Pan-B-Lineage Targeting with Adapter CAR-T Cells Controls Antigen-Heterogeneous Lymphoma

In a significant breakthrough for B-lineage malignancies, researchers have developed a novel approach called Adapter CAR-T cells (AdCAR-T) to overcome the challenges posed by antigen heterogeneity and antigen-negative relapse. This research builds upon the previously successful AdCAR-T platform that allowed for the redirection of engineered T cells to various surface antigens using biotinylated adapter molecules (AMs).

The study showcased the effectiveness of generating AMs from three different sources: an in-house-produced tafasitamab biosimilar targeting CD19, commercial rituximab targeting CD20, and an in-house-produced daratumumab biosimilar targeting CD38. These AMs demonstrated potent, antigen-specific cytotoxicity when used individually.

However, the researchers found that when simultaneously targeting CD19, CD20, and CD38, it effectively controlled a defined heterogeneous Burkitt lymphoma model in vitro and induced sustained tumor control in vivo.

The key advantage of this pan-B-lineage strategy lies in its ability to select for antigen-negative tumor populations while preventing the development of antigen-negative relapse. The researchers observed selective loss of the CD38+ AdCAR-T cell population after exposure to CD38-directed AMs, a phenomenon known as fratricide. Despite this, the surviving CD38low population retained its cytotoxic activity, ensuring the overall effectiveness of the treatment.

These findings pave the way for the development of antibody-derived AM combinations tailored for B-cell malignancies, offering a promising pan-B-lineage approach to tackle pre-existing antigen heterogeneity in these aggressive cancers.