A groundbreaking study presented at the 2025 ESMO Targeted Anticancer Therapies Congress highlights the potential of anti-CD38-CAR γδ T cells in combating multiple myeloma. These specialized immune cells demonstrated significant cytotoxic effects against cancerous cells both in laboratory settings and within animal models. Notably, their activity remained robust even in the presence of CD38 antibody drugs, such as daratumumab and isatuximab. The research also revealed that γδ T cells express lower levels of CD38 compared to conventional alpha-beta T cells, making them less susceptible to interference from therapeutic antibodies. This development could pave the way for an off-the-shelf CAR T-cell therapy that addresses current limitations in cost and scalability.

In recent years, chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape for blood cancers, including multiple myeloma. However, challenges remain regarding the time-consuming and expensive processes involved in creating personalized therapies. To overcome these hurdles, researchers led by Dr. Yuji Hattori focused on utilizing γδ T cells, a unique subset of immune cells capable of targeting malignancies without relying on major histocompatibility complex (MHC) interactions. By isolating and expanding these cells ex vivo before introducing the CAR gene, the team successfully generated potent anti-myeloma agents.

The process began with collecting peripheral blood samples and stimulating γδ T cell proliferation using zoledronate, a compound known for its ability to enhance this specific type of immune cell. Within one week, γδ T cells dominated the viable cell population, demonstrating efficient expansion. Following this, the CAR gene was introduced via retroviral transduction after four days of activation. Cytometry analysis confirmed successful CAR expression through antibodies targeting the G4S linker.

To evaluate functionality, the engineered γδ T cells were co-cultured with multiple myeloma cell lines, showing effective destruction capabilities. Subsequent experiments involved pre-incubation of tumor cells with daratumumab and isatuximab, confirming the cells' efficacy even when exposed to competing antibody treatments. These findings underscored the resilience and potency of anti-CD38-CAR γδ T cells.

Further validation came from in vivo studies conducted on immunodeficient mice models. Tumor progression was monitored using imaging techniques, revealing substantial reductions following intravenous administration of the modified γδ T cells. These results highlight the potential of γδ T cells to serve as a universal, ready-to-use therapy option for multiple myeloma patients, addressing unmet needs in terms of affordability and accessibility.

Dr. Hattori's work represents a critical step forward in advancing CAR T-cell therapy toward more practical applications. By harnessing the unique properties of γδ T cells, the research offers hope for developing scalable solutions that maintain high therapeutic efficacy while reducing costs associated with traditional methods. Future investigations will focus on refining these techniques and exploring broader clinical implications across various hematologic malignancies.