DNA hypomethylating agents potentiate the efficacy of CD3 bispecific T cell engagers [scATAC-seq]

Bispecific T cell engagers targeting tumor-associated antigens and CD3 are promising novel targeted therapeutic agents for both solid and hematologic cancers. However, prolonged TCR stimulation can lead to chromatin rewiring and T cell dysfunction. Here, we investigate the combination of bispecific T cell engagers with the DNA hypomethylating agent decitabine and observe suppressed tumor growth in preclinical models. Utilizing the PSMAxCD3 bispecific antibody for the treatment of prostate carcinoma and in vivo humanized models, we catalog, at the single-cell level, the dynamics of T cell epigenetic states during bispecific therapy, and in combination with decitabine. Importantly, this combination preserves a progenitor exhausted T cell population and delays acquisition of a dysfunctional state, at both chromatin and protein levels. At the DNA methylation level, TCR stimulation in the presence of decitabine maintains a naive-like pattern in gene loci associated with T cell stemness. This study provides a rich resource for understanding the evolution of T cell states during immunotherapy and mechanistic support for combining epigenetic modifiers with bispecific T cell engagers in the clinic.