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Commercially available human platelet lysate (hPL) is produced using expired human platelets obtained from accredited blood banks in the United States. These platelets were originally intended for use in patient transfusion. The safety of platelets used in transfusion is managed by the U.S. Food Drug Administration (FDA), as well as the American Association of Blood Banks (AABB). These organizations set standards, including testing for transmissible diseases. The United States record for blood safety is well established, with extremely low rates of disease transmission, making the platelet units used for hPL manufacture low risk. The Covid-19 pandemic has increased awareness of emerging infectious diseases, even though transmission of Covid-19 via blood transfusion has not been documented. For that reason, gamma irradiated hPL offers an additional safety measure in the clinic. Chimeric Antigen Receptor (CAR) expressing T-cells have demonstrated potent clinical efficacy in patients with hematological malignancies. In addition, there are several phase I clinical trials evaluating the use of CAR-T-cells for targeting of solid tumorassociated antigens. Some of the challenging issues found during production of CAR-T cells are the efficiency of T cell transduction to generate CAR-T cells, the expansion of T cells to clinically relevant numbers and the long-term survival in vivo of the therapeutic cells. The use of human platelet lysate has been demonstrated to improve these issues. Our data from experiments performed using human CD3+ from donors demonstrates that human platelet lysates offer an improved performance on T cell expansion versus serum derived products. hPL efficiently promotes T cell expansion, with higher cell yields and lower cell exhaustion rate. Additionally, we efficiently developed a protocol for suspension culture of T cells, which could facilitate the large-scale expansion of allogeneic CAR-T cells.
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Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. Case Description: A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient's DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient's oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. Discussion(s): This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.Copyright © 2023
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IDWeek is the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS) and the Society of Infectious Diseases Pharmacists (SIDP). For the first time since the COVID-19 public health emergency began, IDWeek 2022 returned to in-person attendance. It was held in Washington, D.C., and the meeting comprised 5 days of live sessions and on-demand content that included posters and oral presentations.Copyright © 2023 Clarivate.
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Three antiviral drugs, including interferon alpha (aerosol inhalation), lopinavir/ritonavir (oral medication), and ribavirin (intravenous infusion), are recommended by Diagnosis and Treatment of Novel Coronavirus Pneumonia (revised version, the 5th ed), which was issued by the National Health Commission of People's Republic of China and National Administration of traditional Chinese Medicine. In addition, clinical trials on a new antiviral drug-remdesivir which is not yet on the market has also been launched in China. Medication safety related data on treatment for infections of severe acute respiratory syndrome coronavirus, middle respiratory syndrome coronavirus, human immunodeficiency virus, lopinavir/ritonavir, and ribavirin, safety data of remdesivir in animal experiment, phase I clinical trials and clinical trials of treating Ebola virus infection, and preliminary reports of treatment in novel coronavirus pneumonia were briefly reviewed, aiming to provide evidence for clinical safety medication.Copyright © 2020 by the Chinese Medical Association.
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Background Taletrectinib is a potent, next-generation, CNS-active, ROS1 tyrosine kinase inhibitor (TKI) with selectivity over TRKB. In previous reports from TRUST-I, taletrectinib showed meaningful clinical efficacy and was well tolerated in pts with ROS1+ NSCLC (n = 109) regardless of crizotinib (CRZ) pretreatment status. We report updated efficacy and safety data with ~1.5 yr follow-up. Methods TRUST-I is a multicenter, open-label, single-arm study with two cohorts: ROS1 TKI-naive and CRZ-pretreated. Pts in both cohorts received taletrectinib 600 mg QD. Key study endpoints included IRC-confirmed ORR (cORR), DoR, disease control rate (DCR), PFS, and safety. A pooled analysis of ORR, PFS, and safety including pts from additional clinical trials was also conducted. Results In the 109 pts from TRUST-I (enrolled prior to Feb 2022) the median follow-up was 18.0 mo in TKI-naive (n = 67) and 16.9 mo in CRZ-pretreated pts (n = 42). cORR was 92.5% in TKI-naive and 52.6% in CRZ-pretreated pts (table). Median DoR (mDoR) and mPFS were not reached. Intracranial-ORR was 91.6%;ORR in pts with G2032R was 80.0%. In a pooled analysis with phase I studies, ORR was 89.5% and 50.0% for TKI-naive and CRZ-pretreated pts, respectively;mPFS was 33.2 mo and 9.8 mo. In 178 pts treated at 600 mg QD, treatment-emergent adverse events (TEAEs) were 92.7%;most (64.0%) were grade 1-2. The most common TEAEs were increased AST (60.7%), increased ALT (55.6%), and diarrhea (55.6%). Neurological TEAEs (dizziness, 18.5%;dysgeusia, 12.4%) and discontinuations due to TEAEs (3.4%) were low. Further updated results will be presented. [Formula presented] Conclusions With additional follow-up, taletrectinib continued to demonstrate meaningful efficacy outcomes including high response rates, prolonged PFS, robust intracranial activity, activity against G2032R, and tolerable safety with low incidence of neurological AEs. Clinical trial identification NCT04395677. Editorial acknowledgement Medical writing and editorial assistance were provided by Arpita Kulshrestha of Peloton Advantage, LLC, an OPEN Health company, and funded by AnHeart Therapeutics, Inc Legal entity responsible for the study AnHeart Therapeutics, Inc. Funding AnHeart Therapeutics, Inc. Disclosure S. He: Financial Interests, Personal, Other, Employment: AnHeart Therapeutics. T. Seto: Financial Interests, Institutional, Research Grant: AbbVie, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical;Financial Interests, Personal, Other, Employment: Precision Medicine Asia;Financial Interests, Personal, Speaker's Bureau, Honoraria for lectures: AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, Towa Pharmaceutical. C. Zhou: Financial Interests, Personal, Other, Consulting fees: Innovent Biologics Qilu, Hengrui, TopAlliance Biosciences Inc;Financial Interests, Personal, Speaker's Bureau, Payment or honoraria: Eli Lilly China, Sanofi, BI, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone LUYE Pharma, TopAlliance Biosciences Inc, Amoy Diagnositics, AnHeart. All other authors have declared no conflicts of interest.Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc.
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A more focused approach is needed to understand the SARS-CoV-2 virulence, structure, and genomics to devise more effective diagnostic and treatment interventions as this virus can evade the immune attack and causes life-threatening complications such as cytokine storm. The spread of the virus is still amplifying and causing thousands of new cases worldwide. It is essential to review current diagnostics and treatment approaches to pave the way to correct or modify our current practices to make more effective interventions against COVID-19. COVID-19 vaccine development has moved at a breakneck pace since the outbreak began, utilizing practically all possible platforms or tactics to ensure the success of vaccines. A total of 42 vaccine candidates have already entered clinical trials, including promising results from numerous vaccine candidates in phase 1 or phase 2 trials. Further, many existing drugs are being explored on broad-spectrum antiviral medications for their use in clinical recovery against COVID-19. The present review attempts to re-examine the SARS-CoV-2 structure, its viral life cycle, clinical symptoms and pathogenesis, mode of transmission, diagnostics, and treatment strategies that may be useful for resorting to more effective approaches for controlling COVID-19. Various antiviral drugs and vaccination strategies with their strengths and weaknesses are also discussed in the paper to augment our understanding of COVID-19 management.Copyright © 2022 Bentham Science Publishers.
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Introduction: Biologics (biopharmaceuticals) present new promising therapies for many diseases such as cancers, chronical inflammatory diseases and today's biggest challenge - COVID-19. Research: Today, most biologics have been synthetized using modern methods of biotechnology, in particular DNA recombinant technology. Current pharmaceutical forms of protein/peptide biopharmaceuticals are intended for parenteral route of administration due to their instability and large size of molecules. In order to improve patient compliance, many companies are working on developing adequate forms of biopharmaceuticals for alternative, non-invasive routes of administration. The aim of this work is to review current aspirations and problems in formulation of biopharmaceuticals for alternative (non-parenteral) routes of administration and to review the attempts to overcome them. These alternative routes of administration could be promising in prevention and treatment of COVID-19, among other serious diseases. Conclusion(s): The emphasis is on stabilizing monoclonal antibodies into special formulations and delivery systems;their application should be safer, more comfortable and reliable. When it comes to hormones, vaccines and smaller peptides, some companies have already registered drugs intended for nasal and oral delivery.Copyright © 2022 Sciendo. All rights reserved.
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The immunogenicity and efficacy of RNA-based vaccine platforms has been abundantly shown through their application in prophylactic SARS-CoV2 vaccines. Contrasting to mRNA based vectors, self amplifying mRNA platforms may offer dose-sparing and superior induction of T cell responses, and may also trigger distinct innate immune pathways, which may exert adjuvanting or inhibiting effects on vaccine-induced immunity. Optimal dosing for a novel self-amplifying mRNA (SAM) in a heterologous prime-boost vaccination approach consisting of Chimpanzee Adenovirus (ChAd) prime and SAM boosts was evaluated in two first-in-human phase 1/2 clinical trials assessing personalized neoantigen vaccines in patients with metastatic cancer (NCT03639714, NCT03953235). SAM vaccine dose escalation was performed to assess safety, tolerability, and immunogenicity, including administration of up to 8 SAM doses at 30, 100, or 300μg following a fixed dose of ChAd (1012 vp) over the course of a year. SAM was safe and well tolerated at all 3 dose levels, with no evidence of increasing reactogenicity with sequential doses. However, while immune monitoring via IFNγ ELISpot revealed that the 30μg SAM dose boosted T cell responses induced by the ChAd prime, the 100μg and 300μg SAM doses resulted in maintenance of T cell levels, without a clear T cell boost, suggesting a non-linear and likely bell-shaped dose-response curve to SAM in humans. Follow-up studies in non-human primates (NHPs) using a model antigen revealed dose-dependent increases in serum IFNa levels following administration of increasing SAM doses. Similarly, while multiple inflammatory cytokines were transiently increased following both ChAd and SAM administration in patients, serum IFNa levels were only increased 24h post SAM administration and correlated positively with SAM dose. Increased IFNa levels post SAM dosing suggested activation of mRNA-sensing innate immune pathways that may reduce the amplification of, and/or antigen expression by, the SAM vector and thus blunt T cell boosting at higher SAM doses. In addition, analysis of T cell responses in patients and NHPs showed increased boosting of T cell responses with longer intervals. These data lead to a reduction of the SAM dose to 30μg and adjusting SAM dosing intervals to 8 weeks in the Phase 2 portion of these clinical studies. Multiple patients have been dosed with the adjusted vaccine regimen, and preliminary data suggest robust boosting of ChAd-induced neoantigen-specific T cell responses with the selected SAM dosing regimen and the 30μg dose. We anticipate that this translational approach of adjusting clinical vaccine regimens based on strong translational immune data will increase the potency of our heterologous neoantigen vaccine, and subsequently provide more durable clinical benefit to patients with cancer.
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Introduction: Chinese Sinopharm-CoronaVac® vaccine is safe and well tolerated, its skin reactions are rarely reported. We report the case of a cutaneous adverse reaction due to this vaccine. Observation: A 32-year-old female with no remarkable medical history. She was admitted for a generalized itchy maculo-papular rash appearing 4 days following the administration of the first dose of the Sinopharm-CoronaVac®. The causality reveals a possible association between the vaccine and the drug reaction. Discussion: Published data from randomized trials Phase I and II trials have shown that the Sinopharm-CoronaVac® has good immunogenicity, safety and tolerability in the majority of patients with few reported adverse events. In literature, we found only one case that developed a cutaneous rash due to Sinopharm-CoronaVac® vaccine but without any precisions. Conclusion: We report the first case of a cutaneous adverse reaction type Maculopapular rash after the first dose of the Sinopharm-CoronaVac® vaccine.
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The 2022 American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting held virtually, with "Disruptive innovation" as the motto, offered attendees an outstanding scientific program focused on clinical pharmacology, translational medicine, drug discovery and drug development. It is the most important event for scientists involved in clinical pharmacology and translational medicine. The ASCPT conference offers scientists from different professional scopes and around the world the perfect opportunity to discuss emerging science. It focuses on improving the understanding and use of existing drug therapies and developing safer and more effective treatments for the future. Oral and poster presentations were available for participants during the running of the conference to accommodate the different time zones. Presentations covered the latest research with the option to ask questions after each presentation via a chat function. Discussion boards were available to provide networking opportunities for virtual attendees.
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Objective: To investigate the impact of the COVID-19 pandemic on clinical trials in the field of neurology. Background: The COVID-19 pandemic and initiatives to curtail its spread disrupted the conduction of clinical research, forcing reimagination of the existing frameworks to execute scientifically sound human subjects research. In this study, we quantify the impact of the pandemic on clinical trial initiation and trial withdrawal in the field of neurology. Design/Methods: We used the largest publicly available database of clinical trials, clinicaltrials.gov, to compute the annual rate of change in clinical trial initiation and withdrawal in the field of neurology from January 2010 to December 2020 compared to the anticipated rate. Results: Our analysis showed a significant decrease in neurology clinical trial initiation in 2020 compared to pre-pandemic years [decrease by 12.4% in 2020 contrasted with the projected 9.7% overall increase (p < 0.0001)]. Significant decreases were maintained across all analyzed neurological subspecialties and study phases, except for combined Phase II/Phase III. Early Phase I (observed = -39.6%, expected = +37.3%, p < 0.05) and Phase I studies (observed = -20.4%, expected = +3.8%, p < 0.05) saw the greatest decreases. Study subtype analysis also revealed significant decreases in both interventional (observed = -12.4%, expected = +9.5%, p < 0.001) and observational studies (observed = -13.6%, expected = +10.3%, p < 0.01). In the analyzed time period from 2010 to 2020, 2020 was the only year demonstrating trial initiation declines compared to the preceding year. Conclusions: Our analysis demonstrated a significant reduction in neurology clinical trial initiation in the 2020 calendar year when compared to prior years, and that this pattern was seen across clinical research in neurology subspecialties. These data further demonstrate the inclusion of human subjects research in neurology as another consequence of SARS-CoV-2.
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Vaccines prevent 4-5 million deaths a year making them the principal tool of medical intervention worldwide. Nucleoside-modified mRNA was developed over 15 years ago and has become the darling of the COVID-19 pandemic with the first 2 FDA approved vaccines based on it. These vaccines show greater than 90% efficacy and outstanding safety in clinical use. The mechanism for the outstanding immune response induction are the prolonged production of antigen leading to continuous loading of germinal centers and the adjuvant effect of the LNPs, which selectively stimulate T follicular helper cells that drive germinal center responses. Vaccine against many pathogens, including HIV, HCV, HSV2, CMV, universal influenza, coronavirus variants, pancoronavirus, nipah, norovirus, malaria, TB, and many others are currently in development. Nucleoside-modified mRNA is also being developed for therapeutic protein delivery. Finally, nucleoside-modified mRNA-LNPs are being developed and used for gene therapy. Cas9 knockout to treat transthyretin amyloidosis has shown success in phase 1 trials. We have developed the ability to target specific cells and organs, including lung, brain, heart, CD4+ cells, all T cells, and bone marrow stem cells, with LNPs allowing specific delivery of gene editing and insertion systems to treat diseases such as sickle cell anemia. Nucleoside-modified mRNA will have an enormous potential in the development of new medical therapies.
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This year's ECTRIMS brought scientists and specialists together to discuss developments in multiple sclerosis (MS), including how to define and monitor disease progression, imaging pathology, and, of course, the impact of the COVID-19 pandemic on MS patient care.
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Purpose of Study The COVID-19 pandemic has presented a major challenge to the global medical community resulting in many necessary changes in worldwide research publication trends. As focus and funding of research have shifted throughout the pandemic, so too have publication types, topics, and country-wide research output. While changes during the pandemic have undoubtedly had an impact on publications, these impacts and their implication for long-term research have been poorly characterized. We aim to illustrate these shifting changes in publications during the COVID-19 pandemic. Methods Used Publications were accessed using PubMed Advanced Search Criteria. The beginning of the COVID-19 pandemic was set as the date of the first reported case in Wuhan on 12/31/2019. Searches were conducted on 9/10/ 2021. We generated searches based on type of publication, country affiliation of the first author, date ranges, and specific topics such as 'COPD' or 'Diabetes'. We analyzed the changes in publications during the 4 months before the first case of COVID-19 and every 4 months thereafter. Results were analyzed using SPSS. Summary of Results In the two years before the pandemic, 3541.9 PubMed-indexed articles were published per day, while 4379.9 such articles have been published each day during the pandemic. Covid-19 resulted in net increases relative to baseline in case reports, reviews, and retracted publications with net decreases in clinical trials, multicenter studies, and randomized control trials in most yearly tertiles relative to the 4 months before Covid-19. Meta-analysis and observational studies demonstrated initial net increases followed by subsequent net decreases. The largest percent decrease in publication type relative to baseline has been seen in Phase I (- 82.6%) and Phase IV (-80.5%) clinical trials. In the first yearly tertile, China had the largest percent increase in publications relative to baseline (38.4%) followed by Italy in the second tertile (32.0%) and India in the third tertile (43.5%). Increases in daily publications were seen in many research topics including diabetes (32.8/day), asthma (4.6/day), heart disease (2.9/day), and COPD (2.4/day). Conclusions COVID-19 has caused a shift in research focus and funds towards pandemic-related research. This has emphasized lower evidence research, such as case reports, and shifted focus away from high evidence studies, such as clinical trials and meta-analysis. Production of high-evidence studies does not appear to be recovering as the pandemic continues. Research output of individual countries appears to coincide with COVID-19 related infection surges in each respective country. Despite new emphasis on Covid-related research, many important topics such as diabetes and heart disease have experienced increases in publications.
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Neutrophils, which are among the first immune cells to respond to both infection and injury, when activated can release pre-stored serine proteases such as neutrophil elastase, cathepsin G and proteinase 3. An abundant release of these proteolytic enzymes in the alveolar compartment as well as the airways can trigger collateral pulmonary tissue damage. Indeed, much of the tissue destruction that characterizes non-cystic fibrosis bronchiectasis appears to be caused by serine proteases. The transitory pharmacological inhibition of bone marrow dipeptidyl peptidase 1 (DPP1), which converts neutrophil proteolytic enzymes into their mature active form, is a therapeutic possibility to decrease the constitutively produced serine protease pool of neutrophils. Brensocatib (also called INS-1007 or AZD-7986) is a potent reversible DPP1 inhibitor that has been successfully evaluated in a phase II trial as a treatment for non-cystic fibrosis bronchiectasis and, consequently, has been granted breakthrough therapy designation by the U.S. Food and Drug Administration and Priority Medicines (PRIME) designation by the European Medicines Agency.