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cytoplasmic IL-2 receptor β-chain domain with a
binding site for the transcription factor STAT3, providing
all three synergistic signals required for full T
cell activation and proliferation (Figure 2B).
CAR-natural killer (NK)
Natural killer (NK) cells are innate lymphoid cells
that can detect and eliminate virus-infected and tumor
cells. Over the past two decades, CAR-NK cells
have been successfully applied as immunotherapy
for advanced-stage leukemia. New strategies to enhance
NK cell potency and persistence have been
developed using costimulatory signaling, checkpoint
inhibition, and cytokine armors, which redirect
NK cell specificity to the tumor through CAR
or engager molecules. The promising results of
the first generation of CAR-NK cell therapies have
sparked continued innovation in the field, such as
the development of genetically modified CAR-NK
cells, which can kill tumor cells both in CAR-dependent
and CAR-independent ways.
Compared to traditional CAR-T cells, both CAR-NK
cells and unmodified NK cells have safety advantages,
such as reduced risks of graft-versus-host
disease and alloreactivity. Therefore, they are ideal
for immune cell sourcing from sources other than
autologous cells, such as NK92 cells, peripheral
blood mononuclear cells (PBMCs), umbilical cord
blood (UCB), and induced pluripotent stem cells
(iPSCs). Unlike T cells, NK cells produce different
cytokines, such as GM-CSF, IL-3, and TNF-α, decreasing
the incidence and severity of inflammatory
cytokine release syndrome and neurological
toxicity. In addition, the limited lifespan of CAR-NK
cells reduces the risk of cell toxicity.
According to clinicaltrials.gov, there are currently
26 ongoing clinical trials on CAR-NK targeting of
specific antigens in multiple myeloma (CD33, CLL1
Figure 3. Various sources of NK cells. Source: adapted from Zhang
L, et al. 2022
and BCMA), acute myeloid leukemia (CD123 and
NKG2D), relapsed B cell non-Hodgkin lymphoma
(CD19 and CD70), solid tumors (PD1, CTLA4,
Lag3, and 5T4), small cell lung cancer (DLL3),
prostate cancer (PSMA), and head and neck cancer
(PD-L1). However, CAR-NK therapies are not yet
FDA-approved.
CAR-NK and CAR-T therapies share common challenges,
such as on-target/off-tumor toxicity, where
the CAR-modified cells attack not only the tumor,
but also healthy tissues expressing the targeted
antigen. Another challenge is the potential for antigen
loss or downregulation, leading to treatment
failure. Additionally, both therapies face difficulties
targeting solid tumors due to the immunosuppressive
TME. However, CAR-NK has several advantages
over CAR-T due to its potential for off-the-shelf use,
lower risk of cytokine release syndrome (CRS), and
ability to target a wider range of tumors due to the
lack of major histocompatibility complex restric22
https://www.sinobiological.com/resource/cytokines/il-2-interleukin-2-receptor https://www.sinobiological.com/category/stat3 https://www.sinobiological.com/category/solutions https://www.sinobiological.com/category/bcma/proteins https://www.sinobiological.com/category/il3ra https://www.sinobiological.com/category/nkg2d https://www.sinobiological.com/category/cd19 https://www.sinobiological.com/research/cancer-drug-targets/cd70 https://www.sinobiological.com/research/cancer-drug-targets/pd1 https://www.sinobiological.com/category/ctla-4 https://www.sinobiological.com/category/lag3 https://www.sinobiological.com/category/5t4-tpbg https://www.sinobiological.com/resource/dll3 https://www.sinobiological.com/category/psma https://www.sinobiological.com/category/pd-l1 https://www.sinobiological.com/areas/stem-cells/embryonic-and-induced-pluripotent-stem-cells https://www.sinobiological.com/category/cytokine-protein/gmp-level-cytokine https://www.sinobiological.com/category/gm-csf https://www.sinobiological.com/category/il3 https://www.sinobiological.com/category/tnf-alpha http://www.clinicaltrials.gov https://www.sinobiological.com/category/cd33

eBook: Breakthroughs and Innovations in Immunology Research

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