Highlighted Research Articles

Srinagesh and colleagues describe clinical and biologic features of immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), a frequently lethal complication of chimeric antigen receptor (CAR) T-cell therapy. IEC-HS occurred in 19 of 54 patients treated with CD22-directed CAR T-cell therapy for B-cell leukemia or lymphoma. IEC-HS was associated with high rates of non-relapse mortality and lower rates of progressive cancer. CAR T-cell expansion in peripheral blood preceded IEC-HS. A cytokine signature primarily driven by IFN-γ, IL-10, and IL-1Ra was associated with severe IEC-HS. Their findings suggest CAR T-cell proliferation and multiple dysregulated cytokine networks are associated with IEC-HS.See article, p. 225.To expand salvage therapy options after BCMA-targeted treatments, Lin and colleagues characterize CD70-targeting approaches. They show in two multiple myeloma (MM) cohorts that CD70 is highly and uniformly expressed on myeloma cells, particularly in high-risk and t(4;14) cases. The authors generated CD70-targeting CAR-NK cells by engineering chimeric antigen receptor (CAR)-expressing CD27 (CD70 ligand) and IL-15. CAR27/IL-15-NK cells exert anti-myeloma activity in vitro and in vivo comparable to CAR27/IL-15 CAR T cells. The efficacy is on par with anti–B-cell maturation antigen (BCMA) CAR and is advantageous in the model of BCMA-negative relapse. These findings support CD70’s potential as an immunotherapy target for high-risk MM and patients who relapse after BCMA-directed therapy.See article, p. 234.Anilkumar Sithara and colleagues dissect the immune cell states and composition of extramedullary multiple myeloma (EMM), an aggressive stage of myeloma associated with increased treatment-resistance. Using single-cell RNA-sequencing, flow cytometry, and spatial transcriptomics, they show that T and NK cells are prevalent in the EMM microenvironment, but with a reduced effector-to-tumor cell ratio, compared with bone marrow counterparts. EMM lesions are enriched for regulatory-phenotype CD16- NK cells and, in some cases, CD8+ T cells with a neoantigen-reactive gene signature, accompanied by increased immune checkpoint expression, suggesting a distinct immune state in extramedullary disease.See article, p. 250.Ohlstrom and colleagues map how multiple myeloma (MM) and immune cell states co-evolve in the bone marrow throughout disease course. By multi-omic profiling of 243 longitudinal samples from 102 patients with MM at diagnosis, and before and after autologous transplantation (ASCT), they characterize signaling cross-talk between T cells and myeloid cells during post-transplant immune recovery. Naive B-cell reconstitution and immunoglobulin diversity were associated with durable remission. At progression, MM upregulated cancer-testis antigens and immunosuppressive cytokines. Immunophenotypic correlates of relapse were T-cell exhaustion, myeloid-derived suppressor cells, and low B-cell abundance. These findings of early indicators of relapse highlight potential targets for therapeutic intervention.See article, p. 266.TET2-mutant (TET2-m) clonal hematopoiesis (CH) is common in humans. Murine Tet2-m hematopoietic stem/progenitor cells (HSPC) display clonal advantage, but paradoxically, human HSPCs don’t. This study reveals a lineage-dependent differential effect of lipopolysaccharide (LPS)-driven inflammation on TET2-m hematopoiesis. Using state-of-the-art in vivo imaging and cultures of primary gene-edited human HSPCs, Encabo and colleagues find that LPS elicits exacerbated pro-inflammatory cytokine production and expansion of TET2-m myeloid cells as compared to the wild-type, whereas TET2-m HSPCs are hyporesponsive. Single-cell multi-omic profiling points to altered AP-1 transcriptional network as a plausible mediator of these differential responses.See article, p. 287.Fetal gene expression signatures in pediatric cancers are commonly attributed to a developmental maturation block resulting from their prenatal origin. Hartmann and colleagues tested this hypothesis by reconstructing hematopoietic ontogeny of juvenile myelomonocytic leukemia (JMML). Transcriptional profiling of JMML clinical samples suggests that leukemic stem cells undergo postnatal developmental maturation and then reactivate fetal-like gene expression, termed oncofetal reprogramming (OFP). Postnatal induction of a RAS-activating mutation recapitulates OFP in mice. Integrative multi-omic analysis identified high CD52 expression as a feature distinguishing high-risk JMML stem cells from their normal counterparts. CD52 targeting by alemtuzumab eliminated JMML propagation in xenografts.See article, p. 306.