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Table 3 Challenges in building more efficient CAR NK cells for treatment of solid tumors and possible solutionsa

From: Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy

Challenges Possible solutions References
Lack of available targets   
 TAA expression not homogenous Use of oncolytic viruses in combination therapy or bi-specific CARs [116, 228]
  Clonal evolution   
  On-target, off-tumor effects   
Anatomical barriers   
  Insufficient trafficking or infiltration Intra-tumoral injection of CAR NK cells; focused ultrasound guided delivery of CAR NK cells into tumor; targeting tumor vasculature; CAR NK cells expressing a chemokine(s) [149, 155]
  Locoregional injection, use of stronger co-stimulatory domains, lymph depletion, in vivo administration of chemokine or cytokine-expressing CARs [146, 169]
Insufficient NK cell proliferation and/or activation in vivo  
  Immunosuppressive TME TGF-β inhibition through neutralizing antibodies or dominant negative receptors [229]
  Use of cytokines such as IL-2, IL-15, IL-12, or IL-18 to simulate NK cell proliferation and activation [68]
  Inhibition of checkpoint blockades using anti-PD1, anti-TIGIT, etc [165]
  Metabolic abnormalities Metabolic stimulation through inhibition of CD73 or arginase [162]
  NKG2D inhibition by TME NKG2D activation through histone deacetylase inhibitors [160, 230]
  1. aTAA tumor associated antigens, TME tumor microenvironment