Development of cord-blood derived CAR-NK cells with the expression of the Interleukin-15 for the treatment of Multiple Myeloma.

• Grant number: 24/18226-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Nelson Hamerschlak
• Grantee: Thiago Giove Mitsugi
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Multiple myeloma is a neoplasm of plasmocyte cells with an incidence starting from age 60. Despite advances in the treatment of multiple myeloma, it remains an incurable disease. CAR-T cells have achieved great success in the treatment of hematological neoplasms, reaching results that represent a potential cure for relapsed and refractory patients. However, a portion of patients does not achieve deep and lasting responses. Additionally, the autologous application of CAR-T cells currently faces logistical, financial, and clinical challenges. NK cell therapies, on the other hand, demonstrate the potential to simplify logistics, reduce costs, and facilitate clinical application due to the possibility of allogeneic and off-the-shelf use. CAR-NK cells have the ability to direct anti-tumor responses through the CAR receptor. In this project, we propose to develop CAR-NK cells against a well-established target for the treatment of multiple myeloma, BCMA, as well as to develop new chimeric receptors against a new target present in multiple myeloma cells. We will also perform gene editing-using CRISPR-Cas9-of NK cells to assess whether deleting an inhibitory gene of effector immune cells can enhance the anti-tumor capacity of CAR-NK cells. To this end, we will produce CAR-NK cells, with and without CRISPR-Cas9 editing, and evaluate their potential to recognize and eliminate multiple myeloma cells in vitro. Finally, we will investigate the efficacy and safety of this potential treatment in vivo in a murine xenograft model of multiple myeloma. (AU)