TET2, tumor control, and CAR T cell hyperproliferation

Abstract

A recent study by Jain et al. published in Nature followed up on evidence suggesting that depletion of 5-methylcytosine dioxygenase TET2 in chimeric antigen receptor CAR T cells could enhance their expansion, persistence, and antitumor efficacy. Their findings are cautionary, but offer hope of a path forward.

Keywords: CAR; T cell; TET2; clonal; hyperproliferation; lymphocyte.

Figure 1.. The discussed instances of human CAR T cells with impaired or no TET2 function.

(Upper panel) Timeline of treatment and response in CLL Patient-10 [1]. A first infusion of CD19-specific CAR T cells elicited partial regression of the leukemia, followed by renewed tumor growth. A second infusion initially stabilized tumor size without causing regression. Several weeks after the second infusion, a single CAR T cell clone with diminished TET2 function expanded rapidly, cleared the tumor, and then contracted in numbers leaving behind memory CAR T cells. The precise level of residual TET2 enzymatic activity in the expanded clone was not determined, and whether TET2 nonenzymatic functions were impaired is unknown. (Lower panel) Timeline of treatment, response, and late CAR T cell hyperproliferation in a mouse model that tested TET2-deficient human CAR T cells [4]. Human NALM6 leukemia cells were implanted into an immunodeficient NSG mouse, followed by adoptive transfer of CD19-specific human CAR T cells. In the condition depicted, the T cell TET2 locus had been subjected to CRISPR–Cas9 editing that rendered a substantial fraction of the T cells TET2-deficient. CAR T cells at a sufficient dose rapidly cleared the tumor. However, many weeks later, some CAR T cell clones deficient in both TET2 alleles proliferated extensively, effectively replacing the original leukemia with a CAR T cell-based disease. Abbreviations: CAR T cells, chimeric antigen receptor T cells; CLL, chronic lymphocytic leukemia; NALM6, human B cell acute lymphocytic leukemia cell line; NSG mouse, NOD/SCID/IL2Rγ^null mouse.