Risky business: target choice in adoptive cell therapy

Abstract

In this issue of Blood, Casucci et al present an elegant study that describes a potential new target for adoptive cell transfer (ACT), in this case CD44 splice variant 6 (CD44v6), and detail why it may be a good target for ACT and how to manage expected off-tumor/on-target toxicities.

Target antigen types for adoptive cell therapy. T cells can be genetically modified with tumor-targeting receptors (either T-cell receptors or CARs) and administered to patients in adoptive cell therapy trials. The types of tumors and tumor antigens targeted by these modified T cells can have no or significant off-tumor/on-target toxicity dependent on antigen expression. For tumor-specific antigens such as EGFRvIII in glioblastoma (GBM), there will likely be no toxicity due to the lack on antigen expression in normal tissues. Some (but not all) CT antigens have gene expression patterns limited to cancer and the non–MHC-bearing germ cells in the testis (eg, NY-ESO-1 in melanoma). It may be clinically acceptable to target tumor antigens that are expressed in malignancies and nonessential tissues such as the example of CD19, which is expressed in chronic lymphocytic leukemia (CLL) but also in normal B cells. B-cell depletion can be managed by IV immunoglobulin (IVIG) administration. The majority of tumor antigens follow the pattern investigated by Casucci et al, where the CD44v6 antigen is expressed in the tumor (eg, MM) as well as in normal tissues. As a potential method to manage expected monocytopenia, the investigators suggest that a suicide gene could be used to eliminate T cells after the antitumor response is complete.