Highlighted research articles

Anti-BCMA bispecific T-cell engager antibodies (BiTE) have demonstrated impressive efficacy in heavily relapsed multiple myeloma patients; however, infections remain a serious concern with these therapies. In this article, Lancman et al. demonstrate that profound and prolonged hypogammaglobulinemia is universal in patients responding to therapy and is a significant driver of infections. Intravenous immunoglobulin (IVIg) replacement mitigates the risk of serious infections ten-fold. The findings support IVIg as a primary prophylaxis throughout the duration of therapy and raise questions about the optimal schedule and duration of BiTE treatment.

See article, p. 440.

The combination of azacytidine with venetoclax has become the standard first-line treatment for patients with acute myeloid leukemia (AML) unable to tolerate chemotherapy. However, there is still unmet need for not only identifying poor-responding patients but also identifying effective therapeutic strategies for them. In this precision medicine proof-of-concept study, Eide, Kurtz et al. implement ex vivo screening of 25 venetoclax-inclusive drug combinations on primary AML patient samples. The findings highlight combinations with superior responses compared to venetoclax + azacytidine, while the various combinations can themselves be grouped according to the AML differentiation gene expression signature most responsive to treatment. Various clinical and molecular features of patients or their samples also associate with ex vivo responsiveness. The findings offer a guide for prioritizing and pursuing individualized combination treatments for AML.

See article, p. 452.

Therapy-resistant leukemia stem and progenitor cells (LSC) are the main cause of disease relapse in acute myeloid leukemia (AML). To develop immunotherapies that could eliminate those residual cells and thus may improve treatment outcome in AML, Nelde et al. characterize the antigenic landscape of primary LSC using a mass spectrometry–based immunopeptidomics approach. The antigens comprise self-peptides as well as mutation-derived and cryptic neoepitopes. Those that are absent on normal tissues while presented by common HLA alleles on both LSC and bulk AML are promising targets for the development of T cell–based immunotherapeutics. A functional role of the identified antigens is suggested by the evidence of the antigen-specific endogenous and induced T-cell responses, and by immunopeptidome diversity correlation with clinical outcomes.

See article, p. 468.