LitCovid-sentences  

PMC:7652766 / 70729-86349 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T343 0-13 Sentence denotes Immunotherapy
T344 15-37 Sentence denotes Antibody-Based therapy
T345 38-268 Sentence denotes Considered an efficient method for the clinical treatment of different infectious diseases, including MERS-CoV and SARS-CoV-1 (217), antibody-based immunotherapy has been studied as a potentially applicable tool to treat COVID-19.
T346 269-420 Sentence denotes The mechanisms involved with its effects against SARS-CoV-2 are related to preventing the virus from entering the host cells, blocking its replication.
T347 421-615 Sentence denotes The virus entry block was studied for acting both in the cell receptor ACE2 and directly on the virus (neutralizing antibodies [nAbs]), specifically in the S1 subunit of the S protein (218–220).
T348 616-872 Sentence denotes Regarding the blocking of ACE2 receptors, the application of some mechanisms stand out: the soluble version of ACE2 fused to an immunoglobulin Fc domain (ACE2-Fc), RDB domain attached to Fc (RDB-Fc), and receptor-targeted monoclonal antibodies (mAb) (221).
T349 873-995 Sentence denotes Viral neutralization by nAbs is also an immunotherapeutic approach and directly recognizes epitopic regions of SARS-CoV-2.
T350 996-1306 Sentence denotes This effect can be achieved either directly through mAbs manufactured in laboratories or by using polyclonal antibodies (pAbs) (218). nAbs act directly on the virus, preventing its infectivity by activating several pathways, such as the complement system, cell cytotoxicity, and phagocytic clearance (222–224).
T351 1307-1395 Sentence denotes The therapeutic use of mAbs has shown good outcomes, mainly due to its high specificity.
T352 1396-1570 Sentence denotes Recently, several mAbs against viruses have been developed, including SARS-CoV-1 and MERS-CoV, in which the S protein is the major target described both in vitro and in vivo.
T353 1571-1708 Sentence denotes According to some studies, the specific nAbs against SARS-CoV-1 RBD in the S protein could effectively block SARS-CoV-2 entry (218, 225).
T354 1709-1927 Sentence denotes However, Wrapp et al. (226) tested several published SARS-CoV-1 RBD-specific nAbs and found that they do not have substantial binding to the S protein of SARS-CoV-2, suggesting that the cross-reactivity may be limited.
T355 1928-2032 Sentence denotes Thus, the combination of nAbs with different viral targets and sources could improve treatment efficacy.
T356 2033-2234 Sentence denotes In addition to experimental studies, to date, more than 10 clinical trials have aimed at testing human mAbs against SARS-Cov-2 (227–235), which could also represent an alternative, effective treatment.
T357 2235-2319 Sentence denotes Furthermore, some immunomodulatory mAbs have been tested in the context of COVID-19.
T358 2320-2659 Sentence denotes It is remarkable that until now most of the data published regarding the use of immunomodulatory mAbs derive from studies using either anti-IL-6 or anti-IL-6R, probably because using IL-6 blockers seems promising at controlling the cytokine storm associated with the development of ARDS in more aggressive patterns of SARS-CoV-2 infection.
T359 2660-2712 Sentence denotes However, clinical observations remain controversial.
T360 2713-3018 Sentence denotes Although some studies found considerable clinical improvements resulting from treatment with IL-6 blockers (236–239), others do not report any significant difference between the clinical features of groups treated with anti-IL6/IL-6R mAbs and their respective controls (without anti-IL-6/IL-6R) (240–243).
T361 3019-3244 Sentence denotes These controversial results can be explained by the pleiotropic function of IL-6, which also play an important anti-inflammatory role, questioning the use of IL-6 blockade to suppress inflammation-induced tissue damage (244).
T362 3245-3447 Sentence denotes Additionally, severe side effects have been associated with the use of IL-6 blockers, including enhanced hepatic enzymes, thrombocytopenia, severe bacterial and fungal infections, and sepsis (241, 245).
T363 3448-3547 Sentence denotes In general, data from analyses on the use of this type of mAbs remain inconclusive (243, 246, 247).
T364 3548-3822 Sentence denotes Recent findings are optimistic, but data validation by robust scientific evidence has been hampered by the small sample size in most case reports and studies on the use of mAbs blocking other immune mediators, such as IL-1β, GM-CSF, and complement protein C5 (238, 248–250).
T365 3823-3964 Sentence denotes However, seeking to verify the effectiveness of using mAbs blocking inflammatory mediators, dozens of clinical trials are currently underway.
T366 3965-4374 Sentence denotes Aiming at reducing the hyper inflammation found in the lungs of SARS-CoV-2-infected patients, different clinical studies are currently investigating the activities of mAbs anti-JAK, anti-GM-CSF, anti-GM-CSF receptor, anti-M-CSF receptor, anti-CD14, anti-IFNγ, anti-VEGF, anti-BKT, anti-CCR5, anti-IL-6, anti-IL-6 receptor, anti-TNFα, anti-IL1β, anti-IL1β receptor, and complement C5 inhibitor (220, 251, 252).
T367 4375-4573 Sentence denotes Similarly, ongoing clinical trials have sought to reverse the hyper-thrombotic state found in critically ill patients by using anti-P-selectin, anti-CTGF, and factor XIIa antagonist mAbs (253, 254).
T368 4574-4787 Sentence denotes Furthermore, to restore the exhausted T lymphocytes’ and NK cells’ immunity, other clinical studies applied anti-PD1 mAbs under the hypothesis of a stimulus of anti-viral response and prevention of ARDS (255–257).
T369 4788-5207 Sentence denotes More recently, the passive administration of pAbs has also been tested in COVID-19 patients (222–224, 258–267), also known as convalescent plasma (CP) or immune plasma, which is already used effectively and safely in the treatment of other severe acute respiratory syndrome infections of viral etiology, such as SARS, MERS, and H1N1, and offers only a short-term but rapid immunity to the susceptible individuals (268).
T370 5208-5346 Sentence denotes A strict criterion to select the CP donor states that the individual must show clinical recovery and test negative for the virus presence.
T371 5347-5476 Sentence denotes Thus, after being confirmed, a high titer of neutralizing antibodies against SARS-CoV-2 must be stored in blood banks (269, 270).
T372 5477-5683 Sentence denotes Some reviews related to patients who received transfusion with CP showed a reduction in viral load, improvement in clinical symptoms, better radiological findings, and improved survival (260, 261, 271–273).
T373 5684-5904 Sentence denotes In addition, after having received CP containing nAbs, COVID-19 patients had significant improvements from the beginning of treatment (until 22 days), presenting lower fever, decreased viral load, and higher nAbs levels.
T374 5905-5986 Sentence denotes Further, 60% of the patients were discharged one month after the treatment (271).
T375 5987-6138 Sentence denotes Better outcomes were found in early administration of CP (before SARS-CoV-2 seroconversion), preferably on day 5, for obtaining maximum efficacy (268).
T376 6139-6314 Sentence denotes More recently, Li et al. found no statistically significant clinical improvement or mortality reduction in a randomized clinical trial with CP-treated COVID-19 patients (274).
T377 6315-6484 Sentence denotes However, the authors reported that CP treatment is potentially beneficial to critically ill patients by suggesting a possible antiviral efficiency of high titer of nAbs.
T378 6485-6796 Sentence denotes Notably, there are clinical controversies, ethical issues, and potential risks associated with convalescent plasma therapy (275), such as the possibility of ADE development, exacerbating the disease severity, and causing a significant illness in future exposure to coronaviruses infection (268, 276, 277) (REF).
T379 6797-7084 Sentence denotes Divergences between studies may be caused by variations in the composition of CP, which is highly variable and includes a variety of blood-derived components, timing of CP administration, titer of the specific antibody in administered plasma, and presence of blood borne pathogens (268).
T380 7085-7206 Sentence denotes Nonetheless, understanding the efficacy and safety of CP therapy relies on the completion of the ongoing clinical trials.
T381 7207-7493 Sentence denotes Another therapeutic strategy using antibodies is intravenous immunoglobulin (IVIg) that contains polyclonal IgG isolated from healthy donors, which can be further enhanced by using IgG antibodies collected from recovered COVID-19 patients in the same geographical region as the patient.
T382 7494-7671 Sentence denotes Results have been mostly positive, although many of these therapies have not been formally evaluated through a randomized, double-blind, placebo-controlled clinical trial (278).
T383 7672-7942 Sentence denotes According to recent studies, IVIg can be used effectively in early stages of SARS-CoV-2 infection (before the initiation of systemic damage), reducing the use of mechanical ventilation, preventing the progression of pulmonary lesions, and promoting early recovery (268).
T384 7943-8148 Sentence denotes Also, cross-neutralization activity was shown against SARS-CoV-2 in commercial IVIg manufactured prior to the COVID-19 pandemic and are currently under evaluation as potential therapies for COVID-19 (279).
T385 8149-8497 Sentence denotes Thus, intravenous use of immunoglobulins can prove helpful in therapy against SARS-CoV-2, however, adjustments in the therapeutic regimen are necessary for all IVIg possibilities, as well as a complete understanding of the possible adverse effects, such as the risk of ADE (278, 279), that are being studied in more than 10 ongoing clinical trials.
T386 8498-8682 Sentence denotes Some works have shown that therapies focusing on the interaction between SARS-CoV-1 and the ACE2 receptor may be extended for use in SARS-CoV-2 patients as an immunotherapy tool (218).
T387 8683-8853 Sentence denotes However, other authors refute this idea based on the fact that recent studies showed limited cross-neutralization between SARS-CoV-1 antibodies and SARS-CoV-2 (280, 281).
T388 8854-9028 Sentence denotes Furthermore, it was shown that SARS-CoV-2 S protein binds ACE2 with a higher affinity than SARS-CoV-1, suggesting that such interaction differs between the two viruses (266).
T389 9030-9055 Sentence denotes Immune Cell-Based Therapy
T390 9056-9223 Sentence denotes In addition to antibody-based therapies, scientists have been studying immune cell-based therapies as a tool to combat COVID-19, focusing especially on NK and T cells.
T391 9224-9427 Sentence denotes The importance of NK cells as the first antiviral responders can be seen in patients with NK cell deficiency and immunocompromised individuals who have increased susceptibility to viral infections (282).
T392 9428-9683 Sentence denotes In this sense, Market et al. (282) gathered the main reports so far addressing potential therapies focusing on mediating NK cell activity to mitigate the immunopathological consequences of COVID-19, and consequently lighten the load on our health systems.
T393 9684-9788 Sentence denotes Some ongoing clinical trials have been studying the use of NK cell therapy through different approaches.
T394 9789-10041 Sentence denotes A randomized phase I/II trial studied the infusions of CYNK-001 cells, an allogeneic off-the-shelf cell therapy enriched for CD56+/CD3- NK cells expanded from human placental CD34+ cells in 86 hospitalized patients with moderate COVID-19 disease (283).
T395 10042-10175 Sentence denotes Another randomized phase I/II study explored the use of NKG2D-ACE2 CAR-NK cells with each common, severe, and critical type COVID-19.
T396 10176-10420 Sentence denotes The authors hypothesize that these cells target the S protein of SARS-CoV-2 and NKG2DL on the surface of infected cells with ACE2 and NKG2D, respectively, seeking out the elimination of SARS-CoV-2 virus particles and their infected cells (284).
T397 10421-10646 Sentence denotes The unregulated profile of the immune response in critically ill COVID-19 patients may be due to the reduction of Treg cells, which culminates in excessive release of inflammatory mediators and cytokine storms (153, 191–193).
T398 10647-10797 Sentence denotes Thus, the use of adoptive transfer of these cells as a measure of inflammatory control in critically ill patients is a promising therapeutic approach.
T399 10798-11153 Sentence denotes The infusion of autologous polyclonal Treg has already been used to treat inflammatory diseases, such as type 1 diabetes (285), however the use of autologous cells takes a long time, due to the period necessary for differentiation and clonal expansion, making this an unviable and costly method for infectious diseases, as is the case with COVID-19 (286).
T400 11154-11328 Sentence denotes A viable alternative is the use of allogeneic human leukocyte antigen-matched umbilical cord-derived Tregs (UBC-Treg) which can be widely expanded and used on a larger scale.
T401 11329-11582 Sentence denotes A recent case study used 1x108 administration of UBC-Treg in two patients with COVID-19 who had severe respiratory failure, and both demonstrated significant clinical improvement and reduced inflammatory markers four days after starting treatment (287).
T402 11583-11704 Sentence denotes There are currently two clinical trials underway that aim to infuse Treg cells in patients with severe COVID-19 and ARDS.
T403 11705-11889 Sentence denotes The first one is a multi-center, prospective, double-blinded, placebo-controlled phase 1 randomized clinical trial, which has 45 patients who will receive cryopreserved UBC-Treg (288).
T404 11890-12070 Sentence denotes The second one is a randomized, double-blind, placebo-controlled phase 2 study with 88 participants who will receive off-the-shelf allogeneic hybrid Treg/Th2 cells (RAPA-501-ALLO).
T405 12071-12198 Sentence denotes RAPA-501-ALLO cells will be generated from healthy donors, cryopreserved, banked, and made available for off-the-shelf therapy.
T406 12199-12429 Sentence denotes The cells are manipulated ex vivo to differentiate into two anti-inflammatory phenotypes simultaneously, generating hybrid Treg/Th2 cells, with the potential to reduce inflammation and mediate a protective effect on tissues (289).
T407 12430-12672 Sentence denotes In addition to therapeutic approaches using Treg cell infusion, another three clinical trials are underway with the aim of evaluating treatment using specific SARS-CoV-2 T cells isolated from individuals who recovered from COVID-19 (290–292).
T408 12673-12859 Sentence denotes The use of virus-specific T cells for off-the-shelf treatment has been used in several viral infections, such as cytomegalovirus, HHV6, adenoviruses, Ebola virus, and BK virus (293–296).
T409 12860-13178 Sentence denotes Although vaccination provides T cells-based virus-specific immunity, the path to its development is long, so the use of adoptive cell transfer techniques from healthy individuals who recovered from COVID-19 and developed an effective cell response is probably the fastest way to treat critically ill individuals (297).
T410 13179-13454 Sentence denotes Besides that, as mentioned before, asymptomatic or mild symptomatic patients may possibly mount robust SARS-CoV-2 specific CD8+ T cell responses (200, 201), therefore, the use of these individuals’ cells to treat critically ill patients with COVID-19 can be a promising tool.
T411 13455-13677 Sentence denotes The clinical use of IL-7 has been implemented in the treatment of cancer patients and infectious diseases, mainly with the objective of improving the immune response by stimulating the generation of lymphocytes (298, 299).
T412 13678-13988 Sentence denotes In addition, IL-7 administration has been reported to increase CD4 + and CD8 + T lymphocyte counts without inducing the production of pro-inflammatory mediators, making it a promising method of recovering immune function in patients with disorders related to cytokine storms, such as sepsis and COVID-19 (300).
T413 13989-14254 Sentence denotes In a case study conducted by Monneret et al. (301), compassionate administration of IL-7 to a patient with severe COVID-19 significantly improved total lymphocyte count and HLA-DR expression in circulating monocytes four days after administration of the first dose.
T414 14255-14349 Sentence denotes The patient also showed a significant improvement in lung involvement and negative viral load.
T415 14350-14722 Sentence denotes Another study conducted by Laterre et al. (302), who administered IL-7 to COVID-19 patients found that there was a significant improvement in the lymphocyte count after starting treatment, in addition, the patients did not show any change in TNF-α levels, IL-1β, and IL-12p70, which may indicate that IL-7 therapy may be safe for patients with severe inflammatory changes.
T416 14723-14863 Sentence denotes Thus, the use of IL-7-based immunotherapy can be an important tool to be used in future clinical trials in patients with severe lymphopenia.
T417 14864-15086 Sentence denotes Therefore, the data available to date do not ensure the success of immunotherapy applied in patients with COVID-19, thus, further studies specifically targeting SARS-CoV-2 should be performed to provide more specific data.
T418 15087-15169 Sentence denotes However, immunotherapy is effective and of immediate use, being of short duration.
T419 15170-15342 Sentence denotes This approach also presented limitations, such as the possibility of abnormal reactions and other serious risks, such as induction of severe acute lung injury or ADE (225).
T420 15343-15620 Sentence denotes Although we are living through a unique moment in science, with some mismatched information and novel, important discoveries being made every day, immunotherapy seems to be a possibly effective option to help patients until an effective, safe vaccine or treatment is developed.