Table 1

Shared mechanisms of action between COVID-19 and immunotherapy, and potential common therapeutic strategies

Molecular targetRole in immunotherapyRole in COVID-19Available drugsTrials in COVID-19Results in COVID-19Comments
IL-6Elevation during CRS following CAR-T and mAb infusion.119Elevated levels correlate with severity of disease55 58Tocilizumab
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 signalingApproved for steroid-refractory GVHD.131JAK kinases are activated after stimulation of IL receptorsBaricitinib
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-1In CAR-T-related CRS, the release of IL-1 seems to precede that of IL-6.56IL-1b was significantly elevated in patients with severe COVID-19146AnakinraActive trials: 14
Completed: 2
Evaluating the efficacy in reducing the number of patients requiring mechanical ventilationIL-1 may precede the production of IL-6 in COVID-19, as it seems to happen during CAR-T toxicity
IFN-γBlocking 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-1960EmapalumabActive trials: 1
Completed: 0
Comparing anakinra to emapalumab which demonstrated efficacy in pediatric HLH137Data in COVID-19 are insufficient to draw a conclusion
TNF-αLargely used in the treatment of severe forms of autoimmune diseases.TNF-α is elevated in early phases of disease51InfliximabActive trials: 1
Completed: 1
An anti-TNF-α mAb used in autoimmune diseases has shown effectiveness in treating patients with COVID-19138Potential high risk of bacterial superinfection
PlasminDysregulated in SOS/VOD and DIC for all causes.141Hypercoagulation is secondary to endothelialitis and ACE2-dependent hypofibrinolysis33DefibrotideActive trials: 4
Completed: 0
No results from small observations or trials so farPotential benefit in association with other anticoagulants
C5 protein of the complementHyperactivated during TA-TMA and HUS.147Both 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 ARDS144EculizumabActive trials: 1
Completed: 0
Strong anti-inflammatory response in a small trial144Potential benefit in patients with consumption of complement factors and signs of microthrombosis and kidney injury. Contraindicated if there is bacterial infection
All pro-inflammatory cytokinesCRS 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-19116Current 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 148Some limit due to the time of manufacturing, but potential use of third-party sources for off-the-shelf production
Spike protein of SARS-CoV-2No recognized role of ACE2 receptor in IMTX.It is the protein that mediated the entry of the viral particles into the cells149mAbsActive trials: 33
Completed: 1
Chi et al111 isolated, from convalescent patients with COVID-19, 3 mAbs displaying neutralization against SARS-CoV-2Utility for treating patients until a vaccine will be available, and then to transfer adoptive immunity to immunosuppressed patients
Anti-spike CAR-T cellsActive trials: 0
Completed: 0
No results from anti-spike CAR-T so farCAR-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 cellsActive trials: 6
Completed: 0
NK and CAR-NK cells seem to control viral replication without increased risk of CRS75Compared 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 cellsActive trials: 0
Completed: 0
No data availableTCR-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.