Harnessing the Power of ALLO-819: A Breakthrough Allogeneic Flt3 CAR T-Cell Therapy with an Intrinsic Off-Switch for Acute Myeloid Leukemia Management

Individuals with recurring acute myeloid leukemia (AML) face a grim outlook and have scant therapeutic choices. CAR T cells, which are engineered to target cancer cells, have shown remarkable success in treating blood cancers, providing long-term remissions for patients who have undergone extensive prior treatments. The use of T cells to combat AML is a promising strategy with the potential for a cure. However, creating personalized CAR T therapies for AML is challenging due to the rapid progression of the disease and the time required to produce the cells. Additionally, it can be difficult to collect enough healthy T cells from AML patients. Therefore, the development of a readily available CAR T product is advantageous.

The study focuses on the preclinical assessment of ALLO-819, an allogeneic CAR T therapy aimed at Flt3 (CD135), a receptor tyrosine kinase that is a common target in AML and is not extensively expressed in tissues outside of the blood-forming system. A Flt3 CAR was created using a range of high-affinity, fully-human antibodies obtained through phage display technology. These antibodies were tested for their ability to direct T cells towards AML cells. The most effective CAR was selected and modified to include a safety feature that allows for the destruction of the CAR T cells in the presence of the drug rituximab.

The modified CAR T cells were designed to minimize the risk of graft-versus-host disease and to be resistant to lysis by anti-CD52 antibodies. This was achieved through gene-editing techniques that disrupted specific genetic loci in the T cells. The resulting ALLO-819 Flt3 CAR T cells showed activation, cytokine production, and cytotoxic activity against AML cells in laboratory tests.

Although Flt3 is also present on some normal blood stem cells, the study found that the off-tumor effects of the CAR T cells were limited and associated with antitumor efficacy. The use of rituximab effectively removed the CAR T cells from the bloodstream, allowing for the rapid recovery of normal blood stem cells.

In conclusion, the findings support the potential of ALLO-819 Flt3 CAR T as an innovative treatment for AML.