Shared mechanisms of action between COVID-19 and immunotherapy, and potential common therapeutic strategies
| Molecular target | Role in immunotherapy | Role in COVID-19 | Available drugs | Trials in COVID-19 | Results in COVID-19 | Comments |
| IL-6 | Elevation during CRS following CAR-T and mAb infusion.119 | Elevated levels correlate with severity of disease55 58 | Tocilizumab Sarilumab128 | Active trials: 38 Completed: 8 Active trials: 9 Completed: 3 | Recommended in recently hospitalized patients with severe respiratory disease in combination with Dex.123–125 127 No clear evidence in patients requiring hospitalization.128 The SARICOR Study is testing whether the administration of sarilumab (an IL-6 receptor inhibitor) in hospitalized patients with COVID-19, pulmonary infiltrates and a high IL-6 or D-dimer serum level could reduce the progression of ARDS.145 | Clear cut-off of IL-6 levels still have to be determined.51 The NIH COVID-19 Treatment Guideline Panel recommends tocilizumab+Dex to recently hospitalized patients (not in the ICU) with rapidly increasing oxygen needs and who have significantly increased markers of inflammation. |
| JAK/STAT intracellular signaling | Approved for steroid-refractory GVHD.131 | JAK kinases are activated after stimulation of IL receptors | Baricitinib Ruxolitinib | Active trials: 9 Completed: 1 Active trials: 16 Completed: 1 | Better outcome for hospitalized patients in association with remdesivir compared with remdesivir alone.134 Apparent efficacy at reducing progression of ARDS and need for respiratory support.132 | Now recommended for hospitalized patients in combination with remdesivir Potential toxic effects on the bone marrow |
| IL-1 | In CAR-T-related CRS, the release of IL-1 seems to precede that of IL-6.56 | IL-1b was significantly elevated in patients with severe COVID-19146 | Anakinra | Active trials: 14 Completed: 2 | Evaluating the efficacy in reducing the number of patients requiring mechanical ventilation | IL-1 may precede the production of IL-6 in COVID-19, as it seems to happen during CAR-T toxicity |
| IFN-γ | Blocking IFN is approved for familiar HLH, not approved for post-IMTX CRS. | Potential benefit in early blockage of TNF-α/IFN-γ axis in COVID-1960 | Emapalumab | Active trials: 1 Completed: 0 | Comparing anakinra to emapalumab which demonstrated efficacy in pediatric HLH137 | Data in COVID-19 are insufficient to draw a conclusion |
| TNF-α | Largely used in the treatment of severe forms of autoimmune diseases. | TNF-α is elevated in early phases of disease51 | Infliximab | Active trials: 1 Completed: 1 | An anti-TNF-α mAb used in autoimmune diseases has shown effectiveness in treating patients with COVID-19138 | Potential high risk of bacterial superinfection |
| Plasmin | Dysregulated in SOS/VOD and DIC for all causes.141 | Hypercoagulation is secondary to endothelialitis and ACE2-dependent hypofibrinolysis33 | Defibrotide | Active trials: 4 Completed: 0 | No results from small observations or trials so far | Potential benefit in association with other anticoagulants |
| C5 protein of the complement | Hyperactivated during TA-TMA and HUS.147 | Both C3 and C5 inhibitors showed a robust anti-inflammatory response, reflected by a steep decline in IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated ARDS144 | Eculizumab | Active trials: 1 Completed: 0 | Strong anti-inflammatory response in a small trial144 | Potential benefit in patients with consumption of complement factors and signs of microthrombosis and kidney injury. Contraindicated if there is bacterial infection |
| All pro-inflammatory cytokines | CRS and ICANS are associated with remarkably high serum concentrations of many inflammatory cytokines. | Many proinflammatory cytokines are produced after SARS-CoV-2 infection. They cause tissue damage, promote NETs, and activate the coagulation and complement systems. | Dexamethasone (Dex) | Active trials: 21 Completed: 2 | At the time of writing, Dex is the only drug that has shown a reduction in mortality due to COVID-19116 | Current recommendation for Dex in COVID-19 is restricted to patients experiencing initial ARDS and signs of CRS |
| Mesenchymal cells (MSC) | Active trials: 49 Completed: 5 | First trials show capacity of MSC to attenuate lung and systemic inflammation96 148 | Some limit due to the time of manufacturing, but potential use of third-party sources for off-the-shelf production | |||
| Spike protein of SARS-CoV-2 | No recognized role of ACE2 receptor in IMTX. | It is the protein that mediated the entry of the viral particles into the cells149 | mAbs | Active trials: 33 Completed: 1 | Chi et al111 isolated, from convalescent patients with COVID-19, 3 mAbs displaying neutralization against SARS-CoV-2 | Utility for treating patients until a vaccine will be available, and then to transfer adoptive immunity to immunosuppressed patients |
| Anti-spike CAR-T cells | Active trials: 0 Completed: 0 | No results from anti-spike CAR-T so far | CAR-T cells are very successful in the treatment of hematologic tumors,150 but there remain many complications, including severe CRS and ICANS, that have discouraged their use in COVID-19 | |||
| Anti-spike NK cells | Active trials: 6 Completed: 0 | NK and CAR-NK cells seem to control viral replication without increased risk of CRS75 | Compared with CAR-T, the use of wild-type NK and NK-CAR cells seems to be safer even if there is no definitive answer about their efficacy | |||
| Anti-spike TCR-engineered cells | Active trials: 0 Completed: 0 | No data available | TCR-engineered T cells have the same limitations of CAR-T for the treatment of active disease. However, as anti-viral mAbs, they might be useful in the future to confer adoptive cell-mediated immunity against SARS-CoV-2 in immunocompromised patients.151 |
ARDS, acute respiratory distress syndrome; CAR-T, chimeric antigen receptor-T cell; CRS, cytokine release syndrome; DIC, diffuse intravascular coagulation; GVHD, graft-versus-host disease; HLH, hemophagocytic lymphohistiocytosis; HUS, hemolytic uremic syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; ICU, intensive care unit; IFN-γ, interferon γ; IL, interleukin; IMTX, immunotherapy; mAb, monoclonal antibody; NETs, neutrophil extracellular traps; NIH, National Institutes of Health; NK, natural killer; SOS/VOD, sinusoidal obstruction syndrome/veno-occlusive disease; TA-TMA, transplant-associated thrombotic microangiopathy; TCR, T cell receptor; TNF-α, tumor necrosis factor-α.