key: cord-0769215-sp7u0sag
authors: Conway, Susan R.; Keller, Michael D; Bollard, Catherine M
title: Cellular Therapies for the Treatment and Prevention of SARS-CoV-2 Infection
date: 2022-03-05
journal: Blood
DOI: 10.1182/blood.2021012249
sha: 2de7ca46c377923f0450746992efc13b7d9954c6
doc_id: 769215
cord_uid: sp7u0sag

Patients with blood disorders who are immune suppressed are at increased risk for infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Sequelae of infection can include severe respiratorydisease and/or prolonged duration of viral shedding. Cellular therapies may protect these vulnerable patients by providing anti-viral cellular immunity and/or immune modulation. In this recent Review of the field, phase I/II trials evaluating adoptive cellular therapies with virus-specific T cells or natural killer cells are described along with trials evaluating the safety, feasibility, and preliminary efficacy of immune modulating cellular therapies including regulatory T cells and mesenchymal stromal cells. In addition, the immunological basis for these therapies is discussed.

Despite the development of highly efficacious vaccines, the COVID-19 pandemic continues to take a massive toll on populations internationally. Multiple studies have demonstrated elevated hospitalization and mortality rates in immunocompromised patients, including those with inborn errors of immunity (IEI), cancer, hematopoietic stem cell transplantation (HSCT), or solid organ transplantation. [1] [2] [3] [4] Registry reports have indicated that mortality rates in immunocompromised patients requiring hospitalization for severe COVID-19 are as high as 20% despite currently available therapies. While some individuals with underlying immunodeficiency who become infected with SARS-CoV-2 will achieve effective viral clearance, 5, 6 multiple reports have demonstrated a risk of prolonged shedding of viable virus with intra-host accrual of novel viral variants over time. [7] [8] [9] [10] [11] Studies of immunocompromised populations have shown suboptimal responses to vaccination, [12] [13] [14] [15] [16] [17] and while booster vaccines in these populations is required, it is unclear how durable their protective immunity will be compared with immune competent individuals. Disease severity and the potential for new variants highlight the need for new preventative and therapeutic approaches to protect immunocompromised populations from COVID-19. Adoptive cellular therapy has been utilized in prior studies to prevent or treat viral infections in the setting of IEI or transplantation, with evidence of safety and efficacy against herpesviruses, polyomaviruses, and some respiratory pathogens such as adenovirus. [18] [19] [20] [21] [22] [23] Accordingly, adoptive T cell therapy is being explored as a preventative or therapeutic adjunctive therapy against SARS-CoV-2.

Among adults infected with SARS-CoV-2, severe disease is accompanied by characteristic immunologic profiles, including markedly elevated plasma levels of inflammatory cytokines.

Several studies have demonstrated patterns of cytokine elevation, including IL-6 and IL-10, which correlate with risk of mortality. 24-26 Treatment with dexamethasone among patients requiring respiratory support improves outcomes, 27 suggesting that anti-inflammatory agents may be beneficial in some patients with COVID-19. Trials of immunosuppressive agents including tocilizumab, 28 Janus kinase (JAK) inhibitors and Bruton's tyrosine kinase (BTK) inhibitors have yielded mixed results. [29] [30] [31] [32] [33] In this context, regulatory T cells and mesenchymal stromal cells may be beneficial adjunctive treatments with immune modulatory and tissue reparative properties that could improve outcomes among patients with severe COVID-19.

Cellular therapies for SARS-CoV-2 can be conceptually classified based on their intended function as either: 1) adoptive immunotherapies designed to enhance viral clearance in patients with ineffective immune responses to SARS-CoV-2 or 2) immune modulatory therapies to correct a dysregulated immune response contributing to clinical deterioration (Figure 1 ). Within the former category, adoptive immunotherapy may be used for the prevention or treatment of active SARS-CoV-2 infection in immunocompromised patients, and includes adoptive immunotherapy with SARS-CoV-2-specific T cells or natural killer (NK) cells. By contrast, immune modulatory cellular therapies include regulatory T cells and mesenchymal stromal cells.

Phase I/II trials are underway to evaluate these therapies clinically. Hence, this review focuses on the immunological basis for their development, and the results to date.

The adaptive immune response to SARS-CoV-2 has been an area of intense investigation since the onset of the pandemic. Understanding antigen-specific B cell, CD4 + T cell, and CD8 + T cell responses has been essential for developing effective vaccines and defining the immunopathology that contributes to severity of illness due to SARS-CoV-2. While maladaptive immune responses to SARS-CoV-2 remain incompletely understood, several studies to date suggest a link between severe COVID-19 and insufficient early innate immune responses to SARS-CoV-2, resulting in weak or delayed adaptive response, 24, 34 rather than a primary pathological role of antigen-specific humoral or cell mediated adaptive immunity. 34-39 Indeed, circulating CD4 + SARS-CoV-2-specific T cells (CSTs) are detected in PBMCs from >90% of convalescent individuals, CD8 + CSTs are detected in >70%, and the presence of CSTs is associated with recovery and decreased severity of illness. 40-44 Lymphopenia is associated with poorer outcomes in COVID-19, and analysis of bronchoalveolar lavage (BAL) fluid from patients with varying illness severity indicates decreased clonal T cell expansion, suggesting a suboptimal CST presence in the lungs of patients with severe or fatal disease. 37, 45 Moreover, in patients with hematologic malignancies, CD8 + T cell depletion has been associated with poor outcomes, particularly in patients who also have impaired humoral responses to SARS-CoV-2. 46 These findings suggest that T cell responses, particularly CSTs, are important for effective viral clearance and are associated with improved outcomes in patients with acute infection. Thus, adoptive cellular therapy with CSTs and/or natural killer (NK) cells may be an effective strategy for improving outcomes in immunocompromised patients with or at risk for SARS-CoV-2 infection.

The potential application of immunotherapy could be relevant to many patient groups. For example, immunomodulatory immunotherapy could be applicable to any patient at high risk of severe COVID-19. CST or NK therapy would be most applicable to immunocompromised patients with T cell deficiency or those receiving immunosuppressive therapies. In these patients, early identification and treatment of those at high risk for immune dysregulation due to SARS-CoV-2 might enhance viral clearance and prevent severe disease, since lower initial viral load, 47 early bystander CD8 + T cell activation, 48 and adequate early type I interferon response 38, 39, 49 correlate with decreased mortality related to SARS-CoV-2. 35, 50 For example, in patients with autoantibodies to type I interferon, CST therapy could theoretically bypass early defects in interferon signaling and restore immune responses to SARS-CoV-2. Additionally, analysis of T cell subsets has shown that Th1-skewed and CD8 + T cell responses are associated with decreased COVID-19 severity, 51, 52 suggesting that enhanced cell therapy products might be manufactured to favor protective T cell subsets. 53 Whether adoptive immunotherapy with CSTs and/or NK cells administered later in the disease course worsens ongoing inflammation and immunopathology is not known but will be addressed by ongoing phase I/II trials (Tables 1 and   2) .

Adoptive cellular therapy with VSTs has been used safely and effectively for more than 25 years to treat and prevent viral infections in patients with immune deficiencies, especially in the post hematopoietic stem cell transplant (HSCT) setting. 22, 54-57 Manufacture of VSTs for clinical use involves either selection or ex vivo expansion from donor PBMCs. VST selection uses MHCantigen multimers or cytokine capture technology to isolate VSTs from PBMCs while ex vivo expansion involves PBMC culture in the presence of growth-enhancing cytokines and viral antigens for 10-12 days to generate a product enriched in VSTs targeting one or more viruses. 21, 56 In the post-HSCT population, treatment with donor-derived VSTs results in reconstitution of anti-viral immunity with persistence of VSTs for years following infusion. 58, 59 For patients who have not undergone HSCT or for whom a donor is not available, banking of cryopreserved ex vivo expanded VSTs has developed as an effective "off-the-shelf" approach to VST therapy, allowing for rapid treatment of fulminant viral infections with partially HLA matched VST products. 57, 60-62 HLA matching strategies vary across protocols and research continues to determine the optimal approach. Recent studies have demonstrated that small banks using strategically chosen donors based on their HLA type and immunity to the target of interest can provide potential treatment to a large number of referred patients. 63 Evidence to date points to increased efficacy if at least one shared HLA allele is known to mediate anti-viral T cell immunity. 57 Therefore, in the setting of SARS-CoV-2 infection, donor-derived CSTs could be an option as treatment or prophylaxis for high-risk patients post-HSCT, and third party partially HLA-matched CSTs could be used as an early treatment for COVID-19 infection in high-risk patients with blood disorders in general.

CSTs can be expanded from the PBMCs of most convalescent donors, along with some individuals who have not been infected with SARS-CoV-2, likely due to cross-reactivity with common cold coronaviruses. 40, 64-66 Epitope mapping has established immunogenic hot spots within SARS-CoV-2, including multiple regions of the spike and nucleocapsid proteins, as well highly conserved regions of the membrane protein, allowing for design of peptide pools for rapid expansion of CSTs for clinical use. 64, 65 Convalescent donors who have seroconverted display broader T cell antigenic responsiveness, but even seronegative convalescent individuals can elicit an expandable CST population. 64 Spike-directed T cell responses have also been demonstrated in individuals who have been vaccinated against SARS-CoV-2, thus providing a large pool of potential donors for the generation of CST banks. [67] [68] [69] [70] [71] Moreover, these spikedirected T cell responses elicited from vaccinated but previously uninfected donors against peptide pools created from the Wuhan strain, have shown cross reactivity to other variant strains thereby broadening the applicability of this approach. 72 Currently, there are seven registered phase I/II trials evaluating allogeneic CSTs for the treatment or prevention of COVID-19, four of which are actively recruiting patients ( Table 1) .

Six trials are designed to test third party allogeneic CSTs for treatment of SARS-CoV-2 infection in high-risk patients (based on illness severity score, underlying comorbidities, and/or age) and one (NCT05141058) tests HSCT donor-derived CSTs for prophylaxis against SARS-CoV-2 infection in SARS-CoV-2 negative participants post allogeneic HSCT. Two trials (NCT05141058 and NCV04745295) specifically target immunocompromised patients with blood disorders; three others include malignancy and/or immune suppression as risk factors for severe disease, which are required for eligibility ( Table 1) . To date, data from one trial (NCT04401410) have been presented detailing 4 patients who were treated with partially HLA-matched CSTs to treat SARS-CoV-2 infection in high-risk individuals. One patient experienced symptoms consistent with cytokine release syndrome, but recovered. Three of the 4 treated patients achieved resolution of their infection post CST infusion, 73 but without results from the control group, the extent of the CST effect is unclear. Unfortunately, this trial was terminated early due to feasibility concerns with insufficient numbers of patients meeting inclusion criteria.

As SARS-CoV-2 variants arise, CSTs generated for therapeutic use must be evaluated for cross-reactivity against new circulating viral strains. Studies to date demonstrate moderate to high T cell cross-reactivity against circulating variants, including the Omicron variant, 74-76 with strong reactivity particularly in the CD4 + compartment. 67, 70, 72, [77] [78] [79] Indeed, T cell epitopes identified in CSTs from convalescent patients span the viral proteome 40, 50, 80-82 and stimulate T cell responses to viral variants that are partially resistant to vaccine-induced humoral spikespecific responses. [83] [84] [85] Importantly, high throughput systematic analysis of CD8 + T cell activity in response to mutant peptides from SARS-CoV-2 variants of concern-including alpha, beta, and delta variants-has suggested decreased ability of some mutant epitopes to bind to certain HLA, 86, 87 which highlights the need to ensure that CSTs generated for clinical use maintain activity against circulating strains as new variants arise. 72 SARS-CoV-2-specific T cells are longlasting in convalescent individuals, retaining activation and proliferation capacity ex vivo for at least 10 months, 88 and supporting the assertion that CSTs may provide durable protection against severe illness due to SARS-CoV-2, even as humoral immunity wanes. 89

Though many groups have classified T cell immunity to SARS-CoV-2 and demonstrated the feasibility of CST generation, the hyperinflammatory nature of critical COVID-19 calls into question whether T cell therapy may be beneficial in the setting of pneumonia or ARDS.

Dexamethasone is standard treatment for hypoxic patients following the demonstration of a survival advantage in randomized controlled trials, and this therapy is highly likely to inactivate both endogenous lymphocytes as well as any unmodified adoptive cell therapies. Basar et al. showed that corticosteroid resistant T cells targeting SARS-CoV-2 could be generated via CRISPR/Cas9 knockout of the glucocorticoid receptor (NR3C1), and the resulting cells maintain viability and effector function in the presence of dexamethasone in vitro. 90 These and similar approaches may facilitate the use of cell therapy even when immunosuppressive pharmacotherapy must be administered simultaneously.

Natural killer cells are an essential component of antiviral defense, as demonstrated by many inborn errors of immunity in which NK cell defects result in viral susceptibility. 91, 92 Studies of COVID-19 have demonstrated that NK lymphopenia is common in acute illness, with loss of CD56 dim effector NK cells in patients with severe cases. 93 Reports have revealed inverse correlations between NK counts and serum IL-6 level 94 as well as IL2Ra 95 . Robust NK activation has been observed in both peripheral blood and BAL samples from COVID-19 patients, though elevation of adaptive NK cells (NKG2C + /Ksp37 + /perforin + ) was exclusively seen in severe disease. 96 A recent study suggested that the IL-15-IL-15R axis may be a key driver of immune dysfunction in COVID-19 infection, with excess signaling resulting in NK dysfunction. 97 Ma et al. also demonstrated that NK cells modified with a chimeric antigen receptor (CAR) utilizing a single chain variable fragment (scFv) derived from the Spike-targeting S309 monoclonal antibody killed Spike-expressing targets and had cross-reactivity with common Spike variants. 98 Presently, there are 7 clinical trials evaluating allogeneic NK cell immunotherapy as adjunctive treatment for COVID-19, as well as 1 trial of NK CAR immunotherapy targeting SARS-CoV-2 ( Table 2) ; none specifically target immunocompromised populations. No study results have been published to date and at least one such trial is no longer recruiting (NCT04365101).

While characterization of COVID-19 immunopathology has been complicated by the dynamic 113 and has an inflammatory profile unique from severe COVID-19 in adults. 114, 115 Additionally, this syndrome has been associated with activation of CX3CR1 + vascular patrolling T cells. 116 

The full phenotype and function of Tregs in vivo is well-reviewed elsewhere [132] [133] [134] and is beyond the scope of this review. In brief, Tregs are characteristically CD4 + CD25 hi CD127 lo T lymphocytes that express the transcription factor Forkhead Box Protein 3 (FOXP3) and inhibit the activation and proliferation of inflammatory effector cells, including CD4 + and CD8 + effector T lymphocytes, macrophages, B cells, neutrophils, and dendritic cells. 132, 135, 136 Treg products for cellular therapy may be either autologous or allogeneic depending on the clinical context and have been safely administered to patients for the treatment of GVHD, solid organ transplant rejection, and autoimmune diseases in phase I/II clinical trials. [137] [138] [139] [140] [141] In the setting of an acute and life-threatening viral infection, such as severe COVID-19, rapid availability of an "off-the-shelf" product is needed. Thus, clinical trials of Tregs in COVID-19

( Table 3) While MSCs show efficacy in pre-clinical disease models and safety in early clinical trials, the results of phase III trials have been mixed. This is likely due in part to variation in tissue source and manufacturing protocols, including culture conditions and number of passages, which can lead to functional and phenotypic differences in MSCs that might go undetected based on minimal release criteria. 160 Furthermore, best methods of isolation (plastic adherence versus selection) and ex vivo expansion are also unclear, as head-to-head studies of clinical outcomes using differing manufacturing methods have not been performed. 161 

Based on pre-clinical and early clinical data supporting their use in ARDS and observation of the inflammatory response to SARS-CoV-2, several groups completed pilot studies using MSCs to treat severe COVID-19, with no observed treatment-related adverse events. [162] [163] [164] [165] [166] [167] These included an open-label, individually randomized pilot study conducted by Shu et al. 162 There are currently more than 30 registered clinical trials evaluating safety, feasibility, and efficacy of MSCs for the treatment of COVID-19.

While multiple studies of cellular therapy targeting COVID-19 are underway or planned, there remain many potential hurdles for these treatments. Though some of the current studies include control groups, randomized controlled studies of cellular therapies are difficult to carry out, particularly when focused on rare patient populations. Cellular therapies can be costly due to the manufacturing requirements. However, current antiviral cell therapies are roughly on par with the cost of IV antiviral medications, and if effective in reducing hospitalization time, they may be economical. As SARS-CoV-2 infection has the potential to progress rapidly, both antiviral and anti-inflammatory cellular therapies would likely require rapid turnaround (likely on the order of days) in order to be feasible as treatment options. This would likely eliminate individualized cellular therapies for treatment in most cases. Furthermore, the standard use of immunosuppressive medications including corticosteroids in patients with severe respiratory disease may inactivate infused cellular therapies. Gene engineered products may overcome this limitation but would add to the cost of product generation. Use of previously generated cell banks from healthy donors could overcome many of these hurdles.

There remains a need for novel therapies to protect vulnerable populations from SARS-CoV-2 as well as future emerging infectious diseases, and adoptive cellular therapy may play a role in the prevention of disease in patients with blood disorders who are unable to mount a vaccine response. In addition, cell-based therapies are a potential treatment for these patients as well as high risk individuals with complicated COVID-19. Randomized controlled trials of antiviral and anti-inflammatory immunotherapy are however required to help determine if these therapies will have an established place in our armamentarium against COVID-19.

SRC conducted the literature review and wrote the paper, MDK conducted the literature review and edited the paper, CMB oversaw the literature review and edited the paper 

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