Reasons why some cancer cell therapy research is transitioning from CAR-T to CAR-NK.

Reasons why some cancer cell therapy research is transitioning from CAR-T to CAR-NK.

Reasons why some cancer cell therapy research is transitioning from CAR-T to CAR-NK.

Immunotherapy has revolutionised cancer treatment. Chimeric antigen receptor (CAR)-T cell therapy has emerged as promising cancer immunotherapy. CAR-T cells are genetically engineered T cells producing artificial T cell receptors targeting specific antigens on the cancer cells. Currently, there are six FDA-approved CAR-T therapies. All are approved for the treatment of blood cancers. Kymriah is the first FDA-approved CAR-T cell therapy for the treatment of acute lymphoblastic leukaemia (ALL).

However, despite their clinical efficacy, CAR-T cells have limitations. One of the challenging limitations is the loss of target antigen after therapy. This renders CAR-T cells ineffective due to their dependence on antigens for efficacy. CAR-T cell therapy is also associated with high rates of toxicities, such as cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, which can be life-threatening. On-target off-tumour toxicities are another major concern as the targets recognised by CAR-T cells are the most common tumour-associated antigens, which are also expressed in healthy tissues.

Natural killer (NK) cells have been identified as promising candidates for CAR-based cellular immunotherapy because of their unique characteristics. NK cells are cytotoxic killer cells that target tumour cells via both innate and adaptive anti-tumour activity.

CAR-NK cells have several advantages over CAR T cells. As NK cells have spontaneous cytotoxic activity, they can kill cancer cells through both CAR-dependent and CAR-independent pathways, while T lymphocytes only kill their targets by a CAR-dependent pathway. Therefore, in the setting where tumour antigen is downregulated, NK cells would still be effective against tumour cells. Unlike the long-term persistence of CAR-T cells, NK cells are short-lived, therefore are unlikely to maintain on-target off-tumour toxicity, cytokine-release syndrome and neurotoxicity. NK cells can be generated from various sources such as umbilical cord blood, bone marrow, human embryonic stem cells, and induced pluripotent stem cells. This provides accessibility and availability as an off-the-shelf CAR-NK therapy, which is not possible for CAR-T cells as it is usually from an autologous source. In addition, as CAR-NK is allogenic, the risk of GVDH is also significantly reduced.  

Due to these unique features, CAR-NK cell immunotherapy may likely serve as an alternative to CAR-T therapy. However, further investigation and clinical trials are still required to ensure the safety profile of CAR-NK cells.

Cell sourceAutologous or MHC-matched allogeneicAutologous, non-MHC-matched allogeneic or NK cell lines
Off-the-shelf ready to use CAR productsUnlikely, as it is usually autologous. Maybe allogenic MHC-matched CAR-T cellsPossible with NK cell lines and allogeneic NK cells
Cytotoxicity MechanismsCAR-dependent cell killingBoth CAR-dependent and CAR-independent NK-mediated cell killing
Cytokine release syndrome and neurotoxicityCommon and often seriousLess common and serious
FDA-Approved TherapiesYescarta (CD19), Kymriah (CD19), Breyanzi (CD19), Tecartus (CD19), Abecma (BCMA), Carvyti (BCMA)Currently, there are no FDA-approved therapies
Table 1: Comparison of CAR-T and CAR-NK Cancer Cell Therapy

GemPharmatech, a leader in genetically modified mouse models has created a range of mouse models to support the evaluation of NK cell therapies. NK cells require the cytokine Interleukin 15 (IL15) for its development and function in vivo. However, the mouse IL15 poorly supports human NK cells due to its low affinity to human IL15 receptors. To overcome this, GemPharmatech generated a knocked-in of human IL15 gene in an immunodeficient mouse model (NCG) to express hIL15 cytokine – NCG-hIL15 (T004886). NCG-hIL15 engrafted with CD34+ human stem cells (HSC) develop significantly higher levels of functional human CD56+ NK cells than the NCG controls (see Figures 1 & 2). This NCG-hIL15 mouse strain offers a novel mouse model for studying human NK cell biology and human NK-mediated cancer immunotherapy in vivo.

Figure 1: Immunophenotypes of huHSC-NCG and huHSC-NCG-hIL15 mice

Peripheral blood was collected at weeks 5, 7, 9, 11 and 13 post engraftment to characterize immunophenotypes in huHSC-NCG and huHSC-NCG-hIL15 mice by flow cytometry. Compared with huHSC-NCG mice, CD56+ NK cells displayed higher reconstitution levels in huHSC-NCG-hIL15 mice.

Figure 2: Expression of typical NK cell functional genes in huHSC-NCG and huHSC-NCG-hIL15 mice

Peripheral blood was collected at week 13 post engraftment to characterize NK cell functional genes in huHSC-NCG and huHSC-NCG-hIL15 mice by flow cytometry. Compared with huHSC-NCG, the humanization of NK cell reconstruction level was significantly increased in huHSC-NCG-hIL15 mice, and the functional proteins KIR3DL and NKG2D were also detected.

Check out the list of next-generation NCGs for specific immune cell research.

Can’t find the NCG mouse model that you need? Reach out to us at [email protected] for our full catalogue.



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