| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T319 |
0-250 |
Sentence |
denotes |
A Phase I/II study in early stage COVID-19 patients (within 14 days of illness) employing CAR-NK cell therapy is currently being tested using off-the-shelf NK cells derived from human umbilical cord blood expressing NKG2D and ACE2 CARs (NCT04324996). |
| T320 |
251-464 |
Sentence |
denotes |
This complex five-arm study will compare the efficacy of different CAR-NK constructs: (i) NK cells, (ii) NK cells secreting IL-15, (iii) NKG2D CAR-NK cells, (iv) ACE2 CAR-NK cells, and (v) NKG2D-ACE2 CAR-NK cells. |
| T321 |
465-727 |
Sentence |
denotes |
NKG2D CAR-NK cells have shown promising preclinical results in cancer studies (166), and although not proven for SARS-CoV-2, the rationale for expressing NKG2D derives from work showing that NKG2D-ligands (NKG2DL) are upregulated on virally infected cells (167). |
| T322 |
728-1098 |
Sentence |
denotes |
Similarly, the investigators hypothesize that expressing ACE2 on NK cells will facilitate the elimination of SARS-CoV-2 virions and infected cells by binding the viral spike proteins–but it is unknown whether or not CAR-NK cells can eliminate virions or if infected cells display sufficient levels of spike protein to be recognized by ACE2-NK cells upon viral infection. |
| T323 |
1099-1300 |
Sentence |
denotes |
The investigators also suggest that expressing ACE2 on NK cells may also have a secondary benefit as a decoy cell that will be infected by the virus thereby indirectly protecting lung epithelial cells. |
| T324 |
1301-1507 |
Sentence |
denotes |
As described previously, it is unclear whether this strategy will work to stop viral spread to healthy epithelial cells or if it will serve to perpetuate viral spread if the virus can replicate in NK cells. |
| T325 |
1508-1686 |
Sentence |
denotes |
In arms ii-v of this trial, the CAR-NK cells have been engineered to secrete IL-15 based on studies showing improved in vivo persistence of CAR-NK cells in cancer patients (168). |
| T326 |
1687-2026 |
Sentence |
denotes |
However, the addition of the proinflammatory cytokine IL-15 to this treatment strategy should be monitored closely for life-threatening toxicities, as elevated IL-15 has been previously reported to accompany chronic pulmonary inflammatory diseases (169) and MERS-CoV infection (170) even if no correlation has been reported for SARS-CoV-2. |
| T327 |
2027-2264 |
Sentence |
denotes |
Interestingly, a study compared IL-15 levels from lung tissue homogenates following SARS-CoV infection in aged vs. juvenile monkeys and showed that IL-15 concentrations were only elevated in juvenile monkeys 10 days post-infection (171). |
| T328 |
2265-2442 |
Sentence |
denotes |
This study would suggest that IL-15 therapy may be tolerated and effective in older COVID-19 patients that may not be able to produce IL-15, however this has not been confirmed. |
| T329 |
2443-2745 |
Sentence |
denotes |
Lastly, all the CAR-NK cells in this trial secrete GM-CSF neutralizing scFv antibodies, since this cytokine has a known role in CRS in cancer patients treated with CAR-T cells (172), and has been shown to be correlated with COVID-19 disease severity in association with pathogenic CD4+ Th1 cells (173). |
