Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat?
Abstract
:1. Introduction
2. Immune Response in SARS-CoV-2 Pathogenesis
2.1. Innate and Adaptive Immune Cells in COVID-19 Patients
2.2. High-Throughput Sequencing Approach to Understand Immune Cell Dysfunctions in SARS-CoV-2-Infected Patients
2.3. Hyper-Cytokine Activation
2.4. SARS-COV-2 Severity in Cancer Patients
2.5. Immune Responses of Asymptomatic Patients with SARS-CoV-2 Infection
3. Treatment Options for SARS-CoV-2-Infected Patient
3.1. Convalescent Plasma (CP) Therapy and ACE2 Blocker
3.2. Targeting Deregulated Signaling in SARS-COV-2-Infected Patients and Treatment Strategies
3.3. Regenerative Medicine in COVID-19 Treatment
3.3.1. Stem Cell-Based Therapeutic Interventions
3.3.2. Extracellular Vesicles (EVs) for COVID-19 Treatment
3.3.3. NK Cell-Based Therapy
3.3.4. Chimeric Antigen Receptor (CAR) T-Cell Therapy
3.4. Antineoplastic Therapy for SARS-CoV-2-Infected Patients
3.5. Vaccine Development for COVID-19
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Trial No | Clinical Stage | COVID-19 Patient (n) | Interventions | Primary Endpoint (day) | Brief Description of Study | Location |
---|---|---|---|---|---|---|
NK Cell-Based Therapy | ||||||
NCT04324996 | Phase (I/II) | 90 | NKG2D CAR-NK cells, NKG2D-ACE2 CAR-NK cells (108 cells/kg, IV) | CR, safety and tolerability (day 28) | NK cells from umbilical cord blood and engineered genetically, secreting IL15 and GM-CSF. | China |
NCT04375176 | Recruiting | 150 | Functional analysis of monocytes and NK cells | Immune cells activity (6 months) | Phenotypic and functional analysis of monocytes and NK cells | Italy |
NCT04280224 | Phase (I) | 30 | NK cells (0.1–2 × 108 cells/kg, twice per week) | CR, safety and tolerability (day 28) | NK cells in combination with standard therapy | China |
NCT04365101 | Phase (I/II) | 86 | CYNK-001 allogeneic NK cells (days 1, 4, and 7) | AE and clinical improvement (day 28) | CD56+/CD3- NK cells derived from human placental CD34+ cells and culture-expanded | USA (multiple locations) |
NCT04363346 | Phase (I) | 12 | FT516 (9 × 107 cells day-1, 3 × 108 cells day-4, 9 × 108 cells day-7). | MTD of FT516 using 3 dose-escalation strategies, Dose Limiting Toxicity Events (day 36) | NK cell product derived from an iPSC transduced with ADAM17 non-cleavable CD16 | USA |
NCT04344548 | Phase (I/II) | 10 | Three doses of allogeneic NK cell transfer | AE and safety | Safety and immunogenicity of allogeneic NK cells from PBMCs of healthy donors in patients infected with COVID-19 collected by apheresis | Colombia |
Mesenchymal Stem Cell-Based Therapy in Phase ¾ of Clinical Trial | ||||||
NCT04444271 | Phase (II) | 20 | MSCs, 2 × 106 cells/kg, day 1 and 7 | Overall survival | Efficacy of MSCs as an add-on therapy to standard supportive treatment | Pakistan |
NCT04416139 | Phase (II) | 10 | MSCs 1 million/kg single dose, IV | CR, safety and tolerability | Efficacy of MSCs | Mexico |
NCT04366063 | Phase (II/III) | 60 | Two doses MSCs 100 × 106, IV+CT. | AE and safety, 28 days | MSCs for ARDS | Iran |
NCT04336254 | Phase (I/II) | 20 | 3 × 107 human dental pulp stem cells, day 1,4,7 | CR, safety and tolerability | Human dental pulp MSCs | China |
NCT04366323 | Phase (I/II) | 26 | Two doses, 80 million MSCs | AE and safety, 28 day | Allogeneic adult MSCs of expanded adipose tissue | Spain |
NCT04366271 | Phase (II) | 106 | 1 infusion of undifferentiated allogeneic MSCs | AE and safety, 28 days | MSCs from umbilical cord tissue | Spain |
NCT04390139 | Phase (I/II) | 30 | 2 infusions of Wharton-Jelly MSCs, 1 × 106 cells/kg.dose | AE and safety, 28 days | Drug: XCEL-UMC-BETA | Spain |
NCT04333368 | Phase (I/II) | 40 | 1 million/kg, day 1,3,5 | CR, safety and tolerability | Umbilical Cord-derived MSCs | France |
Convalescent Plasma in Phase ¾ of Clinical Trial | ||||||
NCT04348656 | Phase (III) or Phase (II/III) | 1200 | 200–500 mL ABO compatible CP plasma or two doses of 250 mL CP | Recovery or decrease mortality in hospital | CONCOR-1 trial for efficacy of transfusion of COVID-19 CP | The multicenter USA and Canada |
NCT04362176 | 500 | Passive Immunity Trial of Nashville II | ||||
NCT04376034 | 240 | CP treatment in pediatric and adults | ||||
NCT04361253 | 220 | Infusion of high-titer COVID-19 CP | ||||
NCT04425915 | 400 | India | ||||
NCT04342182 | 426 | CONCOVID Study | Netherlands | |||
NCT04374526 | 182 | LIFESAVER | Italy | |||
NCT04385043 | 400 | COV2-CP | ||||
NCT04345289 | 1500 | Six parallel treatment arms of CP, sarilumab, hydroxychloroquine, baricitinib, IV and SC | Denmark | |||
Extracellular Vesicle as COVID-19 Therapy | ||||||
NCT04276987 | Phase (I) | 30 | 5 times aerosol inhalation of MSCs-derived Exo (2 × 108 particles) | AE, safety and tolerability (day 28) | Exo derived from allogeneic adipose MSCs | China |
NCT04384445 | Phase (I/II) | 20 | Organicell Flow, 2–5 × 1011 particle/mL, IV. | AE, safety and tolerability (day 60) | Organicell Flow derived from human amniotic fluid contain chemokines, cytokines and EVs | USA |
NCT04389385 | Phase (I) | 60 | 5 times aerosol inhalation of CSTC-Exo (2 × 108 particles) | AE, safety and tolerability (day 28) | CSTC-Exo, in vitro expanded and cultured with virus peptide and GFs. | Turkey |
Adoptive Cell Therapy (Chimeric Antigen Receptor CAR Therapy) | ||||||
NCT04351659 | NA | 8 | Donors who had tested positive for SARS-CoV-2 in the past and have recovered are suitable for blood donation. | The success rate in production of SARS-CoV-2 specific T cells from a convalescent donor | Development of treatment protocol for adoptive T-cell therapy | Singapore |
Drug Class | Active Agent | Targetable Action | Cancer Treatment | Trial Number | Size | Clinical Phase |
---|---|---|---|---|---|---|
Corticosteroid | Dexamethasone | Anti-inflammatory Immunosuppressive | Lymphomas, leukemias | NCT04325061 | 200 | Phase 4 |
NCT04347980 | 122 | Phase 3 | ||||
Methylprednisolone | NCT04341038 | 84 | Phase 3 | |||
NCT04438980 | 72 | Phase 3 | ||||
NCT04244591 | 80 | Phase 3 | ||||
NCT04263402 | 100 | Phase 4 | ||||
Immunomodulators | Lenalidomide | Antiangiogenic, TNF-α signaling modulation | Multiple myeloma, myelodysplastic syndromes | NCT04361643 | 120 | Phase 4 |
Thalidomide | NCT04273529 | 100 | Phase 2 | |||
NCT04273581 | 40 | Phase 2 | ||||
Nuclear export inhibitor | Selinexor | Binds to exportin 1 | Relapsed/refractory multiple myeloma | NCT04355676 | 80 | Phase 2 |
NCT04349098 | 230 | Phase 2 | ||||
Chemotherapy | Methotrexate | Antimetabolite for antifolate type | Multiple cancers including breast, lymphoma, epidermoid, small-cell lung cancer, head and neck, squamous cell lung cancer. | NCT04352465 | 42 | Phase ½ |
Etoposide | Inhibits topoisomerase-II | NCT04356690 | 64 | Phase 2 | ||
Anti-vascular endothelial growth factor | Bevacizumab | The humanized monoclonal antibody that blocks angiogenesis by inhibiting VEGF-A | Number of types of cancers and a specific eye disease | NCT04305106 | 140 | NA |
NCT04344782 | 130 | Phase 2 | ||||
NCT04275414 | 20 | Phase 2/3 | ||||
Immune check-point inhibitors | Pembrolizumab | Block PD1 receptor | Multiple cancer types | NCT04335305 | 24 | Phase 2 |
Nivolumab | NCT04413838 | 120 | Phase 2 | |||
NCT04343144 | 92 | Phase 2 | ||||
NCT04356508 | 15 | Phase 2 | ||||
Kinase inhibitors | Ibrutinib | Irreversible covalent BTK inhibitor | B-cell lymphoma, including CLL, MCL, ABC-DLBCLs | NCT04375397 | 46 | Phase 2 |
NCT04439006 | 72 | Phase 2 | ||||
Acalabrutinib | NCT04380688 | 60 | Phase 2 | |||
NCT04346199 | 140 | Phase 2 | ||||
Duvelisib | inhibitor of PI3K | CLL, SLL | NCT04372602 | 25 | Phase 2 | |
Imatinib | Inhibits bcr-abl tyrosine kinase | CML, ALL | NCT04394416 | 204 | Phase 3 | |
NCT04422678 | 30 | Phase 3 | ||||
NCT04346147 | 165 | Phase 2 |
Company/Sponsor | Vaccine | Trial Number | Size | Clinical Stage | Brief Description | Intervention | Location |
---|---|---|---|---|---|---|---|
DNA-Based Vaccine for COVID-19 | |||||||
Genexine, Inc. | GX-19 | NCT04445389 | 190 | Phase ½ | For safety, tolerability, and immunogenicity in HV | Expressing SARS-CoV-2 S-protein antigen, IM via EP | Korea |
Inovio Pharma. | INO-4800 | NCT04336410 | 120 | Phase 1 | For safety, tolerability, and immunological profile in HV | A Prophylactic Vaccine Against SARS-CoV-2, ID then EP | USA |
Symvivo Corp. | bacTRL-Spike | NCT04334980 | 112 | Phase 1 | For safety, tolerability, and immunity in HV | Bacterial medium with live Bifidobacterium longum, with plasmid expressing SARS-CoV-2 spike protein, 1–10 billion CFU | USA, Canada |
Zydus Cadila | ZyCoV-D | - | - | Phase ½ | For safety, tolerability | India | |
mRNA-Based Vaccine for COVID-19 | |||||||
CureVac AG | CVnCoV | NCT04449276 | 168 | Phase 1 | Reactogenicity, Immunogenicity in HV | Participants will receive an IM injection in deltoid area | Germany |
NIAID, | mRNA-1273 | NCT04283461 | 155 | Phase 1 | Safety Immunogenicity in HV | LNP dispersion containing mRNA for spike protein of SARS-CoV-2, IM, 10–250 microgram | USA |
ModernaTX,Inc. | mRNA-1273 | NCT04405076 | 600 | Phase 2 | Dose-confirmation study in HV | mRNA-1273: 50 microgram, IM | USA |
Biontech SE | BNT162 | NCT04368728 | 7600 | Phase ½ | Safety, tolerability, immunogenicity in HV | Anti-viral RNA vaccine for active immunization against COVID-19, IM various doses | USA |
Adenovirus-Based Vaccine for COVID-19 | |||||||
PLA of China | Ad5-nCoV | NCT04341389 | 508 | Phase 2 | Immunogenicity and safety in HV | Encodes for a full-length spike (S) protein of SARS-CoV-2, IM, 0.5–1 × 1011 VP | China |
CanSino Biologics | Ad5-nCoV | NCT04313127 | 108 | Phase 1 | Dose-escalating, in HV | IM, 0.5–1.5 × 1011 VP | China |
CanSino Biologics | Ad5-nCoV | NCT04398147 | 696 | Phase ½ | Safety, tolerability, and immunogenicity, in HV | Single dose, 5–10 × 1010 VP, IM | Canada |
Gamaleya Research Institute | Gam-COVID-Vac Lyo | NCT04437875 NCT04436471 | 38 | Phase 1–2 * | Safety, tolerability, and immunogenicity in HV | rAd26, type 26 adenovirus, containing the SARS-CoV-2 S protein gene, IM | Russia |
Altimmune, Inc. | NasoVAX | NCT04442230 | 96 | Phase 2 | Safety and effectiveness in early COVID-19-infected people | Replication-deficient adenovirus vectors in suspension | USA |
Inactivated SARS-CoV-2 | |||||||
Chinese Academy of Medical Sciences | Unname | NCT04412538 | 942 | Phase ½ | Safety and immunogenicity in HV | SARS-CoV-2 inactivated vaccine, two doses at 0, 28 day, 50–150 U/0.5 mL | China |
Sinovac R & D Ltd. | Unname | NCT04352608 | 744 | Phase ½ | Safety and immunogenicity in HV | Two doses at day 0, 28, 600–1200 SU/0.5 mL | China |
Bharat Biotech | COVAXIN | - | - | Phase ½ | Safety and immunogenicity | - | India |
Dendritic cell-based vaccine for COVID-19 | |||||||
Shenzhen Geno-Immune Medical Institute | LV-SMENP-DC | NCT04276896 | 100 | Phase ½ | Covid-19 minigenes engineered using lentiviral vector system (NHP/TYF) to modify DCs | 5 × 106 LV-DC vaccine and 1 × 108 CTLs via sub-cutaneous injections and IV infusions respectively | China |
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Kothari, A.; Singh, V.; Nath, U.K.; Kumar, S.; Rai, V.; Kaushal, K.; Omar, B.J.; Pandey, A.; Jain, N. Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat? Biology 2020, 9, 243. https://doi.org/10.3390/biology9090243
Kothari A, Singh V, Nath UK, Kumar S, Rai V, Kaushal K, Omar BJ, Pandey A, Jain N. Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat? Biology. 2020; 9(9):243. https://doi.org/10.3390/biology9090243
Chicago/Turabian StyleKothari, Ashish, Vanya Singh, Uttam Kumar Nath, Sandeep Kumar, Vineeta Rai, Karanvir Kaushal, Balram Ji Omar, Atul Pandey, and Neeraj Jain. 2020. "Immune Dysfunction and Multiple Treatment Modalities for the SARS-CoV-2 Pandemic: Races of Uncontrolled Running Sweat?" Biology 9, no. 9: 243. https://doi.org/10.3390/biology9090243