Postvaccine Anti-CD20 Does Not Abrogate Vaccine Responses
See article, p. 95.
Shree et al. find that up to a year after anti-CD20 treatment, most patients with lymphoma do not generate neutralizing antibody responses to COVID-19 vaccination. However, if patients are vaccinated and mount an antibody response prior to anti-CD20 treatment, they tend to maintain these antibody responses through subsequent anti-CD20 lymphoma therapy, suggesting a strategy of vaccinating first and treating later. These results also call to weigh the risks of maintenance therapy with rituximab or other B cell–depleting antibodies during the COVID-19 era.
Aberrant Splicing of CD22 Impairs Responses to Immunotherapy in B-ALL
See article, p. 103.
Downregulation of surface epitopes, including CD22, causes postimmunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Zheng et al. report that CD22 mRNA is pervasively misspliced in B-ALL cell lines and primary samples. Some misspliced isoforms still encode plasma membrane–bound CD22 variants, while others lack the start codon in exon 2 and are noncoding. These exon 2–skipping isoforms are prevalent in high-risk B-ALL patients treated with the CD22-directed antibody–drug conjugate inotuzumab, where they correlate with low CD22 surface expression and are likely to account for treatment failure in two cases. Thus, aberrant CD22 splicing is an important mechanism of resistance to immunotherapy.
BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming in Leukemia
See article, p. 116.
Polycomb repressive epigenetic complexes are recurrently dysregulated in cancer. The mechanisms by which genetic alterations affect polycomb regulatory function to drive oncogenesis are poorly understood. By combining human genomics with biochemical and functional approaches, Schaefer et al. demonstrate that highly recurrent mutations in leukemia of the PRC1.1 subunits BCOR and BCORL1 dissociate DNA binding from enzymatic subunits. Uncoupling of the PRC1.1-repressive function from target genes alters epigenetic and signaling states, including FGFR derepression. BCOR deletion or truncation confers ibrutinib resistance, which is abrogated by FGFR inhibition. This epigenetic mechanism explains PRC1.1 tumor-suppressive activity and informs therapeutic approaches in PRC1.1-mutated cancer.
IFNγ Is Not Required for CAR-T Efficacy against Hematologic Malignancies
See article, p. 136.
IFNγ production has long been considered necessary for antitumor T-cell response. IFNγ also fuels macrophage activation in cytokine release syndrome (CRS), a significant toxicity of chimeric antigen receptor (CAR) T-cell therapy. Bailey et al. have discovered that either blockade or genetic knockout of IFNγ does not impair the anticancer activity of CAR T cells in preclinical models of hematologic malignancies. Further, there is reduced expression of immune checkpoint receptors on the CAR T cells and less activation of macrophages. Thus, it may be possible to separate the toxicity from the efficacy of CAR T cells for safer yet effective use.
Targeting Epigenetic Silencing to Restore Arrested Development in ENKTL
See article, p. 154.
Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with very poor clinical outcomes. Mundy-Bosse et al. demonstrate that ENKTL cells are arrested at early stages of NK-cell maturation, characterized by broad epigenetic silencing of genes involved in normal NK-cell development. Treatment with the DNA hypomethylating agent 5-azacytidine led to a reduction of DNA hypermethylation, reexpression of normal NK-cell developmental genes, phenotypic NK-cell differentiation, and significant prolongation of survival in recipient mice. These studies lay the foundation for epigenetic-directed therapy targeting the developmental blockade in ENKTL.