CT Antigen-Specific Immune Response From DAC/DC Vaccine Correlates With Clinical Outcome In Patients With Relapsed Neuroblastoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2023-2023
Author(s):  
Deepa Kolaseri Krishnadas ◽  
Fanqi Bai ◽  
Kenneth Lucas
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Cell Response ◽  
T Cell Response ◽  
Specific Immune Response ◽  
Cd4 T Cell ◽  
Dc Vaccine ◽  
Ct Antigen ◽  
Ct Antigens

Abstract Neuroblastoma is the most common solid tumor in children in the first year of life. Despite high-dose chemotherapy, irradiation and autologous stem cell transplantation, nearly half of these patients relapse, a group for whom there are limited treatment options. The cancer-testis (CT) antigens MAGE-A1, MAGE-A3 and NY-ESO-1 are expressed on neuroblastoma cells in low levels and we have previously shown that the demethylating chemotherapy drug decitabine (DAC) can upregulate the expression of CT antigens in neuroblastoma. We developed a clinical study combining DAC to upregulate CT antigens followed by a dendritic cell (DC) vaccine targeting CT antigens MAGE-A1, MAGE-A3 and NY-ESO-1. Here we report the effects of DAC/DC vaccine in generating antigen-specific immune response and evaluate if there exists a correlation between development of antigen-specific immune responses and clinical responses. The treatment regimen includes 4 cycles of therapy, each consisting of DAC 10mg/m2/day for 5 days, followed by 2 weekly vaccinations consisting of autologous DC pulsed with overlapping peptide mixes derived from full length MAGE-A1, MAGE-A3 and NY-ESO-1. The number of DC administered in the vaccine was based on patient weight, and ranged from 3 to 10 x106 cells. The topical TLR agonist imiquimod was used at the site of vaccination to facilitate immune responses to the vaccine. Peripheral blood was collected weekly to assess antigen-specific immune response. Peripheral blood mononuclear cells were archived at various time points, stimulated for 24 h with MAGE-A1, MAGE-A3 and NY-ESO-1 peptide mixes and studied for the presence of CD137+ antigen-specific cells by flow cytometry. The regimen was well tolerated and highly feasible. We were able to culture DC for 10/10 neuroblastoma patients enrolled on the study. Development of an antibody or a T cell response to the vaccine was defined as either new onset or a two fold increase in the level of antibodies or number of MAGE-A1, MAGE-A3 and NY-ESO-1 specific, CD137+ T cells over baseline levels. The clinical and immunological outcomes of seven neuroblastoma patients treated so far with the DAC/CT antigen vaccine is summarized in table 1. Two patients are in complete remission, one of whom is two years from completing therapy, and another patient is 9 months from therapy. Both these patients demonstrated an increase in the number of circulating CD3+CD8+CD137+ and CD3+CD4+CD137+ T cells against one of the CT antigens in the vaccine. Of the five patients who had disease progression, one had a partial response to his chemotherapy and radiation resistant tumor 2 months post-vaccine. This patient had an antibody response to these antigens post-vaccination but no CD8+ or CD4+ T cell response. Another patient who had no evidence of disease for 8 months following the last vaccine prior to disease recurrence had an antigen-specific CD8+ T cell response against MAGE-A1, MAGE-A3 and NY-ESO-1 antigens but no CD4+ T cell response. These data indicate that DAC/DC vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 are efficient in generating an antigen-specific immune response in four of seven patients studied and there exist a correlation between the presence of immune response and positive clinical outcome. Disclosures: No relevant conflicts of interest to declare.

EBV-positive lymphoma patients have a selective deficiency in EBV immunity

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21032-21032
Author(s):  
K. N. Heller ◽  
P. G. Steinherz ◽  
C. S. Portlock ◽  
C. Münz
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Healthy Volunteers ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Specific Immune Response ◽  
Cell Responses

21032 Background: Epstein-Barr virus (EBV) asymptomatically establishes persistent infections in more than 90% of the adult population. However, due to effective immune control, only a minority of infected carriers develops spontaneous EBV-associated lymphomas. Since EBV nuclear antigen-1 (EBNA1) is the only protein expressed in all proliferating EBV infected cells we hypothesize that EBNA1 specific immune response is critical in preventing EBV-positive lymphomas. Methods: After informed consent, peripheral blood from healthy volunteers and lymphoma patients (prior to therapy- no evidence of cytopenia) were stimulated (ex vivo) with overlapping peptides covering the immunogenic EBNA1 (aa400–641) sequence. Frequency of EBNA1-specific T-cells were assessed by intracellular cytokine staining and flow cytometric proliferation assays. Cytokine pattern, surface marker phenotype and functional reactivity against EBV specific and control antigens were analyzed. Results: Patient and volunteer immune responses to control antigens and other viruses were assessed and statistically indistinguishable. EBNA1 specific CD4+ T cell responses were detected among 18 of 20 healthy carriers, and among 10 of 16 patients with EBV-negative lymphoma (relative to healthy volunteers p=0.145 via paired student T test). None of the patients with EBV-positive lymphomas (n=8) had a detectable EBNA1-specific CD4+ T-cell response (p<0.003 relative to healthy volunteers and patients with EBV-negative lymphomas). Conclusions: Healthy volunteers and patients with EBV-negative lymphoma have statistically similar EBNA1-specific CD4+ T cell responses. Although patients with EBV-positive lymphoma have intact immune responses to common viruses and antigens, they selectively lack an EBNA1-specific CD4+ T cell response. An intact EBNA1 specific immune response among patients with EBV-negaitve lymphoma implies that lymphoma is not a cause of a selective immune deficiency. On the contrary, these findings suggest that EBNA1-specific CD4+ T cells are critical in the prevention of EBV mediated lymphomas, and a defect in EBNA1 specific immunity may leave EBV carriers suseptible to EBV-positive lymphomas. EBNA1- specific CD4+ T cell function may be a new target for therapies of EBV-associated malignancies. No significant financial relationships to disclose.

scholarly journals The Cytomegalovirus-Specific CD4+ T-Cell Response Expands with Age and Markedly Alters the CD4+ T-Cell Repertoire

2007 ◽  
Vol 81 (14) ◽  
pp. 7759-7765 ◽  
Author(s):  
Batoul Pourgheysari ◽  
Naeem Khan ◽  
Donna Best ◽  
Rachel Bruton ◽  
Laxman Nayak ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Immune Response ◽  
T Cell Repertoire ◽  
Immune Senescence ◽  
Cell Repertoire

ABSTRACT Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.

scholarly journals Preferential CD8 rather than CD4 T-cell response to wear particles of polyether-ether-ketone and highly cross-linked polyethylene

RSC Advances ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 1866-1874 ◽  
Author(s):  
Zhe Du ◽  
Shujun Wang ◽  
You Wang
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Wear Particles ◽  
Adaptive Immune ◽  
Polyether Ether Ketone ◽  
Ether Ketone

Enriching the understanding of the effects of the particles on the adaptive immune response.

scholarly journals CD8+ T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Huarong Huang ◽  
Shihua Li ◽  
Yongli Zhang ◽  
Xiaojuan Han ◽  
Baoqian Jia ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Immune Responses ◽  
Zika Virus ◽  
Cell Response ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Zikv Infection

ABSTRACT Zika virus (ZIKV) infection causees neurologic complications, including Guillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8+ T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8+ T cell response was elicited, major histocompatibility complex class I-restricted CD8+ T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8+ T cells was developed, and virus-specific memory CD8+ T cells were generated in these mice. The CD8+ T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8+ T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection. IMPORTANCE ZIKV infection has severe clinical consequences, including Guillain-Barré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8+ T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKV-specific CD8+ T cells in vivo, which simplified the detection and evaluation of ZIKV-specific immune responses. In addition, the finding that tetramer-positive memory CD8+ T cell responses were generated and that CD8+ T cells can traffic to a ZIKV-infected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design.

scholarly journals Orf Virus-Based Vaccine Vector D1701-V Induces Strong CD8+ T Cell Response against the Transgene but Not against ORFV-Derived Epitopes

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 295 ◽  
Author(s):  
Alena Reguzova ◽  
Michael Ghosh ◽  
Melanie Müller ◽  
Hanns-Joachim Rziha ◽  
Ralf Amann
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cellular Immunity ◽  
Cell Response ◽  
Vaccine Development ◽  
Viral Vector ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Specific Immune Response ◽  
Orf Virus

The potency of viral vector-based vaccines depends on their ability to induce strong transgene-specific immune response without triggering anti-vector immunity. Previously, Orf virus (ORFV, Parapoxvirus) strain D1701-V was reported as a novel vector mediating protection against viral infections. The short-lived ORFV-specific immune response and the absence of virus neutralizing antibodies enables repeated immunizations and enhancement of humoral immune responses against the inserted antigens. However, only limited information exists about the D1701-V induced cellular immunity. In this study we employed major histocompatibility complex (MHC) ligandomics and immunogenicity analysis to identify ORFV-specific epitopes. Using liquid chromatography-tandem mass spectrometry we detected 36 ORFV-derived MHC I peptides, originating from various proteins. Stimulated splenocytes from ORFV-immunized mice did not exhibit specific CD8+ T cell responses against the tested peptides. In contrast, immunization with ovalbumin-expressing ORFV recombinant elicited strong SIINFEKL-specific CD8+ T lymphocyte response. In conclusion, our data indicate that cellular immunity to the ORFV vector is negligible, while strong CD8+ T cell response is induced against the inserted transgene. These results further emphasize the ORFV strain D1701-V as an attractive vector for vaccine development. Moreover, the presented experiments describe prerequisites for the selection of T cell epitopes exploitable for generation of ORFV-based vaccines by reverse genetics.

scholarly journals ABO blood group is involved in the quality of the specific immune response

2021 ◽  
Author(s):  
Sergio Gil-Manso ◽  
Iria Miguens Blanco ◽  
Bruce Motyka ◽  
Anne Halpin ◽  
Rocio Lopez-Estaban ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Mononuclear Cells ◽  
Natural Infection ◽  
T Cell Response ◽  
Specific Immune Response ◽  
Cd4 T Cell ◽  
Peripheral Blood Mononuclear ◽  
Chain Reactions ◽  
Over Time

Since December 2019, the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread throughout the world. To eradicate it, it is crucial to acquire a strong and long-lasting anti-SARS-CoV-2 immunity, by either natural infection or vaccination. We collected blood samples 12-305 days after positive polymerase chain reactions (PCRs) from 35 recovered individuals infected by SARS-CoV-2. Peripheral blood mononuclear cells were stimulated with SARS-CoV-2-derived peptide pools, such as the Spike (S), Nucleocapsid (N), and Membrane (M) proteins, and we quantified anti-S immunoglobulins in plasma. After 10 months post-infection, we observed a sustained SARS-CoV-2-specific CD4+ T-cell response directed against M-protein, but responses against S- or N-proteins were lost over time. Besides, we demonstrated that A-group individuals presented significantly higher frequencies of specific CD4+ T-cell responses against Pep-M than O-group individuals. The A-group subjects also needed longer to clear the virus and they lost cellular immune responses over time, compared to the O-group individuals, who showed a persistent specific immune response against SARS-CoV-2. Therefore, the S-specific immune response was lost over time, and individual factors determine the sustainability of the body's defences, which must be considered in the future design of vaccines to achieve continuous anti-SARS-CoV-2 immunity.

Severe murine schistosomiasis results from disruption of the modulation of anti-egg CD4 T cell response by immunodominance of a single egg epitope

2020 ◽  
Author(s):  
Eduardo Finger ◽  
Thaissa Melo Galante Coimbra ◽  
Alessandra Finardi de Souza
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Inflammatory Response ◽  
Cell Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Severe Liver ◽  
Experimental Platform ◽  
Egg Antigen

AbstractThis study exploits the consistent correlation between immunodominance of the major egg antigen Sm-p40234-246, a robust Th1/Th17 anti-egg CD4 response and severe liver immunopathology in experimental murine schistosomiasis as an experimental platform to analyze how different degrees of immunodominance affect CD4 modulation and disease outcome. The results show that strong immunodominance of a restricted egg epitope repertoire skews CD4 modulation towards a pathogenic Th1/Th17 pro-inflammatory response and that neutralizing this immunodominance generates an opposite and restorative effect. These results identify immunodominance as an important pathogenic component that influences CD4 modulation in experimental murine schistosomiasis and can be manipulated to treat this and maybe other CD4 mediated diseases.SummaryAntigen informed CD4 modulation determines how efficiently the immune system neutralizes a threat; however, this process and its components are not fully comprehended. This study analyzes immunodominance as one component able to disrupt CD4 modulation and turn pathogenic an otherwise healthy immune response.

scholarly journals Minor Histocompatibility Antigen DBY Elicits a Coordinated B and T Cell Response after Allogeneic Stem Cell Transplantation

2004 ◽  
Vol 199 (8) ◽  
pp. 1133-1142 ◽  
Author(s):  
Emmanuel Zorn ◽  
David B. Miklos ◽  
Blair H. Floyd ◽  
Alex Mattes-Ritz ◽  
Luxuan Guo ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Cell Clone ◽  
Histocompatibility Antigen ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Minor Histocompatibility Antigen ◽  
T Cell Clone ◽  
Donor T Cells

We examined the immune response to DBY, a model H-Y minor histocompatibility antigen (mHA) in a male patient with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplant from a human histocompatibility leukocyte antigen (HLA)-identical female sibling. Patient peripheral blood mononuclear cells were screened for reactivity against a panel of 93 peptides representing the entire amino acid sequence of DBY. This epitope screen revealed a high frequency CD4+ T cell response to a single DBY peptide that persisted from 8 to 21 mo after transplant. A CD4+ T cell clone displaying the same reactivity was established from posttransplant patient cells and used to characterize the T cell epitope as a 19-mer peptide starting at position 30 in the DBY sequence and restricted by HLA-DRB1*1501. Remarkably, the corresponding X homologue peptide was also recognized by donor T cells. Moreover, the T cell clone responded equally to mature HLA-DRB1*1501 male and female dendritic cells, indicating that both DBY and DBX peptides were endogenously processed. After transplant, the patient also developed antibodies that were specific for recombinant DBY protein and did not react with DBX. This antibody response was mapped to two DBY peptides beginning at positions 118 and 536. Corresponding DBX peptides were not recognized. These studies provide the first demonstration of a coordinated B and T cell immune response to an H-Y antigen after allogeneic transplant. The specificity for recipient male cells was mediated by the B cell response and not by donor T cells. This dual DBX/DBY antigen is the first mHA to be identified in the context of chronic GVHD.

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