August 16, 2022

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FT596: CAR-NK for the treatment of B cell malignant tumors

FT596: CAR-NK for the treatment of B cell malignant tumors



 

FT596: CAR-NK for the treatment of B cell malignant tumors

 

Brief introduce

 

The most popular target of CAR-NK is also CD19. Let’s introduce it in more detail in this article.

The design of CD19-CAR involves taking advantage of the inherent versatility of NK cells, which act by combining multiple signaling pathways activated by a combination of different germline-encoded receptors.

 

Using this method, the combination of the transmembrane region of the activated receptor NKG2D with the intracellular signal domains of SLAM co-receptors 2B4 and CD3ζ proved to be the most effective in triggering antigen-specific functional responses in NK cells.

 

Chimerizing anti-CD19 scFv to the NKG2D-2B4-CD3ζ signal platform produced specific in vitro recognition of CD19+ B-cell lymphoma cells in short-term and long-term NK cytotoxicity tests, which were >80% and <40%, respectively. Tumor cell clearance rate, p<0.001.

 

 


Test results

 

The function of CD19-CAR combined with autonomous IL-15 signal is further enhanced . The introduction of IL-15RF can expand iNK cells without adding soluble cytokines , and greatly improve the lifespan and lifespan of iNK cells in vitro and in animal models. Functional durability.

 

FT596: CAR-NK for the treatment of B cell malignant tumors

 

In addition, iNK cells modified with IL-15RF showed enhanced functional maturity, including up-regulation of effector molecules such as granzyme B.

While having a CD19-CAR and IL-15RF of iNK cells in vitro results in CAR enhancements, and B models demonstrated malignant mouse cells, alone iNK cells alone or CD19-CAR -modified iNK compared to cells with CD19- CAR and IL-15RF modified iNK cell therapy can cure B- cell lymphoma ( p<0.002 ).

 

In combination with hnCD16, the co-expression of CD19-CAR and IL15-RF culminates in dual-specific iNK cells that can be used in combination with monoclonal antibodies to solve antigen escape.

In the long-term killing test, when tested against CD19+ CD20+ B lymphoblastic target cells, FT596 alone showed the same level of CD19-targeted anti-tumor activity as the primary CD19-targeted CAR (CAR19) T cells. -CD20 (rituximab).

 

When targeting CD19-CD20+ B lymphoblastic target cells and used in combination with rituximab, only FT596 can effectively eliminate the target cells escaped by the CD19 antigen (the tumor cell clearance rate at 36H is 64% vs. 30% compared with the use of rituximab alone. Ciximab).

In vivo FT596 showed the same level of tumor cell clearance as primary CAR19 T cells on the CD19+ acute lymphoblastic leukemia cell line NALM6 and CD19+CD20+ Burkits’ lymphoma cell line RAJI, and the combination with rituximab enhanced RAJI The clearance rate of tumor cells (p=0.0002).

 

FT596: CAR-NK for the treatment of B cell malignant tumors

 

In addition, using the NSG mouse model of allogeneic human CD34 transplantation, FT596 showed better performance than primary CAR19 T cells, whether as a monotherapy or as a rituximab combination therapy with RAJI tumor cells. High survival rate and safety.

 


Discussion:

 

In summary, these studies show that FT596 provides a multi-antigen-targeted, effective and durable engineered immune cell, which is derived from the main iPSC line, which uses the inherent versatility of NK cells to be single, standardized, and scalable.

The way to achieve efficient combination therapy. An off-the-shelf platform supports the rationalization of the first phase I study as a monotherapy and combined with CD20-targeted monoclonal antibodies including rituximab for subjects with relapsed/refractory B-cell lymphoma and leukemia sex.

 

 

 

Reference:

FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR-NK Cell with Engineered Persistence for the Treatment of B Cell Malignancies, Blood, 2019

FT596: CAR-NK for the treatment of B cell malignant tumors

(source:internet, reference only)


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