scholarly journals Spike-Directed Vaccination Elicits Robust Spike-Specific T cell Responses Including to Mutant Strains

2021 ◽  
Author(s):  
Maja Stanojevic ◽  
Ashley Geiger ◽  
Brita Ostermeier ◽  
Danielle Sohai ◽  
Christopher Lazarski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Reference Strain ◽  
Critical Role ◽  
T Cell Responses ◽  
Post Vaccination ◽  
Vaccine Responses ◽  
Cell Responses ◽  
Mutant Strains ◽  
Before And After

Abstract While most studies describing COVID-19 vaccine responses have focused on antibodies, there is increasing evidence that T cells play a critical role. Here we evaluated T cell responses in seronegative donors before and after vaccination to define responses to SARS-CoV-2 reference strain, as well as to mutations in the variant strains B.1.1.7 and B.1.351. We observed enhanced T cell responses to reference and variant Spike strains post vaccination.

scholarly journals Baseline Levels of Influenza-Specific B Cells and T Cell Responses Modulate Human Immune Responses to Swine Variant Influenza A/H3N2 Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 126
Author(s):  
Lilin Lai ◽  
Nadine Rouphael ◽  
Yongxian Xu ◽  
Amy C. Sherman ◽  
Srilatha Edupuganti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza A ◽  
Vaccine Dose ◽  
T Cell Responses ◽  
Post Vaccination ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Cellular Immune

The cellular immune responses elicited by an investigational vaccine against an emergent variant of influenza (H3N2v) are not fully understood. Twenty-five subjects, enrolled in an investigational influenza A/H3N2v vaccine study, who received two doses of vaccine 21 days apart, were included in a sub-study of cellular immune responses. H3N2v-specific plasmablasts were determined by ELISpot 8 days after each vaccine dose and H3N2v specific CD4+ T cells were quantified by intracellular cytokine and CD154 (CD40 ligand) staining before vaccination, 8 and 21 days after each vaccine dose. Results: 95% (19/20) and 96% (24/25) subjects had pre-existing H3N2v specific memory B, and T cell responses, respectively. Plasmablast responses at Day 8 after the first vaccine administration were detected against contemporary H3N2 strains and correlated with hemagglutination inhibition HAI (IgG: p = 0.018; IgA: p < 0.001) and Neut (IgG: p = 0.038; IgA: p = 0.021) titers and with memory B cell frequency at baseline (IgA: r = 0.76, p < 0.001; IgG: r = 0.74, p = 0.0001). The CD4+ T cells at Days 8 and 21 expanded after prime vaccination and this expansion correlated strongly with early post-vaccination HAI and Neut titers (p ≤ 0.002). In an adult population, the rapid serological response observed after initial H3N2v vaccination correlates with post-vaccination plasmablasts and CD4+ T cell responses.

scholarly journals Treg Downregulation Was Associated with Augmentation of T Cell Responses Against Immunogenic Antigens and Clinical Responses in Patients with Hematological Malignancies after Donor Lymphocyte Infusion (DLI)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3423-3423
Author(s):  
Jochen Greiner ◽  
Marlies Götz ◽  
Michael Schmitt ◽  
Hartmut Döhner ◽  
Markus Wiesneth ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Research Funding ◽  
T Cell Responses ◽  
Donor Lymphocyte Infusion ◽  
Cytotoxic T Cell ◽  
Epitope Recognition ◽  
Cell Responses ◽  
Before And After

Abstract In order to maintain remission and to prolong overall-survival after allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion (DLI), cytotoxic T-cell responses against malignant cells play a pivotal role, however they are not well characterized so far. In this study, we focused on the detection of immune responses in patients before and after DLI. A broader epitope-specific T cell activity is associated with clinical response of patients treated with DLI and a concurrent reduction of regulatory T cell frequency may contribute to clinical response in patients after DLI. For a better characterization of the T cell responses, frequency and diversity of leukemia-associated antigen (LAA)-specific cytotoxic T cells was assessed using ELISpot and pMHC multimer assays. Furthermore, the frequency of regulatory T cells (Treg) before and after DLI was analyzed. Results were correlated to the clinical course of the patients. Independently of their clinical response, 7/11 patients (63.6%) showed an immunological response through an increase in the number of recognized epitopes over the course of DLI. There was a significant increase (p=0.02) in epitope recognition comparing early screening and maximum response after DLI and a significant increase in the mean augmentation from 1 to 4 of the spotted epitopes in the course of DLI was detected in the cohort of clinical responders (R) compared to non-responders (NR) who did not show any dynamics in epitope recognition with a median of 3 to 4 recognized LAA. The proportion of the CD4+CD25highFoxP3+ Treg within the CD4+CD25high T cell fraction decreased significantly in R from a median of 72.9% to 54.6% when comparing the variation at the time points before and after DLI (p=0.04). In NR there was no significant change in the Treg fraction in the course of DLI. In general, significantly more LAA-derived T cell epitopes (p=0.02) were recognized in R when compared to NR. Moreover, the frequency of Treg in R decreased significantly (p=0.008) while remaining stable in NR. Taken together, an increase of specific CTL responses against several LAA after DLI was detected. This study suggests that decreasing numbers of Treg as well as enhanced LAA diversity in T cell responses contribute to clinical outcome of patients treated with DLI. Disclosures Döhner: AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding.

Prediction the clinical outcomes of cancer patients after peptide vaccination.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14295-e14295 ◽  
Author(s):  
Eniko Rita Toke ◽  
Mónika Megyesi ◽  
Levente Molnar ◽  
József Tóth ◽  
Orsolya Lőrincz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Hla Alleles ◽  
Vaccine Responses ◽  
Cell Responses ◽  
Vaccine Treatment ◽  
Hla Genotype

e14295 Background: Neoantigen vaccines can activate T-cells that specifically kill tumor cells. However, most vaccine peptides, selected either as HLA-binders or as HLA-presented epitopes, do not induce T-cell responses in HLA allele-matched individuals. We hypothesized that personal-epitopes (PEPIs) binding to multiple autologous HLA-alleles induce potent T-cell responses. Methods: Epitopes binding to single HLA and PEPIs binding to 3 autologous HLA-alleles were identified with our novel and validated PEPI Test (CE Marked) and correlated with CD8+ and CD4+ T-cell responses of (pre)malignant patients vaccinated with Synthetic Long Peptides (SLPs) in 2 clinical trials. A Model Population of 433 HLA-genotyped individuals was used to determine the percentage of subjects with PEPIs from SLPs (PEPI-Score). As a proof of principle, a personal vaccine was developed matching with 14 HLA-alleles of a cancer patient with PEPIs from 12 tumor-antigens. T-cell reactivities were tested by interferon-γ ELISPOT. Results: There was no correlation between single HLA-binding epitopes and HPV-specific T-cell responses of patients. In contrast, there was 90% and 69% agreement between HLA-class-I PEPIs and CD8+ T-cell responses (p < 0.001) and HLA-class-II PEPIs and CD4+ T-cell responses (p = 0.005), respectively. PEPI-Score predicted the T-cell response rate of SLP vaccine clinical trials. As predicted by the PEPI Test, personal vaccine treatment activated tumor-specific T-cells: 91% and 100% of the vaccine peptides elicited CD8+ and CD4+ T-cell responses, respectively. Conclusions: A patient’s HLA genotype is a major determinant of vaccine responses and PEPIs are genetic biomarkers of T-cell responses. PEPI Test prediction of vaccine responses can be utilized by clinicians for selecting the vaccine treatment and for the development of highly immunogenic personal vaccines matched to a patient’s complete HLA genotype (NCT03391232).

scholarly journals Transient CD4+T Cell Depletion Results in Delayed Development of Functional Vaccine-Elicited Antibody Responses

2016 ◽  
Vol 90 (9) ◽  
pp. 4278-4288 ◽  
Author(s):  
Nicholas M. Provine ◽  
Alexander Badamchi-Zadeh ◽  
Christine A. Bricault ◽  
Pablo Penaloza-MacMaster ◽  
Rafael A. Larocca ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Specific Antibody ◽  
De Novo ◽  
Current Model ◽  
Critical Role ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cell Responses ◽  
T Cell Help

ABSTRACTWe have recently demonstrated that CD4+T cell help is required at the time of adenovirus (Ad) vector immunization for the development of functional CD8+T cell responses, but the temporal requirement for CD4+T cell help for the induction of antibody responses remains unclear. Here we demonstrate that induction of antibody responses in C57BL/6 mice can occur at a time displaced from the time of Ad vector immunization by depletion of CD4+T cells. Transient depletion of CD4+T cells at the time of immunization delays the development of antigen-specific antibody responses but does not permanently impair their development or induce tolerance against the transgene. Upon CD4+T cell recovery, transgene-specific serum IgG antibody titers develop and reach a concentration equivalent to that in undepleted control animals. These delayed antibody responses exhibit no functional defects with regard to isotype, functional avidity, expansion after boosting immunization, or the capacity to neutralize a simian immunodeficiency virus (SIV) Env-expressing pseudovirus. The development of this delayed transgene-specific antibody response is temporally linked to the expansion ofde novoantigen-specific CD4+T cell responses, which develop after transient depletion of CD4+T cells. These data demonstrate that functional vaccine-elicited antibody responses can be induced even if CD4+T cell help is provided at a time markedly separated from the time of vaccination.IMPORTANCECD4+T cells have a critical role in providing positive help signals to B cells, which promote robust antibody responses. The paradigm is that helper signals must be provided immediately upon antigen exposure, and their absence results in tolerance against the antigen. Here we demonstrate that, in contrast to the current model that the absence of CD4+T cell help at priming results in long-term antibody nonresponsiveness, antibody responses can be induced by adenovirus vector immunization or alum-adjuvanted protein immunization even if CD4+T cell help is not provided until >1 month after immunization. These data demonstrate that the time when CD4+T cell help signals must be provided is more dynamic and flexible than previously appreciated. These data suggest that augmentation of CD4+T cell helper function even after the time of vaccination can enhance vaccine-elicited antibody responses and thereby potentially enhance the immunogenicity of vaccines in immunocompromised individuals.

scholarly journals CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Michelle A Linterman ◽  
Alice E Denton ◽  
Devina P Divekar ◽  
Ilona Zvetkova ◽  
Leanne Kane ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Critical Role ◽  
T Cell Responses ◽  
Cell Polarization ◽  
Helper T Cell ◽  
Cell Responses ◽  
Follicular Helper ◽  
T Cell Priming

The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it is not known whether CD28 has functions in maintaining T cell responses following activation. To determine the role for CD28 after T cell priming, we generated a strain of mice where CD28 is removed from CD4+ T cells after priming. We show that continued CD28 expression is important for effector CD4+ T cells following infection; maintained CD28 is required for the expansion of T helper type 1 cells, and for the differentiation and maintenance of T follicular helper cells during viral infection. Persistent CD28 is also required for clearance of the bacterium Citrobacter rodentium from the gastrointestinal tract. Together, this study demonstrates that CD28 persistence is required for helper T cell polarization in response to infection, describing a novel function for CD28 that is distinct from its role in T cell priming.

Expression of RHAMM and WT1 As Well As T Cell Responses to These Antigens Before and After Allogeneic Stem Cell Transplantation in Patients with Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4315-4315
Author(s):  
Rosaely Casalegno-Garduño ◽  
Claudia Meier ◽  
Jiju Mani ◽  
Kersten Borchert ◽  
Inken Hilgendorf ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Before And After

Abstract Abstract 4315 Introduction: Patients with leukemia undergo chemotherapy as first treatment. Approximately 70–80% of patients with acute myeloid leukemia (AML) reach complete remission. However, most of them will relapse and only 25% survive more than five years. Therefore, there is a need for novel approaches in the treatment of leukemia, such as immunotherapy. Leukemic blasts have an aberrant expression of antigens. They are called leukemia-associated antigens (LAAs) like the receptor for hyaluronan acid-mediated motility (RHAMM) and the Wilms’ tumor gene 1 product (WT1). Epitopes of these LAAs can be recognized by CD8+ T cells. MATERIAL AND METHODS: In the present study, we analyzed the correlation between the clinical course of 18 patients suffering from leukemia (10 AML, 5 MDS, 1 ALL and 2 B-CLL) with the expression of RHAMM and WT1 transcripts before and after allogeneic stem cell transplantation (allo-SCT). Gene transcripts were measured by quantitative real time PCR (RQ-PCR) from RNA of peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) samples. Antigen specific T cells were enriched in a mixed lymphocyte-peptide culture (MLPC) and antigen specific T cell responses were measured by enzyme-linked immunosorbent spot (ELISPOT). Results: We observed a reduction in WT1 transcripts in both PBMC and BMMC after transplantation in all of the WT1 positive patients (6/18 patients: 33%). Four of these six WT1+ patients (67%) remained in complete remission (CR) with low transcripts of WT1 (PBMC: lower than 14 WT1 copies/104 ABL copies, BMMC: lower than 202 WT1 copies/104 ABL copies). In contrast, 2 of 6 WT1+ patients (33%) showed an increase (PBMC: up to 98 WT1 copies/104 ABL copies, BMMC: up to 920 WT1 copies/104 ABL copies) of WT1 transcripts eventually resulting in a relapse. Specific T cell responses were detected against WT1 in two of three WT1+ patients in the presence of blasts (before transplantation or in relapse). However, these specific responses vanished while the patients reached a CR. Furthermore, RHAMM+ patients (12/18: 67%) showed different patterns when correlated with clinical status. Five patients (42%) showed gradually increased levels of RHAMM transcripts during CR. No RHAMM specific T cells could be detected in this group (2/2 MLPCs). Four patients (33%) showed a decrease in the transcripts of RHAMM when they reached a CR. One of these patients developed a T cell response to RHAMM three months after allo-SCT (2/2 MLPCs). One patient showed high transcripts of RHAMM and WT1 during the diagnosis, WT1 transcripts were reduced after allo-SCT. Both RHAMM and WT1 transcripts gradually increased until the patients died. We could detect in this patient both WT1 and RHAMM-specific T cells before transplantation. After allo-SCT the T cell response vanished. CONCLUSION: Taken together, WT1 is a suitable marker for minimal residual disease after allo-SCT. One might speculate that T cells specific for WT1 vanished during the CR due to the absence of the antigen to stimulate the proliferation of specific T cell population. Moreover, the presence of RHAMM-specific T cells may help to maintain a CR. In both cases vaccination with RHAMM and WT1 derived peptide might enhance T cell responses in the patient leading to a better outcome of the patient. Disclosures: Freund: Medac: Honoraria, Research Funding.

scholarly journals The Transcription Factor TCF1 in T Cell Differentiation and Aging

2020 ◽  
Vol 21 (18) ◽  
pp. 6497
Author(s):  
Chulwoo Kim ◽  
Jun Jin ◽  
Cornelia M. Weyand ◽  
Jörg J. Goronzy
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Regulatory Networks ◽  
Critical Role ◽  
T Cell Responses ◽  
Therapeutic Interventions ◽  
Older Individuals ◽  
Chronic Infections ◽  
Cell Responses

The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/β-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals.

scholarly journals Omicron-specific cytotoxic T-cell responses are boosted following a third dose of mRNA COVID-19 vaccine in anti-CD20-treated multiple sclerosis patients

2021 ◽  
Author(s):  
Natacha Madelon ◽  
Nelli Heikkila ◽  
Irene Sabater Royo ◽  
Paola Fontannaz ◽  
Gautier Breville ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccine Dose ◽  
T Cell Responses ◽  
Antibody Responses ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
The Third ◽  
Before And After ◽  
Anti Cd20

Importance: The SARS-CoV-2 variant Omicron escapes neutralizing antibody responses elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third dose of vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses. Objective: To determine T-cell responses to the Spike (S)-protein of Omicron in anti-CD20 treated patients before and after their third mRNA COVID-19 vaccination Design: Prospective observational monocentric study Setting: Conducted since March 2021 at the University Hospital Geneva Participants: Twenty adults with multiple sclerosis on anti-CD20 treatment (ocrelizumab) who received their third dose of mRNA COVID-19 vaccine 6 to 7 months after their second vaccination. Intervention: Blood sampling before and one month after the third vaccine dose Main outcomes and measures: Quantification of CD4 and CD8 (cytotoxic) T cells specific for SARS-CoV-2 S-protein of vaccine strain, Delta and Omicron variants , using activation marker induced assay (AIM) and comparing frequencies before and after the third vaccine dose. Results: S-specific CD4 and CD8 T-cell memory against all variants was maintained in around half of the patients six months after their second vaccination, albeit at lower frequencies against Delta and Omicron variants. A third dose enhanced the number of responders to all variants and significantly increased CD8 T-cell responses. The frequencies of T cells specific to Omicron and Delta remained lower than those specific to the vaccine strain after the boost. Conclusion and relevance: Vaccinated MS patients on anti-CD20 treatment show robust T-cell responses that recognize S from the circulating Delta and Omicron variants. Response rates increased after the third dose, demonstrating that a booster dose might improve cytotoxic T-cell mediated protection against severe disease in patients with low humoral response. The clinical relevance of the reduced frequencies of T cells specific to Omicron will need to be monitored in the future.

Critical Role for CCR1:CCL5 (RANTES) Receptor Ligand Interactions in Modulating Allogeneic T Cell Responses Following Bone Marrow Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3107-3107
Author(s):  
Sung Won Choi ◽  
Gerhard C. Hildebrandt ◽  
Ines Silva ◽  
Krystyna M. Olkiewicz ◽  
Stephen W. Chensue ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
T Cell Responses ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Cell Responses

Abstract Acute graft versus host disease (GVHD) and leukemic relapse are the most serious complications of allogeneic (allo) stem cell transplantation (SCT), and separating desirable graft-versus-leukemia (GVL) effects from GVHD remains the ultimate challenge to successful outcomes. The recruitment of activated T cells to host target tissues (GVHD) or sites of leukemic infiltration (GVL) is likely mediated by chemokine receptor:ligand interactions. CCR1 is a chemokine receptor that binds to CC chemokines including RANTES (CCL5), and is expressed on a variety of cells including activated T cells, monocytes, and macrophages. We have previously shown that mRNA expression of both CCR1 and RANTES is increased in GVHD target tissues following allo-SCT. Using a well established murine SCT model (B6-&gt;B6D2F1) and mice deficient in CCR1, we examined the contribution of CCR1 expression to allo T cell responses in vitro and to GVH and GVL effects in vivo. Lethally (1100cGy) irradiated B6D2F1 mice received SCT either from syngeneic (B6D2F1) or allogeneic (B6) CCR1+/+ or CCR1−/− donors. The severity of GVHD was assessed by survival and a well described clinical scoring system. Syngeneic SCT recipients all survived and were indistinguishable from naïve, untransplanted controls, whereas animals receiving allo-SCT from CCR1+/+ donors developed significant GVHD. By contrast, allo-SCT with CCR1−/− donor cells resulted in significantly improved survival (92% vs. 50%) and less severe clinical GVHD (p&lt;0.01) by day 35 compared to allo-CCR1+/+ controls. GVL effects were next assessed by adding 500 P815 tumor cells (H-2d and syngeneic to host) to the bone marrow inoculum on day 0. F1 recipients of syngeneic BMT all died from tumor infiltration by day +15. Although all allo-SCT recipients effectively rejected their tumor, mice receiving CCR1-/− SCT had significantly improved leukemia free survival (45% vs. 5%) by day 60 compared to allo controls. At higher tumor doses, significant GVL activity remained in CCR1−/− SCT recipients, but the survival advantage was lost. Further examination of allo T cell responses in vivo revealed that day 7 splenic T cell expansion and serum IFNγ levels were significantly lower following CCR1−/− SCT (p &lt; 0.01). Surprisingly, proliferation and IFNγ secretion were also reduced by ~70% when CCR1−/− T cells were stimulated with host antigens in vitro, whereas CTL activity remained equivalent to CCR1+/+ controls. The reduction in proliferation was not secondary to a migration defect, but was dependent on interactions between CCR1 and RANTES; neutralization of RANTES with a monoclonal antibody significantly reduced proliferation of CCR1+/+ T cells in a dose dependent manner. Finally, we found that GVHD mortality was also less when RANTES−/− mice were used as recipients in a second, MHC-disparate, SCT model (p = 0.03). Collectively these data demonstrate a critical role for CCR1 in donor T cell alloreactivity following SCT. These responses contribute to both GVHD and GVL effects in vivo and are likely dependent upon interactions between CCR1 and the chemokine ligand RANTES.

Leukemia-Associated Antigen Specific T-Cell Responses Following Combined PR1 and WT1 Peptide Vaccination in Patients with Myeloid Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 287-287 ◽  
Author(s):  
Katayoun Rezvani ◽  
Agnes S.M. Yong ◽  
Stephan Mielke ◽  
Bipin N. Savani ◽  
Laura Musse ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Post Vaccination ◽  
Myeloid Malignancies ◽  
Cell Responses ◽  
Ifn Γ

Abstract The graft-versus-leukemia (GVL) effect following allogeneic stem cell transplantation (SCT) is evidence that T lymphocytes can eradicate leukemia. The successful identification of a range of leukemia-associated antigens such as proteinase 3 (PR3) and Wilms tumour-1 (WT1) has stimulated efforts to induce leukemia-specific T-cell responses to these antigens using peptide vaccines. Here we describe the safety and immunogenicity of a combined vaccine of two leukemia-associated antigenic peptides, PR1 and WT1. Eight HLA-A*0201 positive patients with myeloid malignancies (2 myelodysplasia, 5 acute myeloid leukemia and 1 chronic myeloid leukemia) received one subcutaneous dose each of PR1 and WT1 vaccines in Montanide adjuvant, with granulocyte-macrophage colony-stimulating factor (GM-CSF). All patients completed 4 weeks follow-up to monitor toxicity and immunological responses. Toxicity was limited to grade 1–2. All remain alive at a median of 252 days (range 105–523). We analyzed the immunological response to vaccination using PR1/HLA-A*0201 and WT1/HLA-A*0201 tetrameric complexes and flow cytometry for intracellular interferon-gamma (IFN-γ) in samples obtained pre- and weekly post-vaccination. A significant CD8+ T-cell response to the vaccine was defined as the emergence of PR1 or WT1-specific CD8+ T-cells when the pre-study analysis was negative or a twofold increase in frequencies when responses were present pre-vaccination. Following vaccination, a significant CD8+ T-cell response to PR1 was seen in 7/8 patients (median 0.34%, range 0.04–0.48%), to WT1 in 5/8 patients (median 0.29%, range 0–0.42%) and to one or both antigens in 8/8 patients. Vaccine-induced CD8+ T-cells were seen as early as 1 week post-vaccination, produced IFN-γ and were preferentially expanded in the effector compartment (CD45RO+/-CD27−). Post-vaccination, there was a strong correlation between the emergence of PR1 or WT1+CD8+ T-cells and a reduction in WT1 mRNA expression, a marker of minimal residual disease, suggesting a vaccine-driven anti-leukemia effect. Loss of response was associated with reappearance of WT1 transcripts (P<0.01). Two patients with detectable CD8+ T-cell responses to PR1 who failed to have a reduction in MRD relapsed 3–6 months following completion of vaccination. This is the first demonstration that a combined PR1 and WT1 vaccine is immunogenic. Based on these results we have initiated a phase 2 study of repeated vaccination with PR1 and WT1 peptides in patients with myeloid malignancies.

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