Harnessing ALLO-819: Off-Switch Enabled Allogeneic CAR T Therapy for Acute Myeloid Leukemia

Individuals battling relapsed acute myeloid leukemia face a grim outlook with few therapeutic avenues. CAR T cell technology has shown remarkable success in treating blood cancers, offering long-lasting remissions to patients who have undergone extensive prior treatments. The exploration of T cell-based immunotherapies that target AML cells is a promising field, with the potential for curing the disease. However, creating personalized CAR T therapies for AML poses logistical hurdles and clinical challenges due to the rapid progression of the disease and the difficulty in obtaining a sufficient quantity of healthy T cells from AML patients. An off-the-shelf CAR T cell product could be advantageous in such cases.

The study described involves a preclinical assessment of ALLO-819, an allogenic CAR T therapy that targets the Flt3 receptor tyrosine kinase, a prevalent AML marker with minimal expression outside of blood-forming tissues. A Flt3 CAR was engineered using a range of high-affinity, fully-human antibodies identified through phage display technology. These antibodies were incorporated into CAR constructs to redirect T cells towards AML cells, with a focus on minimizing unwanted signaling and enhancing antitumor capabilities. The lead CAR was further modified to include a safety mechanism that could be activated by rituximab, an FDA-approved antibody, to control CAR T cell activity.

The allogenic ALLO-819 Flt3 CAR T cells were designed to mitigate the risk of graft-versus-host disease and to be resistant to lysis by anti-CD52 antibodies, using gene-editing techniques to disrupt specific genetic loci. These cells demonstrated target-specific activation and potent antitumor effects when co-cultured with AML cells.

While Flt3 expression was detected on some normal hematopoietic stem and progenitor cells, which were susceptible to CAR T cell cytotoxicity, the off-tumor effects were limited and associated with antitumor efficacy. The administration of rituximab effectively depleted CAR T cells, allowing for the rapid recovery of normal stem cells.

The findings of the study endorse the potential of ALLO-819 Flt3 CAR T as an innovative treatment for AML. The disclosures section lists affiliations and interests of the authors, including employment, equity ownership, and patents related to Allogene Therapeutics, Pfizer Inc., and Cellectis Inc.