Table 4.
A comprehensive comparison between CAR T cell and CAR NK cell therapies
| Difference | CAR T cell | CAR NK cell | References |
|---|---|---|---|
| Key markers | TCR, CD3 | CD16, CD56 | [572] |
| Receptor activated | NKG2D, NKG2C, NKp44, KIR | [572] | |
| CAR generations | Five generations | Four generations | [106, 573–576] |
| Intracellular and co-stimulatory signaling domains | CD3ζ, CD28, 4-1BB (CD137), CD27, CD40, OX40 (CD134) | CD3ζ, DAP10, DAP12, 2B4 (CD244), 4-1BB, CD28 | [318, 576–578] |
| Production of memory cells | + + + | + | [106, 579, 580] |
| Off-the-shelf products | + (HLA-matched allogeneic CAR T cells) | + (non-HLA-matched allogeneic and NK cell lines like NK-92 cells) | [318, 581] |
| Time for manufacturing |
1 to 2 weeks Rapid manufacturing in 24 h is also reported |
Exact timeline can vary (typically 2 to 4 weeks) | [582, 583] |
| Redosing |
Not limited by cell number Risk of alloimmunization |
Not limited by cell number | [319] |
| In vitro expansion during manufacturing | + (Autologous or allogeneic T cells can be expanded after CAR transduction.) | + (autologous NK cell, iPSCs, and NK-92 cells can be pre-expanded before CAR transduction.) | [318, 584] |
| In vivo persistence |
Relative long-term persistence of functional CAR T cells (armored CAR T cells) Intermediate (weeks to months) In some patients with leukemia, CAR-T cells can be identified several years after being infused |
Low and limited persistence in the absence of cytokine Short-term lifespan without IL-15 Cord blood-derived CAR NK cells can persist for at least 12 months (Liu et al.) |
[572, 585, 586] |
| Immune cell sources |
Autologous PBMCs PBMCs from well-matched donor |
Peripheral blood Umbilical cord blood and cord blood HPSCs Differentiated pluripotent stem cells (e.g., iPSCs) NK-92 cell line (an immortalized NK lymphoma cell line) |
[106, 572, 584] |
| Cytotoxicity mechanisms |
In a CAR-dependent manner Perforin and granzyme Inducing apoptotic signaling pathways in tumor cells |
In both CAR-dependent and -independent manners Perforin and granzyme ADCC through CD16 Inducing apoptosis |
[318, 572] |
| Risks and toxicities |
+ + + (CRS, neurotoxicity, and GVHD) Risk of malignancy after treatment (low risk) |
+ (less common) A protocol for freezing and thawing needs to be developed and clinically evaluated for a ready-to-use product |
[319, 572, 587, 588] |
| Infiltration to TME | Poor (particularly in cold tumors) | Usually poor | [318, 589] |
| Combination therapies |
Chemotherapy (like cyclophosphamide) Radiotherapy Immune checkpoint inhibitors (like anti-PD-1) Oncolytic viruses Cancer vaccines Immunomodulatory agents Allogeneic hematopoietic cell transplantation Metabolic inhibitors |
Immune checkpoint inhibitors (anti-NKG2A antibody, monalizumab, lirilumab, and so on) Immunomodulatory drugs (lenalidomide) Epigenetic modulators (vorinostat) Oncolytic viruses (adenoviruses) Small-molecule inhibitors (GSK3i) |
[106, 590] |
| Clinical trials |
Extensive clinical trials Proven effectiveness (at least 6 FDA-approved CAR T cell therapies) |
Limited clinical trials No FDA-approved CAR NK cell therapies yet Clinical efficacy reported in some studies |
[106, 318, 576] |
ADCC: Antibody-dependent cellular cytotoxicity, CAR: Chimeric antigen receptor, CRS: Cytokine release syndrome, FDA: The U.S. food and Drug Administration, GSK3i: Glycogen synthase kinase-3 inhibitor, GVHD: Graft-versus-host disease, HLA: Human leukocyte antigen, HPSCs: Hematopoietic stem and progenitor cells, iPSCs: Induced pluripotent stem cells, KIR: Killer-cell immunoglobulin-like receptor, NK: Natural killer, PBMC: Peripheral blood mononuclear cell, PD-1: Programmed cell death protein 1, TCR: T cell receptor, TME: Tumor microenvironment