82. Blood Gene Expression Profiles in Neonates with Herpes Simplex Virus (HSV) Infection

Abstract Background Neonatal HSV infection is associated with significant morbidity and mortality. Neonates with HSV infection can present with skin, eye, and mouth (SEM), central nervous system disease (CNS), and disseminated disease (DIS). We hypothesize that host immune responses may contribute to differences in disease presentation and outcomes. To address this knowledge gap, we analyzed host transcriptional immune profiles of neonates with HSV infection. Methods Infants < 6 weeks of age (24 (86%) < 4 weeks; 4 (14%) 4-6 weeks old) with neonatal HSV, and healthy infant controls (HC) were enrolled at Children’s Medical Center (Dallas, TX), and Nationwide Children’s Hospital (Columbus, OH) from 2007-2018. Whole blood samples were analyzed by RNA-seq. Modular analyses were performed to identify the immune pathways that were activated or suppressed according to each HSV disease category. Results Of the 28 infants with HSV infection, 9 had SEM (median [IQR] age: 14 [14-28] days), 10 CNS (age: 18 [15-29] days), and 9 DIS (age: 10 [7-10] days). Three infants with DIS died within 5 days of diagnosis. Statistical group comparisons between 13 HC and 18 infants with HSV disease (training set) identified 1,322 differentially expressed genes (neonatal HSV biosignature). This biosignature was validated in the remaining 10 infants with HSV disease (test set), and was characterized by significant overexpression of interferon (INF), inflammation, neutrophils, and monocyte genes and under-expression of T-cell genes. Further analysis according to HSV disease category confirmed overexpression of neutrophil and inflammation genes in infants with SEM, CNS and DIS (Fig 1). On the other hand, overexpression of INF and plasma cell genes, and further suppression of monocytes, cytotoxic/NK cells, and T-cell genes were only evident in children with DIS. Fig 1: Modular immune pathways according to HSV disease category Modules are groups of genes that shared a similar function. Each dot represents a transcriptional module with red indicating overexpression and blue underexpression in relation to healthy controls. The number and color intensity on the dot indicate the percentage of differentially expressed transcripts within a module. SEM: skin, eye mouth; CNS: central nervous system; DIS: disseminated HSV disease. Conclusion Transcriptional profiles of infants with HSV infection exhibited marked activation of the innate immune response irrespective of disease classification. Children with DIS showed more profound dysregulation and suppression of cellular immune responses. Transcriptional profiling may aid unravel mechanisms associated with clinical outcomes in neonatal HSV and inform future therapeutic and preventive strategies. Disclosures Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

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1104. Risk Factors and Outcomes of Refractory and/or Resistant Cytomegalovirus (CMV) Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1290 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S582-S583

Author(s):

Eleni Karantoni ◽

Yiqi Su ◽

Anat Stern ◽

Phaedon D Zavras ◽

Sergio Giralt ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

T Cell ◽

Panel Member ◽

Multivariable Model ◽

Research Support ◽

Review Panel ◽

Material Support ◽

Advisory Boards ◽

Research Grant

Abstract Background The epidemiology of CMV end-organ disease (EOD) after Hematopoietic Cell Transplant (HCT) in the era of preemptive therapy (PET) is defined. In contrast, less data exists on refractory and/or resistant (R/R) CMV. We report on 1) the incidence; 2) risk factors and outcomes of R/R CMV by 1-year post HCT. Methods Retrospective review of 167 CMV seropositive (R+) recipients of first marrow or peripheral blood HCT from 1/2014 - 12/2017 managed by PET. Refractory CMV was defined as failure to achieve >1 log10 decrease in CMV viral load (VL) and having VL >1,000 IU/mL after ≥14 day of PET. Resistant CMV required genotypic confirmation of resistance mutation(s) in UL54 and/or UL97 genes. End organ disease (EOD) was defined by standard criteria. Patients (pts) were followed through 1-year post HCT and were categorized in two mutually exclusive groups as R/R and no R/R. Demographics, clinical characteristics and outcomes were extracted from medical records and hospital databases. Univariable and multivariable logistic models were used to identify risk factors for R/R CMV. Results Of 167 PET recipients, 91 (54.5%) received ex vivo T cell depleted (TCD) HCT; 40 (24.0%) had mismatched donor; and 26 (15.6%) had multiple myeloma. 66/167 (39.5%) pts developed refractory CMV (6 pts also had resistant CMV). Time from HCT to CMV viremia was shorter in R/R group: median (IQR) 21.5 (17.2-27.8) days compared to no R/R group: 26 (19-32) days (p=0.031). Maximum VL was higher for R/R compared to no R/R: median (IQR) 9,118 (2,849-18,456) and 868 (474-1,908), respectively (p< 0.001). In multivariable model, risk factors for R/R included TCD HCT (p< 0.0001) and higher VL at PET initiation (p=0.0002). In contrast, CMV seropositive donor (p=0.035) was protective (Figure 1). CMV EOD developed in 28.2% of R/R and 16.2% of no R/R groups (p=0.085) (Figure 2). Overall survival at 1 year was 59.1% for R/R compared to 83.1% for no R/R group (p=0.00027) (Figure 3). Figure 1. Adjusted odds ratio (OR) and 95% confidence interval (CI) from multivariable model evaluating risk factors of refractory/resistant (R/R) CMV. Figure 2. Cumulative incidence curves of CMV end-organ disease (EOD) at 1-year post HCT Figure 3. Kaplan-Meier survival curves of overall survival (OS) at 1-year post HCT Conclusion 1) Refractory and/or resistant CMV occurred in 39,5% of PET recipients. 2) T-cell depletion and higher CMV VL at PET initiation were risk factors for R/R CMV in multivariable models. 3) R/R CMV was associated with more EOD and worse overall survival. Disclosures Sergio Giralt, MD, Amgen (Advisor or Review Panel member, Research Grant or Support, Served an advisory board for Amgen, Actinuum, Celgene, Johnson & Johnson, JAZZ pharmaceutical, Takeda, Novartis, KITE, and Spectrum pharma and has received research support from Amgen, Actinuum, Celgene, Johnson & Johnson, and Miltenyi, Takeda.) Miguel-Angel Perales, MD, Abbvie (Other Financial or Material Support, Honoraria from Abbvie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda.)ASTCT (Other Financial or Material Support, Volunteer member of the Board of Directors of American Society for Transplantation and Cellular Therapy (ASTCT), Be The Match (National Marrow Donor Program, NMDP), and the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Committee)Cidara Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Serve on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune.)Kite/Gilead (Research Grant or Support, Other Financial or Material Support, Received research support for clinical trials from Incyte, Kite/Gilead and Miltenyi Biotec.) Genovefa Papanicolaou, MD, Chimerix (Research Grant or Support)Merck&Co (Research Grant or Support, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas)

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194. Combinatorial Polyfunctionality Analysis of Antigen-specific T-cell Subsets (COMPASS) as a Predictor for Clinically Significant CMV Infection in the Letermovir Era

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.504 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S225-S226

Author(s):

Danniel Zamora ◽

Elizabeth Duke ◽

Hu Xie ◽

Bradley Edmison ◽

Brenda Akoto ◽

...

Keyword(s):

T Cell ◽

Panel Member ◽

T Cell Responses ◽

Preemptive Therapy ◽

Cmv Infection ◽

Research Support ◽

Review Panel ◽

Cell Responses ◽

Cytokine Responses ◽

Clinically Significant

Abstract Background Increased CMV reactivation is observed following discontinuation of letermovir prophylaxis after hematopoietic cellular transplantation (HCT) and decreased CMV-specific polyfunctional T-cell immunity has been proposed as a possible mechanism (BBMT 2020;26:S68). COMPASS is a novel analytical tool that integrates polyfunctional T-cell cytokine responses into a single score value (Nat Biotechnol 2015;33:610). We employed COMPASS for the first time in the HCT setting to determine if CMV-specific immunodeficiency is associated with late CMV events in a prospective cohort of allogeneic HCT recipients receiving either letermovir or preemptive therapy. Methods Peripheral blood mononuclear cells were collected 3 months post-HCT and assessed with a 13-color intracellular cytokine staining (ICS) assay that includes 5 functional markers. Intermediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) were used to stimulate polyfunctional T-cell responses that were defined using COMPASS generated polyfunctionality scores (PFS). CMV DNAemia was monitored by weekly plasma PCR and patients who reactivated were treated with preemptive therapy per institutional standards. Cumulative incidence of clinically significant CMV infection (cs-CMV; ≥500 IU/mL or CMV disease) by day 270 was assessed. Univariable and multivariable Cox regression were used to estimate the association of polyfunctional T-cell responses (upper quartile versus lower 3 quartiles) with cs-CMV infection by day 270 post-HCT. Results 56 letermovir recipients and 93 preemptive controls were evaluated. Time to first clinically significant CMV (cs-CMV) infection after HCT and among day 100 survivors in both groups is shown in Figure 1. COMPASS PFS at 3 months were significantly lower in letermovir recipients (Figure 2). After adjusting for CMV infection before day 100, CD4 and CD8 PFS to IE-1 and pp65 below the upper quartile were associated with higher risk of late cs-CMV infection, with IE-1 CD8 PFS reaching statistical significance (Figure 3). Conclusion Our findings demonstrate that COMPASS is a valuable tool to evaluate multiple, T-cell cytokine responses to CMV in HCT recipients. COMPASS appears to be useful to identify patients at risk for late cs-CMV infection. Disclosures Elizabeth Duke, MD, Merck (Grant/Research Support) Michael Boeckh, MD PhD, AlloVir (Consultant)EvrysBio (Advisor or Review Panel member, Other Financial or Material Support, share options)Gilead (Consultant, Grant/Research Support)GSK (Consultant)Helocyte (Advisor or Review Panel member, Shareholder)Lophius (Grant/Research Support)Merck (Consultant, Grant/Research Support)SymBio (Consultant)VirBio (Consultant, Grant/Research Support)

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Dendritic Cells Amplify T Cell-Mediated Immune Responses in the Central Nervous System

The Journal of Immunology ◽

10.4049/jimmunol.177.11.7750 ◽

2006 ◽

Vol 177 (11) ◽

pp. 7750-7760 ◽

Cited By ~ 30

Author(s):

Jozsef Karman ◽

Hamlet H. Chu ◽

Dominic O. Co ◽

Christine M. Seroogy ◽

Matyas Sandor ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

The Central Nervous System

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196. Antibodies to Vaccine-preventable Infections After CAR-T Cell Immunotherapy for B Cell Malignancies

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.506 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S226-S227

Author(s):

Carla S Walti ◽

Joyce Maalouf ◽

Jim Boonyaratanakornkit ◽

Jacob Keane-Candib ◽

Justin J Taylor ◽

...

Keyword(s):

T Cell ◽

Stock Options ◽

Panel Member ◽

Research Support ◽

Review Panel ◽

T Cell Therapy ◽

Material Support ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Background Chimeric antigen receptor-modified T (CAR-T) cell immunotherapy for B cell hematologic malignancies results in prolonged B cell depletion. Little is known about the effects of CAR-T cell therapy on pre-existing pathogen-specific humoral immunity. Methods We conducted a prospective, cross-sectional study of children and adults treated with CD19- or BCMA-CAR-T cell therapy. Eligible patients were ≥ 6 months post-CAR-T cell infusion and in remission without subsequent chemoimmunotherapy. We measured total immunoglobulin G (IgG), pathogen-specific IgG levels for 12 vaccine-preventable infections, and B cell subsets from blood. Seroprotective antibody titers were based on standard thresholds. We described the proportion of patients with seroprotective titers and tested for associations between clinical factors and seroprotection using generalized estimating equations. Results We enrolled 65 patients who received CD19- (n=54) or BCMA- (n=11) CAR-T cell therapy. Seven patients were < 18 years old. Samples were collected a median of 20 months (range, 7–68) after CAR T cell infusion. Seroprotection to vaccine-preventable pathogens was generally comparable to the U.S. population (Fig 1) even though blood CD19+ B cell counts were low (< 20 cells/mm3) in 60% of patients. Among 30 patients without IgG replacement in the prior 16 weeks (4 half-lives of IgG), 27 (90%) had hypogammaglobulinemia. Despite this, these individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested pathogens (Fig 2A). The proportion of patients with seroprotection was lowest for mumps, hepatitis A and B, H. influenzae type B (Hib), S. pneumoniae, and B. pertussis. Patients receiving BCMA-CAR-T cells had seroprotection to fewer pathogens than those receiving CD19-CAR-T cells (Fig 2B), but the difference did not reach statistical significance (Fig 3). There were no significant differences by other variables. Figure 1. Proportion of CAR-T cell recipients with seroprotection to vaccine-preventable infections compared to the U.S. population, stratified by receipt of IgG replacement in the previous 16 weeks. Figure 2 A-B. Percentage of pathogens with seroprotective antibody titers among patients without IgG replacement in the previous 16 weeks. Figure 3. Association of clinical factors with seroprotection to vaccine-preventable infections among patients without IgG replacement in the previous 16 weeks (n=30) Conclusion Seroprotection for vaccine-preventable infections after CD19-CAR-T cell therapy was comparable to the general population. BCMA-CAR-T cell recipients may benefit most from replacement IgG. Vaccinations after CAR-T cell therapy should be considered and prioritized for S. pneumoniae, Hib, hepatitis viruses, and B. pertussis. Disclosures Justin J. Taylor, PhD, Vir Biotechnology (Grant/Research Support) Damian J. Green, MD, Cellectar Biosciences (Grant/Research Support)GSK (Advisor or Review Panel member)Juno Therapeutics (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Royalities)Seattle Genetics (Grant/Research Support, Advisor or Review Panel member) Michael Boeckh, MD PhD, AlloVir (Consultant)EvrysBio (Advisor or Review Panel member, Other Financial or Material Support, share options)Gilead (Consultant, Grant/Research Support)GSK (Consultant)Helocyte (Advisor or Review Panel member, Shareholder)Lophius (Grant/Research Support)Merck (Consultant, Grant/Research Support)SymBio (Consultant)VirBio (Consultant, Grant/Research Support) David G. Maloney, MD, PhD, A2 Biotherapeutics (Consultant, Other Financial or Material Support, Stock Options)Bioline Rx (Consultant)Celgene (Consultant, Grant/Research Support)Gilead (Consultant)Juno Therapeutics (Consultant, Research Grant or Support, Other Financial or Material Support, four pending patents, not issued, licensed, no royalities, no licensees)Kite Pharma (Consultant, Grant/Research Support)Novartis (Consultant)Pharmacyclics (Consultant) Cameron J. Turtle, MBBS, PhD, Allogene (Other Financial or Material Support, Ad hoc advisory board (last 12 months))ArsenalBio (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)AstraZeneca (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))Caribou Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Century Therapeutics (Advisor or Review Panel member)Eureka Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Juno Therapeutics (Grant/Research Support, Other Financial or Material Support, Patent: Licensed to Juno Therapeutics)Myeloid Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Nektar Therapeutics (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))PACT Pharma (Other Financial or Material Support, Ad hoc advisory board (last 12 months))Precision Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)TCR2 Therapeutics (Grant/Research Support)T-CURX (Advisor or Review Panel member) Joshua A. Hill, MD, Allogene (Consultant)Allovir (Consultant)Gilead (Consultant)Karius (Grant/Research Support, Scientific Research Study Investigator)Takeda (Grant/Research Support, Scientific Research Study Investigator)

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