Hodgkin lymphoma outcomes in the novel agent era, genomic safe harbors for precision T cell engineering, and a transcriptomic atlas to map imatinib resistance in CML
In this week’s episode, we'll discuss how patients with relapsed or refractory Hodgkin lymphoma survival outcomes have improved after development of several novel agents. Next, precision engineering of therapeutic T cells through extragenic safe harbors. Finally, using a single-cell atlas to map features of imatinib resistance in diagnostic CML bone marrow, investigators present gene expression signatures predictive of response to TKI therapy.
Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents
Spinner and colleagues examined outcomes in patients with relapsed classic Hodgkin lymphoma who underwent autologous stem cell transplantation (ASCT) in the modern era (2011-2020) compared to those treated in the prior decade before the availability of brentuximab vedotin and PD-1 inhibitors. The authors found a significant improvement in 4-year overall survival in the modern era: 89.1% vs 79.0%, respectively. In a multivariable analysis, receipt of a PD-1 inhibitor prior to ASCT associates with improved survival while the 4-year survival of patients with recurrent disease after ASCT is improved from 43.3% to 71.4%, most likely related to more effective salvage with these new agents.
Novel extragenic genomic safe harbors for precise therapeutic T-cell engineering
Targeted integration of chimeric antigen receptor (CAR) transgenes in defined genetic locations is anticipated to improve sustained expression and reduce risks associated with conventional gene transfer methods, such as insertional mutagenesis. Using a CRISPR-Cas9–assisted knock-in technique, Odak et al investigated locations in the noncoding genome that provide stable expression of CAR transgenes in human T cells, identifying GSH6 as such a site that can achieve long-term tumor control. The authors’ data expand our ability to engineer potent CAR T-cell products and provide resources for the identification of other extragenic genomic safe harbor locations.
A single-cell atlas identifies pretreatment features of primary imatinib resistance in chronic myeloid leukemia
Krishnan et al describe a single-cell transcriptomic atlas of chronic myeloid leukemia bone marrow at diagnosis. By comparing groups with varying degrees of response or initial treatment failure on imatinib, the authors identified features at diagnosis predictive of response to tyrosine kinase inhibitor (TKI) therapy. These include gene expression signatures within leukemic stem cells and natural killer (NK) cells and a correlation of expansion of a normally rare subset of hyperfunctional adaptive-like NK cells (CD57+NKG2C+) with TKI response. An antibody panel is described to assist future translation of these findings into practice.
Prognostic value of blood biomarkers in steroid-refractory or steroid-dependent acute graft-versus-host disease: a REACH2 analysis
Socié and colleagues report on the prognostic value of 12 biomarkers for predicting treatment response of steroid-refractory and steroid-dependent acute graft-versus-host disease (GVHD) at day 28 to second-line therapy, using data from the randomized trial of ruxolitinib vs best available care. The authors identified ruxolitinib therapy, nonmyeloablative conditioning, skin GVHD, and lower age as associated with increased likelihood of response and utilized cellular and cytokine biomarkers to develop clinically useful predictive models.
DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity
Dedicator of cytokinesis (DOCK) proteins play important roles in actin cytoskeleton regulation, and immune disorders have been described for deficiencies of some DOCK proteins. Boussard et al identify 8 male patients with a new X-linked actinopathy characterized by impaired CDC42 activity, abnormal actin cytoskeleton remodeling of immune cells, and early onset autoimmunity.
