Comprehensive viromewide antibody responses by systematic epitope scanning after hematopoietic cell transplantation

Abstract

K E Y P O I N T S l VirScan highlights both donor and recipient contributions to the viral antibody repertoire, and acquisition of new viral epitopes after HCT. l Age, CMV serostatus, and receipt of glucocorticoids correlate with recognition of viral epitopes after HCT.Further insight into humoral viral immunity after hematopoietic cell transplantation (HCT) could have potential impact on donor selection or monitoring of patients. Currently, estimation of humoral immune recovery is inferred from lymphocyte counts or immunoglobulin levels and does not address vulnerability to specific viral infections. We interrogated the viral antibody repertoire before and after HCT using a novel serosurvey (VirScan) that detects immunoglobulin G responses to 206 viruses. We performed VirScan on cryopreserved serum from pre-HCT and 30, 100, and 365 days after myeloablative HCT from 37 donor-recipient pairs. We applied ecologic metrics (a-and b-diversity) and evaluated predictors of metrics and changes over time. Donor age and donor/recipient cytomegalovirus (CMV) serostatus and receipt systemic glucocorticoids were most strongly associated with VirScan metrics at day 100. Other clinical characteristics, including pre-HCT treatment and conditioning, did not affect antiviral repertoire metrics. The recipient repertoire was most similar (pairwise b-diversity) to that of donor at day 100, but more similar to pre-HCT self by day 365. Gain or loss of epitopes to common viruses over the year post-HCT differed by donor and recipient pre-HCT serostatus, with highest gains in naive donors to seropositive recipients for several human herpesviruses and adenoviruses. We used VirScan to highlight contributions of donor and recipient to antiviral humoral immunity and evaluate longitudinal changes. This work builds a foundation to test whether such systematic profiling could serve as a biomarker of immune reconstitution, predict clinical events after HCT, or help refine selection of optimal donors. (Blood.

Durable preservation of antiviral antibodies after CD19-directed chimeric antigen receptor T-cell immunotherapy

“…We leveraged the VirScan assay to obtain a comprehensive understanding of the impact of CD19-CARTx on the antivirome. VirScan has high sensitivity and specificity for a range of viruses, 39,40,47 but its performance for all viruses and correlation with clinical outcomes are unknown. Additionally, VirScan does not detect IgG to certain viruses and is nonquantitative except in the breadth of detected epitopes.…”

“…We used a novel systematic viral epitope scanning method (VirScan) to perform a comprehensive serosurvey for IgG to viruses, as previously described. 39,40 VirScan combines DNA microarray synthesis and bacteriophage display to create a synthetic representation of peptide epitopes covering .1000 strains of 206 viruses. We determined the number of unique viruses to which IgG was directed above a predefined seropositivity threshold and the number of viral epitopes recognized by IgG for these viruses (supplemental Methods).…”

Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

“…In an effort to search for better responses to CAR T-cell therapy, multiple studies have investigated combinations of CAR with ibrutinib or anti-PD-1. For example, 22 patients with CLL who had received ibrutinib as a prior therapy received BBz CARs, which resulted in CR in 45.5% [ 83 ]. Improved responses may be the result of enhanced T-cell engraftment and CAR T-cell generation, both of which correlated with clinical response [ 84 ].…”

Targeting the tumor microenvironment in chronic lymphocytic leukemia

“… 89 Due to the multitude of (successful) treatment options for CLL currently, CAR T-cell therapy may first become a relevant option in treating multi-relapsed disease, and preliminary reports from current clinical trials of CD19-targeted CAR T-cell therapy in patients with multi-relapsed CLL show somewhat encouraging results. 90 However, paradoxically, Tcell exhaustion in CLL is demonstrated to worsen with progressive disease, 13 thus pointing towards a need for options that improve T-cell function prior to the manufacture of CAR T cells or during treatment. Furthermore, it was recently elucidated that CLL cells can directly impair CAR T-cell function and induce an exhausted phenotype through the release of plasma extracellular vesicles.…”