Insights into CD24 and Exosome Physiology and Potential Role in View of Recent Advances in COVID-19 Therapeutics: A Narrative Review.

Cluster of differentiation (CD) 24, a long-known protein with multifaceted functions, has gained attention as a possible treatment for Coronavirus Disease 19 (COVID-19) due to its known anti-inflammatory action. Extracellular vesicles (EVs), such as exosomes and microvesicles, may serve as candidate drug delivery platforms for novel therapeutic approaches in COVID-19 and various other diseases due to their unique characteristics. In the current review, we describe the physiology of CD24 and EVs and try to elucidate their role, both independently and as a combination, in COVID-19 therapeutics. CD24 may act as an important immune regulator in diseases with complex physiologies characterized by excessive inflammation. Very recent data outline a possible therapeutic role not only in COVID-19 but also in other similar disease states, e.g., acute respiratory distress syndrome (ARDS) and sepsis where immune dysregulation plays a key pathophysiologic role. On the other hand, CD24, as well as other therapeutic molecules, can be administered with the use of exosomes, exploiting their unique characteristics to create a novel drug delivery platform as outlined in recent clinical efforts. The implications for human therapeutics in general are huge with regard to pharmacodynamics, pharmacokinetics, safety, and efficacy that will be further elucidated in future randomized controlled trials (RCTs).

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy.

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

The Big Potential of Small Particles: Lipid-Based Nanoparticles and Exosomes in Vaccination.

Some of the most significant medical achievements in recent history are the development of distinct and effective vaccines, and the improvement of the efficacy of previously existing ones, which have contributed to the eradication of many dangerous and life-threatening diseases. Immunization depends on the generation of a physiological memory response and protection against infection. It is therefore crucial that antigens are delivered in an efficient manner, to elicit a robust immune response. The recent approval of COVID-19 vaccines containing lipid nanoparticles encapsulating mRNA demonstrates the broad potential of lipid-based delivery systems. In light of this, the present review article summarizes currently synthesized lipid-based nanoparticles such as liposomes, lipid-nano particles, or cell-derived exosomes.

A novel platform for attenuating immune hyperactivity using EXO-CD24 in COVID-19 and beyond.

A small but significant proportion of COVID-19 patients develop life-threatening cytokine storm. We have developed a new anti-inflammatory drug, EXO-CD24, a combination of an immune checkpoint (CD24) and a delivery platform (exosomes). CD24 inhibits the NF-kB pathway and the production of cytokines/chemokines. EXO-CD24 discriminates damage-from pathogen-associated molecular patterns (DAMPs and PAMPs) therefore does not interfere with viral clearance. EXO-CD24 was produced and purified from CD24-expressing 293-TREx™ cells. Exosomes displaying murine CD24 (mCD24) were also created. EXO-CD24/mCD24 were characterized and examined, for safety and efficacy, in vitro and in vivo. In a phase Ib/IIa study, 35 patients with moderate-high severity COVID-19 were recruited and given escalating doses, 108 -1010 , of EXO-CD24 by inhalation, QD, for 5 days. No adverse events related to the drug were observed up to 443-575 days. EXO-CD24 effectively reduced inflammatory markers and cytokine/chemokine, although randomized studies are required. EXO-CD24 may be a treatment strategy to suppress the hyper-inflammatory response in the lungs of COVID-19 patients and further serve as a therapeutic platform for other pulmonary and systemic diseases characterized by cytokine storm.

Clinical Outcomes of Hospitalized COVID-19 Patients Treated with Remdesivir-NEAT ID 909REM Study

Background There are few real-world data on the use of remdesivir (RDV) looking at timing of initiation in relation to symptom onset and severity of presenting disease. Methods We conducted multi-country retrospective study of clinical practice and use of RDV in COVID-19 patients. De-identified medical records data were entered into an e-CRF. Primary endpoints were all-cause mortality at day 28 and hospitalization duration. We assessed time from symptom onset to RDV start and re-admission. We included adults with PCR-confirmed symptomatic COVID-19 who were hospitalized after Aug 31, 2020 and received at least 1 dose of RDV. Descriptive analyses were conducted. Kaplan-Meier methods were used to calculate the mortality rate, LogRank test to compare groups defined by severity of disease. Competing risk regression with discharge and death as competing events was used to estimate duration of hospitalization, and Gray’s test to compare the groups. Results 448 patients in 5 countries (12 sites) were included. Demographics are summarized (table) by 3 disease severity groups at baseline: no supplemental oxygen (NSO), low flow oxygen ≤6 L/min (LFO), and high-flow oxygen > 6L/min (HFO). No demographic differences were found between groups except for the higher percentage of cancer/chemotherapy patients in NSO group. Corticosteroids use was HFO 73.6%, LFO 62.7%, NSO 58.0%. Mortality rate was significantly lower in NSO, and LFO groups compared with HFO (6.2%, 10.2%, 23.6%, respectively;Fig1). Median duration of hospitalization was 9 (95%CI 8-10), 9 (8-9), 13 (10-15) days, respectively (Fig2). Median time from first symptom to RDV start was 7 days in all 3 groups. Patients started RDV on day 1 of hospitalization in HFO and LFO and day 2 on NSO groups. And received a 5 day course (median). Readmission within 28-days of discharge was < 5% and similar across all 3 groups. Table 1. Patients baseline characteristics and primary and secondary outcomes Figure 1. Kaplan-Meier estimates of mortality Figure 2. Competing-risks regression of discharge from hospital Conclusion In this real-world cohort of COVID-19 positive hospitalized patients, RDV use was consistent across countries. RDV was started within a median of 7 days from symptom within 2 days of admission and given for a median of 5 days. Higher mortality rate and duration of hospitalization was seen in the HFO group and similar rates seen in the LFO and NSO groups. Readmission was consistently low across all 3 groups. Disclosures François Raffi, MD, PhD, Gilead Sciences (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Consultant)MSD (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member)Roche (Consultant)Theratechnologies (Advisor or Review Panel member)ViiV (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member) Nadir Arber, MD, MSc, MHA, Check cap (Consultant)Coved cd 24 (Board Member)Israel Innovation Authority (Research Grant or Support)Nucleix (Advisor or Review Panel member)Zion Pharmaceuticals (Advisor or Review Panel member) Casper Rokx, MD PhD, Gilead Sciences (Grant/Research Support, Advisor or Review Panel member, Research Grant or Support)Merck (Grant/Research Support, Research Grant or Support)ViiV (Grant/Research Support, Advisor or Review Panel member, Research Grant or Support) Ameet Bakhai, MBBS, MD, FRCP, FESC, Bayer AG (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Boehringer Ingelheim (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Bristol-Myers Squibb (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Daiichi-Sankyo Europe (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator)Janssen (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Johnson & Johnson (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)MSD (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Novartis (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Pfizer (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Roche (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor)Sanofi (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau, Independent Contractor) Alex Soriano, MD, Angelini (Speaker's Bureau)Gilead Sciences (Research Grant or Support, Speaker's Bureau)Menarini (Speaker's Bureau)MSD (Research Grant or Support, Speaker's Bureau)Pfizer (Research Grant or Support, Speaker's Bureau)Shionogi (Speaker's Bureau) Carlos Lumbreras, MD, PhD, Gilead Sciences (Grant/Research Support)MSD (Consultant) Vicente Estrada, MD, PhD, Gilead Sciences (Consultant, Grant/Research Support)Janssen (Advisor or Review Panel member)MSD (Consultant, Grant/Research Support)Theratechnologies (Consultant)ViiV (Consultant) Adrian Curran, MD, PhD, Gilead Sciences (Advisor or Review Panel member, Research Grant or Support)Janssen (Advisor or Review Panel member, Research Grant or Support)MSD (Advisor or Review Panel member, Research Grant or Support)ViiV (Advisor or Review Panel member, Research Grant or Support) Essy Mozaffari, PharmD, MPH, MBA, Gilead Sciences (Employee, Shareholder) Richard Haubrich, MD, Gilead Sciences (Employee, Shareholder) Paul Hodgkins, PhD, MSc, Gilead Sciences (Employee, Shareholder) Anton Pozniak, MD, FRCP, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)Janssen (Grant/Research Support, Research Grant or Support)Merck (Advisor or Review Panel member)Theratec (Grant/Research Support, Advisor or Review Panel member, Research Grant or Support)ViiV (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)

Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine Among Actively Treated Cancer Patients.

BACKGROUND: Activity and safety of the SARS-CoV-2 BNT162b2 vaccine in actively treated patients with solid tumors is currently unknown. METHODS: We conducted a retrospective study of 326 patients with solid tumors treated with anticancer medications to determine the proportion of cancer patients with immunogenicity against SARS-CoV-2 following 2 doses of the BNT162b2 vaccine. The control group comprised 164 vaccinated healthy adults. Anti-SARS-CoV-2 S immunoglobulin G antibodies were measured using a level greater than 50 AU/mL as a cutoff for seropositivity. Information on adverse effects was collected using a questionnaire. All statistical tests were 2-sided. RESULTS: Most patients (205, 62.9%) were treated with chemotherapy either alone or with additional therapy; 55 (16.9%) were treated with immune checkpoint inhibitors and 38 (11.7%) with targeted therapy alone; 28 (8.6%) received other combinations. The vaccine was well tolerated, and no severe side effects were reported. Among patients with cancer, 39 (11.9%) were seronegative compared with 5 (3.0%) of the control group (P = .001). Median immunoglobulin G titers were statistically significantly lower among patients with cancer compared with control (931 AU/mL vs 2817 AU/mL, P = .003). Seronegativity proportions were higher in the chemotherapy-treated group (n = 19; 18.8%) compared with the immune checkpoint inhibitor-treated patients (n = 5; 9.1%) and with those treated with targeted therapy (n = 1; 2.6%) (P = .02). Titers were also statistically significantly different among treatment types (P = .002). CONCLUSIONS: The BNT162b2 vaccine is safe and effective in actively treated patients with cancer. The relatively lower antibody titers and lower proportion of seropositive patients, especially among chemotherapy-treated patients, call for continuing the use of personal protective measures in these patients, even following vaccination.