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Khushi Rathod https://orcid.org/0000-0003-1845-891X Shravani Rani Shreerachita Satish

Abstract

Introduction: With immunotherapy drugs such as Blinatumomab (Blincyto), the current overall survival rate of relapsed/refractory B Lymphocyte Acute Lymphoblastic Leukemia (B-ALL) is 7.8 months in adults. However, with CRISPR-Cas9 gene editing, CAR T-cell therapy may extend survival. By knocking out T-cell receptors (TCRs) and HLA class I receptors on T-cells, CRISPR-Cas9 edited CAR T-cells could become a universal treatment alternative for B-ALL. This study compares the efficacy of CRISPR-Cas9 edited CAR T-cell therapy, a new era of CAR T-cell therapy, to the treatment of relapsed/ refractory B-ALL with Blinatumomab in mice.


Methods: A cohort of 30 NSG mice receiving xenografts from an 18-24 year old patient with relapsed B-ALL will be randomly assigned to one of three groups, where they will receive treatment with: (1) mock transduced T-cells, (2) Blincyto, or (3) CRISPR-Cas9 edited TRAC- and B2M- knockout CAR T-cells. Another cohort of 30 NSG mice, receiving human skin xenografts from a healthy donor, will also be assigned to one of the groups and treated accordingly. Tumour shrinkage will be analyzed through in vivo antibody fluorescent imaging in the first cohort. Graft Vs Host Disease (GvHD) development will be assessed in the second cohort.


Results: It is expected that mice treated with CRISPR-Cas9 edited CAR T-cells will be more effective at eliminating tumours. Compared to mice treated with Blincyto or mock-transfused T-cells, these mice will exhibit the highest overall response rates, complete response rates and tumour shrinkage rates, and the lowest relapse rates. It is also expected that these mice will not develop GvHD. 


Discussion: The use of CRISPR-Cas9 edited CAR T-cells in the treatment of B-ALL reveals a new facet to cancer therapeutics. The efficacy of this treatment will be demonstrated through greater tumour shrinkage rates and higher overall response rates than treatment with Blincyto, the current standard treatment drug for B-ALL.


Conclusion: Current treatments involving Blinatumomab or conventional CAR T-cell therapy are expensive and therefore inaccessible to many. These results could demonstrate that CRISPR-Cas9 edited CAR T-cell therapy is viable as a safe, universal and more affordable alternative for relapsed/refractory B-ALL treatment.

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Section
Research Protocol