scholarly journals Convergent epitope-specific T cell responses after SARS-CoV-2 infection and vaccination

2021 ◽  
Author(s):  
Anastasia A Minervina ◽  
Mikhail V Pogorelyy ◽  
Allison M Kirk ◽  
Emma Kaitlynn Allen ◽  
Kim J Allison ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Critical Parameters ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cell Responses ◽  
Depth Analysis

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

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 Tracking of Peptide-Specific CD4+ T-Cell Responses after an Acute Resolving Viral Infection: a Study of Parvovirus B19

2006 ◽  
Vol 80 (22) ◽  
pp. 11209-11217 ◽  
Author(s):  
Victoria Kasprowicz ◽  
Adiba Isa ◽  
Thomas Tolfvenstam ◽  
Katie Jeffery ◽  
Paul Bowness ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Parvovirus B19 ◽  
Acute Infection ◽  
T Cell Responses ◽  
T Cell Response ◽  
Immunoglobulin M ◽  
Cell Responses

ABSTRACT The evolution of peptide-specific CD4+ T-cell responses to acute viral infections of humans is poorly understood. We analyzed the response to parvovirus B19 (B19), a ubiquitous and clinically significant pathogen with a compact and conserved genome. The magnitude and breadth of the CD4+ T-cell response to the two B19 capsid proteins were investigated using a set of overlapping peptides and gamma interferon-specific enzyme-linked immunospot assays of peripheral blood mononuclear cells (PBMCs) from a cohort of acutely infected individuals who presented with acute arthropathy. These were compared to those for a cohort of B19-specific immunoglobulin M-negative (IgM−), IgG+ remotely infected individuals. Both cohorts of individuals were found to make broad CD4+ responses. However, while the responses following acute infection were detectable ex vivo, responses in remotely infected individuals were only detected after culture. One epitope (LASEESAFYVLEHSSFQLLG) was consistently targeted by both acutely (10/12) and remotely (6/7) infected individuals. This epitope was DRB1*1501 restricted, and a major histocompatibility complex peptide tetramer stained PBMCs from acutely infected individuals in the range of 0.003 to 0.042% of CD4+ T cells. Tetramer-positive populations were initially CD62Llo; unlike the case for B19-specific CD8+ T-cell responses, however, CD62L was reexpressed at later times, as responses remained stable or declined slowly. This first identification of B19 CD4+ T-cell epitopes, including a key immunodominant peptide, provides the tools to investigate the breadth, frequency, and functions of cellular responses to this virus in a range of specific clinical settings and gives an important reference point for analysis of peptide-specific CD4+ T cells during acute and persistent virus infections of humans.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals Mycobacterium tuberculosis-Specific T Cell Functional, Memory, and Activation Profiles in QuantiFERON-Reverters Are Consistent With Controlled Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheleka A. M. Mpande ◽  
Pia Steigler ◽  
Tessa Lloyd ◽  
Virginie Rozot ◽  
Boitumelo Mosito ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Natural Killer ◽  
Mononuclear Cells ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Th1 Cells ◽  
Functional Responses ◽  
Cell Responses

Reversion of immune sensitization tests for Mycobacterium tuberculosis (M.tb) infection, such as interferon-gamma release assays or tuberculin skin test, has been reported in multiple studies. We hypothesized that QuantiFERON-TB Gold (QFT) reversion is associated with a decline of M.tb-specific functional T cell responses, and a distinct pattern of T cell and innate responses compared to persistent QFT+ and QFT- individuals. We compared groups of healthy adolescents (n=~30 each), defined by four, 6-monthly QFT tests: reverters (QFT+/+/-/-), non-converters (QFT-/-/-/-) and persistent positives (QFT+/+/+/+). We stimulated peripheral blood mononuclear cells with M.tb antigens (M.tb lysate; CFP-10/ESAT-6 and EspC/EspF/Rv2348 peptide pools) and measured M.tb-specific adaptive T cell memory, activation, and functional profiles; as well as functional innate (monocytes, natural killer cells), donor-unrestricted T cells (DURT: γδ T cells, mucosal-associated invariant T and natural killer T-like cells) and B cells by flow cytometry. Projection to latent space discriminant analysis was applied to determine features that best distinguished between QFT reverters, non-converters and persistent positives. No longitudinal changes in immune responses to M.tb were observed upon QFT reversion. M.tb-specific Th1 responses detected in reverters were of intermediate magnitude, higher than responses in QFT non-converters and lower than responses in persistent positives. About one third of reverters had a robust response to CFP-10/ESAT-6. Among those with measurable responses, lower proportions of TSCM (CD45RA+CCR7+CD27+) and early differentiated (CD45RA-) IFN-γ-TNF+IL-2- M.tb lysate-specific CD4+ cells were observed in reverters compared with non-converters. Conversely, higher proportions of early differentiated and lower proportions of effector (CD45RA-CCR7-) CFP10/ESAT6-specific Th1 cells were observed in reverters compared to persistent-positives. No differences in M.tb-specific innate, DURT or B cell functional responses were observed between the groups. Statistical modelling misclassified the majority of reverters as non-converters more frequently than they were correctly classified as reverters or misclassified as persistent positives. These findings suggest that QFT reversion occurs in a heterogeneous group of individuals with low M.tb-specific T cell responses. In some individuals QFT reversion may result from assay variability, while in others the magnitude and differentiation status of M.tb-specific Th1 cells are consistent with well-controlled M.tb infection.

scholarly journals DNA gag/Adenovirus Type 5 (Ad5) gag and Ad5 gag/Ad5 gag Vaccines Induce Distinct T-Cell Response Profiles

2008 ◽  
Vol 82 (16) ◽  
pp. 8161-8171 ◽  
Author(s):  
Kara S. Cox ◽  
James H. Clair ◽  
Michael T. Prokop ◽  
Kara J. Sykes ◽  
Sheri A. Dubey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Adenovirus Type ◽  
T Cell Response ◽  
Cell Responses ◽  
Response Profiles ◽  
Adenovirus Type 5 ◽  
Hiv 1

ABSTRACT Results from Merck's phase II adenovirus type 5 (Ad5) gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against human immunodeficiency virus (HIV) infection in a high-risk population. Among the many questions to be explored following this outcome are whether (i) the Ad5 vaccine induced the quality of T-cell responses necessary for efficacy and (ii) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV type 1 (HIV-1)-specific T-cell responses. Here we present a comprehensive evaluation of the T-cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a regimen with DNA priming followed by Ad5 boosting (n = 50) or a homologous Ad5/Ad5 prime-boost regimen (n = 70). The samples were tested using a statistically qualified nine-color intracellular cytokine staining assay measuring interleukin-2 (IL-2), tumor necrosis factor alpha, macrophage inflammatory protein 1β, and gamma interferon production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T-cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1-specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results for future vaccine development will be discussed.

scholarly journals Activation-induced Markers Detect Vaccine-Specific CD4+ T Cell Responses Not Measured by Assays Conventionally Used in Clinical Trials

Vaccines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 50 ◽  
Author(s):  
Georgina Bowyer ◽  
Tommy Rampling ◽  
Jonathan Powlson ◽  
Richard Morter ◽  
Daniel Wright ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Viral Vectors ◽  
Comprehensive Evaluation ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Vaccine Immunogenicity ◽  
Sensitivity Specificity

Immunogenicity of T cell-inducing vaccines, such as viral vectors or DNA vaccines and Bacillus Calmette-Guérin (BCG), are frequently assessed by cytokine-based approaches. While these are sensitive methods that have shown correlates of protection in various vaccine studies, they only identify a small proportion of the vaccine-specific T cell response. Responses to vaccination are likely to be heterogeneous, particularly when comparing prime and boost or assessing vaccine performance across diverse populations. Activation-induced markers (AIM) can provide a broader view of the total antigen-specific T cell response to enable a more comprehensive evaluation of vaccine immunogenicity. We tested an AIM assay for the detection of vaccine-specific CD4+ and CD8+ T cell responses in healthy UK adults vaccinated with viral vectored Ebola vaccine candidates, ChAd3-EBO-Z and MVA-EBO-Z. We used the markers, CD25, CD134 (OX40), CD274 (PDL1), and CD107a, to sensitively identify vaccine-responsive T cells. We compared the use of OX40+CD25+ and OX40+PDL1+ in CD4+ T cells and OX40+CD25+ and CD25+CD107a+ in CD8+ T cells for their sensitivity, specificity, and associations with other measures of vaccine immunogenicity. We show that activation-induced markers can be used as an additional method of demonstrating vaccine immunogenicity, providing a broader picture of the global T cell response to vaccination.

scholarly journals Safety Profile of a Virus-Like Particle-Based Vaccine Targeting Self-Protein Interleukin-5 in Horses

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 213 ◽  
Author(s):  
Sigridur Jonsdottir ◽  
Victoria Fettelschoss ◽  
Florian Olomski ◽  
Stephanie C. Talker ◽  
Jelena Mirkovitch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Mononuclear Cells ◽  
Clinical Signs ◽  
T Cell Response ◽  
Type I ◽  
Cell Responses ◽  
Virus Like Particle ◽  
Ifn Γ

Background: Insect bite hypersensitivity (IBH) is an eosinophilic allergic dermatitis of horses caused by type I/IVb reactions against mainly Culicoides bites. The vaccination of IBH-affected horses with equine IL-5 coupled to the Cucumber mosaic virus-like particle (eIL-5-CuMVTT) induces IL-5-specific auto-antibodies, resulting in a significant reduction in eosinophil levels in blood and clinical signs. Objective: the preclinical and clinical safety of the eIL-5-CuMVTT vaccine. Methods: The B cell responses were assessed by longitudinal measurement of IL-5- and CuMVTT-specific IgG in the serum and plasma of vaccinated and unvaccinated horses. Further, peripheral blood mononuclear cells (PBMCs) from the same horses were re-stimulated in vitro for the proliferation and IFN-γ production of specific T cells. In addition, we evaluated longitudinal kidney and liver parameters and the general blood status. An endogenous protein challenge was performed in murine IL-5-vaccinated mice. Results: The vaccine was well tolerated as assessed by serum and cellular biomarkers and also induced reversible and neutralizing antibody titers in horses and mice. Endogenous IL-5 stimulation was unable to re-induce anti-IL-5 production. The CD4+ T cells of vaccinated horses produced significantly more IFN-γ and showed a stronger proliferation following stimulation with CuMVTT as compared to the unvaccinated controls. Re-stimulation using E. coli-derived proteins induced low levels of IFNγ+CD4+ cells in vaccinated horses; however, no IFN-γ and proliferation were induced following the HEK-eIL-5 re-stimulation. Conclusions: Vaccination using eIL-5-CuMVTT induces a strong B-cell as well as CuMVTT-specific T cell response without the induction of IL-5-specific T cell responses. Hence, B-cell unresponsiveness against self-IL-5 can be bypassed by inducing CuMVTT carrier-specific T cells, making the vaccine a safe therapeutic option for IBH-affected horses.

scholarly journals Archaeosome Adjuvant Overcomes Tolerance to Tumor-Associated Melanoma Antigens Inducing Protective CD8+T Cell Responses

2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Lakshmi Krishnan ◽  
Lise Deschatelets ◽  
Felicity C. Stark ◽  
Komal Gurnani ◽  
G. Dennis Sprott
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Antigen Delivery ◽  
Antigenic Peptides ◽  
Cell Responses ◽  
Tumor Protection ◽  
Melanoma Antigens

Vesicles comprised of the ether glycerolipids of the archaeonMethanobrevibacter smithii(archaeosomes) are potent adjuvants for evoking CD8+T cell responses. We therefore explored the ability of archaeosomes to overcome immunologic tolerance to self-antigens. Priming and boosting of mice with archaeosome-antigen evoked comparable CD8+T cell response and tumor protection to an alternate boosting strategy utilizing live bacterial vectors for antigen delivery. Vaccination with melanoma antigenic peptides TRP181-189and Gp10025-33delivered in archaeosomes resulted in IFN-γproducing antigen-specific CD8+T cells with strong cytolytic capability and protection against subcutaneous B16 melanoma. Targeting responses against multiple antigens afforded prolonged median survival against melanoma challenge. Entrapment of multiple peptides within the same vesicle or admixed formulations were both effective at evoking CD8+T cells against each antigen. Melanoma-antigen archaeosome formulations also afforded therapeutic protection against established B16 tumors when combined with depletion of T-regulatory cells. Overall, we demonstrate that archaeosome adjuvants constitute an effective choice for formulating cancer vaccines.

The Response to Repeated Vaccination with PR1 and WT1 Peptides Admixed in Montanide Adjuvant Is Transient and Fails to Induce Sustained Anti-Leukemia Responses in Patients with Myeloid Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4096-4096
Author(s):  
Katayoun Rezvani ◽  
Agnes S. M. Yong ◽  
Stephan Mielke ◽  
Behnam Jafarpour ◽  
Bipin N. Savani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Gm Csf ◽  
Cell Responses ◽  
Ifn Γ

Abstract Abstract 4096 Poster Board III-1031 We previously demonstrated the immunogenicity of a combined vaccine approach employing two leukemia-associated antigenic peptides, PR1 and WT1 (Rezvani Blood 2008). Eight patients with myeloid malignancies received one subcutaneous 0.3 mg and 0.5 mg dose each of PR1 and WT1 vaccines in Montanide adjuvant, with 100 μg of granulocyte-macrophage colony-stimulating factor (GM-CSF). CD8+ T-cell responses against PR1 or WT1 were detected in all patients as early as 1 week post-vaccination. However, responses were only sustained for 3-4 weeks. The emergence of PR1 or WT1-specific CD8+ T-cells was associated with a significant but transient reduction in minimal residual disease (MRD) as assessed by WT1 expression, suggesting a vaccine-induced anti-leukemia response. Conversely, loss of response was associated with reappearance of WT1 transcripts. We hypothesized that maintenance of sustained or at least repetitive responses may require frequent boost injections. We therefore initiated a phase 2 study of repeated vaccination with PR1 and WT1 peptides in patients with myeloid malignancies. Five patients with acute myeloid leukemia (AML) and 2 patients with myelodysplastic syndrome (MDS) were recruited to receive 6 injections at 2 week intervals of PR1 and WT1 in Montanide adjuvant, with GM-CSF as previously described. Six of 7 patients completed 6 courses of vaccination and follow-up as per protocol, to monitor toxicity and immunological responses. Responses to PR1 or WT1 vaccine were detected in all patients after only 1 dose of vaccine. However, additional boosting did not further increase the frequency of PR1 or WT1-specific CD8+ T-cell response. In 4/6 patients the vaccine-induced T-cell response was lost after the fourth dose and in all patients after the sixth dose of vaccine. To determine the functional avidity of the vaccine-induced CD8+ T-cell response, the response of CD8+ T-cells to stimulation with 2 concentrations of PR1 and WT1 peptides (0.1 and 10 μM) was measured by IC-IFN-γ staining. Vaccination led to preferential expansion of low avidity PR1 and WT1 specific CD8+ T-cell responses. Three patients (patients 4, 6 and 7) returned 3 months following the 6th dose of PR1 and WT1 peptide injections to receive a booster vaccine. Prior to vaccination we could not detect the presence of PR1 and WT1 specific CD8+ T-cells by direct ex-vivo tetramer and IC-IFN-γ assay or with 1-week cultured IFN-γ ELISPOT assay, suggesting that vaccination with PR1 and WT1 peptides in Montanide adjuvant does not induce memory CD8+ T-cell responses. This observation is in keeping with recent work in a murine model where the injection of minimal MHC class I binding peptides derived from self-antigens mixed with IFA adjuvant resulted in a transient effector CD8+ T cell response with subsequent deletion of these T cells and failure to induce CD8+ T cell memory (Bijker J Immunol 2007). This observation can be partly explained by the slow release of vaccine peptides from the IFA depot without systemic danger signals, leading to presentation of antigen in non-inflammatory lymph nodes by non-professional antigen presenting cells (APCs). An alternative explanation for the transient vaccine-induced immune response may be the lack of CD4+ T cell help. In summary these data support the immunogenicity of PR1 and WT1 peptide vaccines. However new approaches will be needed to induce long-term memory responses against leukemia antigens. To avoid tolerance induction we plan to eliminate Montanide adjuvant and use GM-CSF alone. Supported by observations that the in vivo survival of CD8+ T-effector cells against viral antigens are improved by CD4+ helper cells, we are currently attempting to induce long-lasting CD8+ T-cell responses to antigen by inducing CD8+ and CD4+ T-cell responses against class I and II epitopes of WT1 and PR1. Disclosures: No relevant conflicts of interest to declare.

Dissecting The Potential Role Of Prevnar As An Anti-Myeloma Vaccine

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1980-1980
Author(s):  
Kimberly Noonan ◽  
Lakshmi Rudraraju ◽  
Anna Ferguson ◽  
Amy Sidorski ◽  
Andrea Casildo ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
Plasma Cells ◽  
T Cell Responses ◽  
Fold Increase ◽  
T Cell Response ◽  
Cell Phenotype ◽  
Cell Responses

Abstract Background Prevnar, is a multi-valent conjugate vaccine given to children and adults over 50 for the prevention of Streptococcus pneumonia, otis media and pneumococcal pneumonia. The conjugate in Prevnar is a CRM-197 protein molecule which is a nontoxic recombinant Diphtheria toxin. Prevnar serves as an excellent tool in monitoring overall immune response changes in myeloma patients’ pre and post treatment. Humoral B-cell responses can be measured by antibody responses to the pneumococcal antigens, while T cell responses to CRM-197. Clinical Study We previously conducted a study to determine the efficacy of lenalidomide to augment vaccine specific responses in patients with myeloma. Two cohorts of patients were studied. In cohort A (N=10), the first Prevnar vaccine was given two weeks prior to starting lenalidomide and the second vaccine on day 14 of cycle 2 of lenalidomide. In cohort B (N=7), both Prevnar vaccines were given on lenalidomide (day 14 of cycle 2 and 4). As we previously reported patients in cohort B had an overall better B and T cell response to Prevnar compared to cohort A. These responses were due to an overall change in B and T cell phenotype attained with lenalidomide therapy. Results Prospectively, patients in cohort B also had an unexpected overall increase in disease response and in response duration. In Cohort A only 10% of patients responded to therapy while 60% of patients in Cohort B had a clinical response. The patients with a measurable clinical response had a 5-fold increase in the percentage of tumor specific bone marrow (BM) T cells after two vaccinations with Prevnar whereas the non-responding patients had no increase in tumor specific BM T cells. Parelleling the anti-tumor response, responders showed a 15 fold increase in CRM-197 specific BM T cells after the second vaccination. Patients with no clinical response showed minimal CRM-197 T cell immunity. CRM-197 is a specific inhibitor of HB-EGF; syndecan-1 (CD138) is an HB-EGF co-receptor as well as a marker for myeloma plasma cells. We hypothesized that HB-EGF specific responses produced by vaccination with the Prevnar vaccine, and CRM-197 specifically, may have contributed to the overall increased clinical responses in our clinical trial. Responding patients had a 5-fold increase in HB-EGF specific BM T cells after vaccine 2 while clinical non-responders had no increase in HB-EGF specific BM T cells. T cells specificity for purified HB-EGF correlated with both CRM-197 and tumor specific responses. Finally the myeloma cell lines U266, H929, KMS-11 and KMS-12 co-stained for CD138 and HB-EGF with 47% of CD138+ myeloma cells co-expressing HB-EGF. Conclusions We hypothesize that the CRM-197 moiety of the Prevnar vaccine can prime T cell responses against HB-EGF on plasma cells. This immune response, in turn, weakens the tumor stromal interactions in the tumor microenvironment and potentially enhances the anti-tumor efficacy of immunomodulatory drugs such as lenalidomide. Therefore, Prevnar may possibly serve as a candidate anti-myeloma vaccine. Disclosures: No relevant conflicts of interest to declare.

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