarcinoma with measurable disease refractory to ≥ 1 prior therapy that did not contain ramucirumab. Patients were treated with escalating doses of olaparib with ramucirumab 8 mg/kg every 2 weeks in a 3+3 design. Dose escalation evaluated two dose levels: olaparib 200 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 1) and olaparib 300 mg twice daily with ramucirumab 8 mg/kg every 2 weeks (dose level 2). The primary objective of dose escalation was to assess safety and measure dose limiting toxicities (DLT) to determine the recommended phase 2 dose (RP2D). The primary objective in phase 2 was to evaluate clinical activity at the RP2D in a 40-patient expansion cohort. Results: From 2/8/18 - 9/17/21, 51 patients were enrolled at 10 centers throughout the Experimental Therapeutics Clinical Trials Network and 28/51 (55%) patients had ≥2 prior lines of therapy. In dose escalation 3 patients were treated at dose level 1 and 8 at dose level 2. No DLTs were observed at dose level 1 and at dose level 2 there was 1 DLT (fatigue) in 6 evaluable patients. The RP2D was determined to be olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. Forty patients were treated in dose expansion at the RP2D. Of 46 patients evaluable for a response there were 5/46 (11%) partial responses (PR) and the disease control rate (PR/SD) was 29/46 (63%) at 6 weeks. The median progression free survival (PFS) was 2.8 months (95% CI 2.3 - 4.2) and the median OS was 7.3 months (95% CI 5.6 - 13.0). Grade ≥ 3 treatment related adverse events were seen in 13 (25%) of patients and there were no treatment related deaths. Conclusions: The combination of olaparib and ramucirumab is well tolerated with a RP2D of olaparib 300 mg twice daily and ramucirumab 8 mg/kg every 2 weeks. The ORR, PFS, and OS exceed the historical control with ramucirumab monotherapy, suggesting that the combination is clinically active. Biomarkers are critical to defining patient subsets more likely to benefit from the combination and HRD biomarker analysis is ongoing. Citation Format: Michael Cecchini, Joseph Chao, Yu Shyr, James Cleary, Nataliya Uboha, May Cho, Anthony Shields, Shubham Pant, Laura Goff, Kristin Spencer, Edward Kim, Chih-Yuan Hsu, Stacey Stein, Jaykumar Thumar, Jeremy Kortmansky, John Kunstman, Patricia LoRusso, Percy Ivy, Jill Lacy. A phase 1/2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction adenocarcinoma (GEJ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT170.

Oncology clinical trial disruption during the COVID-19 pandemic: a COVID-19 and cancer outcomes study

BackgroundCOVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct.Patients and methodsThis prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations.ResultsThe institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (−46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from −23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded.ConclusionsSubstantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer Phenotypes.

Esophageal adenocarcinoma is of increasing global concern due to increasing incidence, a lack of effective treatments, and poor prognosis. Therapeutic target discovery and clinical trials have been hindered by the heterogeneity of the disease, the lack of “druggable” driver mutations, and the dominance of large-scale genomic rearrangements. We have previously undertaken a comprehensive small-molecule phenotypic screen using the high-content Cell Painting assay to quantify the morphological response to a total of 19,555 small molecules across a panel of genetically distinct human esophageal cell lines to identify new therapeutic targets and small molecules for the treatment of esophageal adenocarcinoma. In this current study, we report for the first time the dose–response validation studies for the 72 screening hits from the target-annotated LOPAC and Prestwick FDA-approved compound libraries and the full list of 51 validated esophageal adenocarcinoma-selective small molecules (71% validation rate). We then focus on the most potent and selective hit molecules, elesclomol, disulfiram, and ammonium pyrrolidinedithiocarbamate. Using a multipronged, multitechnology approach, we uncover a unified mechanism of action and a vulnerability in esophageal adenocarcinoma toward copper-dependent cell death that could be targeted in the future.