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Adapter chimeric antigen receptor (AdCAR)-engineered NK-92 cells: an off-the-shelf cellular therapeutic for universal
Stefan Grote1, Joerg Mittelstaet2, Caroline Baden1
1Department of Hematology and Oncology, University Hospital Tuebingen, Children's Hospital, Tuebingen, Germany.
Abstract:
Despite the recent success of CAR T cells targeting CD19 and CD22 in hematological malignancies, the production of CAR T cells still requires an extensive manufacturing process. The well-established NK-92 cell line provides a promising alternative to produce CAR-modified effector cells in a GMP-compliant, cost-effective way. NK-92 can be redirected against a variety of surface antigens by our adapter CAR (AdCAR) system utilizing biotinylated antibodies (bAb) as adapter molecules. Selected bAb were capable of inducing significant AdCAR NK-92-mediated lysis of non-Hodgkin lymphoma (NHL) and mantle-cell lymphoma (MCL) cell lines as well as primary MCL and chronic lymphocytic leukemia (CLL) cells. AdCAR specificity was proven using a JeKo-1 CD19/CD20 knockout antigen-loss model. Moreover, through combinations of bAb, AdCAR NK-92 cells are capable of combatting tumor antigen evasion mechanisms. In conclusion, we successfully generated the AdCAR NK-92 cell line which can be manufactured as an "off-the-shelf, on-demand" product allowing universal and tunable tumor targeting.
Insights
The adapter CAR (AdCAR) NK-92 cell line offers a cost-effective, off-the-shelf alternative for cancer immunotherapy. This system enables tunable tumor targeting against hematological malignancies like lymphoma and leukemia.
Area of Science:
- Immunology
- Cell Biology
- Oncology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematological malignancies but involves complex manufacturing.
- The NK-92 cell line presents a viable alternative for producing CAR-modified effector cells efficiently and cost-effectively under Good Manufacturing Practice (GMP) guidelines.
Purpose of the Study:
- To develop an adaptable CAR-NK cell platform for universal and tunable cancer targeting.
- To evaluate the efficacy of the adapter CAR (AdCAR) NK-92 system in targeting various hematological malignancies.
Main Methods:
- Utilized the NK-92 cell line engineered with the AdCAR system.
- Employed biotinylated antibodies (bAb) as adapter molecules for antigen redirection.
- Assessed AdCAR NK-92 cell-mediated cytotoxicity against lymphoma and leukemia cell lines and primary cells.
- Validated AdCAR specificity using a CD19/CD20 antigen-loss model.
Main Results:
- AdCAR NK-92 cells demonstrated significant lysis of non-Hodgkin lymphoma (NHL), mantle-cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL) cells.
- Specificity was confirmed in an antigen-loss model, showing targeted killing based on antibody selection.
- Combinations of bAb enabled AdCAR NK-92 cells to overcome tumor antigen escape mechanisms.
Conclusions:
- The AdCAR NK-92 cell line provides an "off-the-shelf, on-demand" therapeutic product.
- This platform allows for universal and adaptable tumor targeting in hematological cancers.
- The AdCAR system offers a promising strategy to enhance CAR-based immunotherapies.
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