6 results on '"Lingaraju, Chetan Raj"'
Search Results
2. Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial.
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Aldoss, Ibrahim, La Rosa, Corinna, Baden, Lindsey R., Longmate, Jeffrey, Ariza-Heredia, Ella J., Rida, Wasima N., Lingaraju, Chetan Raj, Zhou, Qiao, Martinez, Joy, Kaltcheva, Teodora, Dagis, Andy, Hardwick, Nicola, Issa, Nicolas C., Farol, Len, Nademanee, Auayporn, Al Malki, Monzr M., Forman, Stephen, Nakamura, Ryotaro, Diamond, Don J., and TRIPLEX VACCINE Study Group
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CYTOMEGALOVIRUSES ,STEM cell transplantation ,VIREMIA ,HEMATOPOIETIC stem cells ,VACCINES ,CYTOMEGALOVIRUS disease prevention ,RESEARCH ,VIRAL vaccines ,RESEARCH methodology ,EVALUATION research ,MEDICAL cooperation ,COMPARATIVE studies ,RANDOMIZED controlled trials ,BLIND experiment ,RESEARCH funding ,HEMATOPOIETIC stem cell transplantation - Abstract
Background: Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT).Objective: To determine the safety and efficacy of Triplex.Design: First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933).Setting: 3 U.S. HCT centers.Participants: 102 CMV-seropositive HCT recipients at high risk for CMV reactivation.Intervention: Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens.Measurements: The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection.Results: A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients.Limitation: The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial.Conclusion: No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia.Primary Funding Source: National Cancer Institute and Helocyte. [ABSTRACT FROM AUTHOR]- Published
- 2020
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3. Vaccination of Hematopoietic Stem Cell (HCT) Donors with Triplex, a Novel Cytomegalovirus Vaccine: Safety, Feasibility and Adoptive Transfer of Protective CMV-Specific T Cells in HCT Recipients
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Nakamura, Ryotaro, La Rosa, Corinna, Aldoss, Ibrahim, Zhou, Qiao, Lingaraju, Chetan Raj, Martinez, Joy, Kaltcheva, Teodora, and Diamond, Don J.
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- 2020
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4. Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Nonviremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax.
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La Rosa, Corinna, Longmate, Jeffrey, Lingaraju, Chetan Raj, Zhou, Qiao, Kaltcheva, Teodora, Hardwick, Nicola, Aldoss, Ibrahim, Nakamura, Ryotaro, and Diamond, Don J.
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T cells , *MAJOR histocompatibility complex , *CYTOMEGALOVIRUS diseases , *CELL transplantation , *PHENOTYPES , *IMMUNOLOGIC memory - Abstract
Highlights • PepVax is an investigational cytomegalovirus (CMV) vaccine that has shown tolerability and clinical benefits in a Phase Ib trial. • Longitudinal immune monitoring of memory phenotypes was performed in enrolled patients to study the functionality and antiviral role of CMV-specific T cells. • In vaccinated hematopoietic cell transplantation recipients, PepVax elicited marked levels of differentiated effector memory pp65-specific CD8+ T cells in the absence of viremia. • The functional memory phenotype of the expanded CMV-specific T cell subsets may have been key to the favorable outcomes of the PepVax clinical trial. ABSTRACT Early cytomegalovirus (CMV) reactivation remains a significant cause of morbidity and mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine designed to control CMV infection in HCT recipients seropositive for CMV by stimulating the expansion of T cell subsets that target the CMV tegument protein pp65. In a randomized Phase Ib pilot trial (ClinicalTrials.gov NCT01588015), two injections of CMVPepVax (at days 28 and 56 post-HCT) demonstrated safety, immunogenicity, increased relapse-free survival, and reduced CMV reactivation and use of antivirals. In the present study, we assessed the phenotypes and time courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. The functionality and antiviral role of CMV-specific T cells have been linked to immune reconstitution profiles characterized predominantly by differentiated effector memory T (TEM) subsets that have lost membrane expression of the costimulatory molecule CD28 and often reexpress the RA isoform of CD45 (TEMRA). Major histocompatibility complex class I pp65 495 - 503 multimers, as well as CD28 and CD45 memory markers, were used to detect immune reconstitution in blood specimens from HCT recipients enrolled in the Phase Ib clinical trial. Specimens from the 10 (out of 18) vaccinated patients who had adequate (≥.2%) multimer binding to allow for memory analysis showed highly differentiated TEM and TEMRA phenotypes for pp65 495-503 -specific CD8 T cells during the first 100days post-transplantation. In particular, by day 70, during the period of highest risk for CMV reactivation, combined TEM and TEMRA phenotypes constituted a median of 90% of pp65 495-503 -specific CD8 T cells in these vaccinated patients. CMV viremia was not detectable in the patients who received CMVPepVax, although their pp65 495-503 -specific CD8 T cell profiles were strikingly similar to those observed in viremic patients who did not receive the vaccine. Collectively, our findings indicate that in the absence of clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated pp65 495-503 -specific CD8 TEMs early post-HCT. Our data indicate that the rapid reconstitution of CMV-specific T cells with marked levels of effector phenotypes may have been key to the favorable outcomes of the CMVPepVax clinical trial. Graphical abstract Image, graphical abstract [ABSTRACT FROM AUTHOR]
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- 2019
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5. Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Non-Viremic Hematopoietic Stem Transplant Recipients Vaccinated with Cmvpepvax.
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Nakamura, Ryotaro, La Rosa, Corinna, Longmate, Jeffrey, Lingaraju, Chetan Raj, Zhou, Qiao, Kaltcheva, Teodora, Aldoss, Ibrahim, and Diamond, Don J.
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CYTOMEGALOVIRUS disease treatment , *HEMATOPOIETIC stem cell transplantation , *PEPTIDES , *T cells , *PHENOTYPES , *IMMUNE response - Abstract
Background Early CMV reactivation remains a significant cause of morbidity/mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine based on an HLA-A0201-restricted immune-dominant peptide (pp65 495-503). In a randomized Phase 1b trial, CMVPepVax (given on days 28 & 56 post-HCT) demonstrated safety, immunogenicity, and reduced CMV reactivations (Lancet Haem 2017). In the current study, we assessed the detailed phenotypes and time-courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. Patients (pts)/methods Of 18 pts in the vaccine arm (VA) and 18 in the observation arm (OA), 12 VA and 8 OA pts were included for the current study as they developed levels of CMV-specific T cells evaluable for memory phenotyping. Eleven of the 12 VA pts did not reactivate CMV during the 6-month while 5 OA and 1 VA pts developed viremia requiring antiviral treatment. The differentiation status of CMV-specific CD3+CD8+ T cells, identified by pp65 495-503 dextramers, was determined based on CD28/CD45RA expression using polychromatic flow cytometric panels. CD137 expression assay was used to evaluate T cell responses to pp65 or IE1 peptide library. Results The VA pts more often achieved ³0.2% levels of pp65 495-503 -specific CD8 T cells in the absence of clinically detectable CMV viremia (10 non-reactivating pts of 17 in the VA vs. 1 non-reactivating pts of 12 in the OA, p=0.008). Phenotype proportions are displayed in Figure 1. In contrast, when T cells were stimulated with pp65 or IE1 peptide libraries encoding T cell epitopes specific for a variety of HLA alleles, the T cell responses measured by CD137 expression in both VA and OA pts did not significantly differ. These results suggest that the enhanced pp65 495-503 response measured in the VA pts (without viremia) was likely driven by PepVax. When the differentiation status was analyzed, pp65 495-503 -specific T cells in viremic OA pts had a median % of effector phenotype profiles of 91% (range: 31-99%), similar to those of the evaluable non-viremic VA patients, for whom the median % of effector phenotype profiles was 93% (range: 13-100%). Importantly, 2 weeks after the 2nd PepVax vaccination, >80% of pp65 495-503 -specific T cells were TEM and TEMRA in 9 out of the 10 evaluable VA pts. Thus, in these HCT recipients who did not develop CMV viremia, PepVax rapidly expanded CMV-specific T cells with substantial EM profiles. Figure 2 depicts longitudinal dynamic of pp65 495-503 -specific CD8 T cells and their memory profiles. Conclusion Collectively, our analysis indicates that, in the absence of clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated effector memory CD8 T cells specific to the vaccine epitope of pp65 495-503 early post-HCT, which may have been key to the favorable outcomes of the CMVPepVax clinical trial. [ABSTRACT FROM AUTHOR]
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- 2019
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6. A phase II randomized, placebo-controlled, multicenter trial to evaluate the efficacy of cytomegalovirus PepVax vaccine in preventing cytomegalovirus reactivation and disease after allogeneic hematopoietic stem cell transplant.
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Nakamura R, La Rosa C, Yang D, Hill JA, Rashidi A, Choe H, Zhou Q, Lingaraju CR, Kaltcheva T, Longmate J, Drake J, Slape C, Duarte L, Al Malki MM, Pullarkat VA, Aribi A, Devine S, Verneris MR, Miller JS, Forman SJ, Aldoss I, and Diamond DJ
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- Adult, Aged, Female, Humans, Male, Middle Aged, Transplantation, Homologous, Virus Activation immunology, Cytomegalovirus immunology, Cytomegalovirus Infections prevention & control, Cytomegalovirus Infections immunology, Cytomegalovirus Infections etiology, Cytomegalovirus Vaccines immunology, Hematopoietic Stem Cell Transplantation adverse effects
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- 2024
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