Immune Cell-Based Therapy
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. 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). 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.
Some ongoing clinical trials have been studying the use of NK cell therapy through different approaches. 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). Another randomized phase I/II study explored the use of NKG2D-ACE2 CAR-NK cells with each common, severe, and critical type COVID-19. 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).
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). Thus, the use of adoptive transfer of these cells as a measure of inflammatory control in critically ill patients is a promising therapeutic approach. 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).
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. 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).
There are currently two clinical trials underway that aim to infuse Treg cells in patients with severe COVID-19 and ARDS. 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). 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). RAPA-501-ALLO cells will be generated from healthy donors, cryopreserved, banked, and made available for off-the-shelf therapy. 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).
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). 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). 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). 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.
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). 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).
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. The patient also showed a significant improvement in lung involvement and negative viral load. 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. 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.
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. However, immunotherapy is effective and of immediate use, being of short duration. 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). 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.