Clinical BCR-ABL Peptide Vaccination in Chronic Myeloid Leukaemia: Results of the EPIC Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2197-2197
Author(s):  
Jose M. Rojas ◽  
Katy Knight ◽  
Li-Hui Wang ◽  
Richard E. Clark
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Myeloid Leukaemia ◽  
Immune Responses ◽  
Myeloid Leukaemia ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Peptide Vaccination ◽  
Molecular Responses ◽  
Junctional Region

Abstract Chronic myeloid leukaemia (CML) is characterised by the BCR-ABL oncoprotein. The amino-acid sequences spanning the junctional region are completely leukaemia-specific. In vitro pulsing of antigen presenting cells elicits immune response to CML cells. Vaccination of CML patients with peptides from this junctional region could therefore elicit/augment immune responses to CML cells. In our Evaluation of Peptide Immunisation in CML (EPIC) study, the patient’s entry requirements were as follows: first chronic phase of CML, expression of e14a2 (b3a2) BCR-ABL transcript, and prior treatment with imatinib daily (at least 400mg) at a stable dose for at least 6 months. Each patient received intradermally a cocktail of 3 BCR-ABL peptides: a 9-mer spanning the e14a2 region, the same 9-mer linked to PADRE (a 15-mer non-natural peptide shown to activate CD4+ T cells), and a 13-mer consensus e14a2 junctional peptide linked to PADRE. Peptides were administered at either 100 (5 patients), 300 (5 patients), 600 (5 patients), or 1000μg (4 patients) with sargramostim on 6 occasions over 2 months. Immune responses to the vaccine were monitored by IFN-γ and IL-5 ELISPOT assays on peripheral blood mononuclear cells. Molecular responses were assessed by quantitative real-time PCR of BCR-ABL mRNA. At entry no patient showed a detectable immune response to PADRE, but all 19 patients had detectable CD4+ T cells responses within 3 months of commencing vaccination. This indicated that the vaccination protocol was capable of stimulating T cell responses in all 19 patients. Immune responses to the 9-mer BCR-ABL junctional peptide used in the vaccine were detected in 11/19 patients, and demonstrated to be CD8+ T cells by cytokine analysis in flow cytometry. BCR-ABL immune responses were also assessed against a longer 18-mer peptide spanning the whole e14a2 junctional region. CD4+ T cells specific for this 18-mer peptide were detected in 14/19 patients. Interestingly, immunophenotyping indicated that these BCR-ABL-specific T cells were of a memory phenotype (CD45RO+). Serial molecular responses were available for at least 12 months on all cases. Of the 6 patients not in major cytogenic response (MCR) at baseline, molecular improvement was only observed in one case. However 12/13 patients in at least MCR at baseline had at least a 1 log fall in BCR–ABL transcripts, though this occurred several months after completing vaccination. Moreover, vaccination improved the fall in BCR–ABL transcripts in patients who had received imatinib for more than 12 months. These data show that peptide immunisation in CML can elicit anti-BCR-ABL peptide responses in CD4+ and CD8+ T cells. It also demonstrates that BCR-ABL peptide vaccination may improve control of CML, especially in patients responding well to imatinib.

scholarly journals The effect of Kefir on The Immune Response of Healthy Volunteers In Vitro

2017 ◽  
Vol 3 (2) ◽  
pp. 28
Author(s):  
Desie Dwi Wisudanti
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Healthy Volunteers ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Fermented Milk ◽  
Bioactive Components ◽  
Ifn Γ

Kefir is a functional foodstuff of probiotics, made from fermented milk with kefir grains containing various types of beneficial bacteria and yeast. There have been many studies on the effects of oral kefir on the immune system, but few studies have shown the effect of bioactive components from kefir (peptides and exopolysaccharides/ kefiran), on immune responses. The purpose of this study was to prove the effect of kefir supernatant from milk goat on healthy immune volunteer response in vitro. The study was conducted on 15 healthy volunteers, then isolated PBMC from whole blood, then divided into 5 groups (K-, P1, P2, P3 and P4) before culture was done for 4 days. The harvested cells from culture were examined for the percentage of CD4+ T cells, CD8+ T cells, IFN-γ, IL-4 using flowsitometry and IL-2 levels, IL-10 using the ELISA method. The results obtained that kefir do not affect the percentage of CD4+ T cells and CD8+ T cells. The higher the concentration of kefir given, the higher levels of secreted IFN- γ and IL-4, but a decrease in IL-2 levels. Significant enhancement occurred at levels of IL-10 culture PBMC given kefir with various concentrations (p <0.01), especially at concentrations of 1%. These results also show the important effects of kefir bioactive components on immune responses. The conclusion of this study is that kefir can improve the immune response, through stimulation of IL-10 secretion in vitro.

452 Combination treatment using KISIMATM protein-based cancer vaccine and systemic STING agonist results in profound modulation of tumor microenvironment and improved tumor control

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A479-A479
Author(s):  
Matteo Rossi ◽  
Elodie Belnoue ◽  
Susanna Carboni ◽  
Wilma Besson-Di Berardino ◽  
Erika Riva ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Cancer Vaccine ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Tumor Control ◽  
Therapeutic Vaccination ◽  
Potent Tumor

BackgroundKISIMATM platform allows the development of protein-based cancer vaccines able to induce a potent, tumor-specific CD8 and CD4 T cells response. While the cell penetrating peptide and the Anaxa portions confer, respectively, the cell delivery and self-adjuvanticity properties, the multiantigenic domain allows the targeting of different cancer antigens, resulting in anti-tumoral efficacy in different murine models.1 The first clinical candidate developed from KISIMATM is currently tested, together with anti-PD-1 blockade, in a phase I study in metastatic colorectal cancer patients. Stimulator of interferon genes agonists (STINGa) were shown to induce a potent type I interferon response in preclinical studies. The intratumoral administration of STINGa, to promote tumor inflammation, was shown to result in a protective spontaneous immune response in several murine tumor models. However, the encouraging preclinical results are not supported by recent clinical data, challenging the efficacy of unspecific monotherapy.As it is more and more clear that an effective cancer immunotherapy will require the combination of different treatment strategies, we investigate here the efficacy of combining KISIMATM cancer vaccine with STINGa treatment.MethodsMice were vaccinated with subcutaneous (s.c.) injection of KISIMATM vaccine combined with s.c. administration of STINGa. Safety and immunogenicity were assessed by measuring temperature, serum cytokines and the peripheral antigen-specific response. Anti-tumoral efficacy as well as in depth monitoring of TILs and tumor microenvironment modulation were assessed following therapeutic vaccination in a HPV16 E6 and E7 expressing TC-1 cold tumor model.ResultsCombination treatment was well tolerated and promoted the development of circulating antigen-specific CD8 T cells. In TC-1 tumor bearing mice, KISIMATM therapeutic vaccination resulted in the infiltration of both antigen-specific CD8 and CD4 T cells within the tumor, as well as a switch of tumor associated macrophages polarization toward the more inflammatory type 1. Combination therapy further increased the tumor microenvironment modulation induced by KISIMATM vaccine, promoting the polarization of inflammatory Thelper 1 CD4 T cells and increasing the effector function of antigen-specific CD8 T cells. The profound modulation of the tumor microenvironment induced by combination therapy enhanced the beneficial effect of KISIMATM vaccination, resulting in a prolonged tumor control.ConclusionsCombination of KISIMATM cancer vaccine with systemic STINGa treatment induces the development of a potent, tumor-specific immune response resulting in a profound modulation of the TME. As check-point inhibitor (CPI) therapy is ineffective on poorly infiltrated tumors, combination with therapies able to highly enhance tumor infiltration by T cells could expand CPI indications.Ethics ApprovalThe study was approved by the Canton of Geneva Ethic Board, under the license number GE165/19ReferenceBelnoue E, et al. Targeting self and neo-epitopes with a modular self-adjuvanting cancer vaccine. JCI Insight 2019. 4:11.

scholarly journals Sustained treatment‐free remission in chronic myeloid leukaemia is associated with an increased frequency of innate CD8(+) T‐cells

2019 ◽  
Vol 186 (1) ◽  
pp. 54-59 ◽  
Author(s):  
Emilie Cayssials ◽  
Florence Jacomet ◽  
Nathalie Piccirilli ◽  
Lucie Lefèvre ◽  
Lydia Roy ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cd8 T Cells ◽  
Treatment Free Remission

C5a Depletion As a Novel Strategy to Inhibit T Regulatory Cells and Enhance Antigen-Specific Immune Responses

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3285-3285
Author(s):  
Suresh Veeramani ◽  
George J. Weiner
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Regulatory Cells ◽  
Complement Components ◽  
Novel Strategy

Abstract Abstract 3285 Background: The complement system has complex activity that impacts on the immune response in a broad variety of ways. The current study was designed to assess the effect of complement components, specifically C5a, on the immune regulatory cells and on the development of an antigen-specific active immune response. Methods: Myeloid dendritic cells (mDCs), enriched from healthy human peripheral blood mononuclear cells, were pulsed with antigen (tetanus toxoid) and co-cultured with autologous, enriched human CD4+ T cells in the presence of various purified complement components. The percent of CD4+ T-cells that were CD25highFoxp3+ (henceforth referred to as Tregs) was determined. The presence of cytokines in supernatant of mDCs cultured with purified complement proteins was also evaluated. In murine models, the effect of C5a on in vivo induction of Tregs and on the development of immune response to ovalbumin was determined by analyzing anti-ovalbumin antibody. This was done in C5-sufficient (B10-D2-HC1) and C5-deficient (B10-D2-HC0) mice immunized with 100 μg of ovalbumin, and in wild type C57Bl/6 mice immunized with 100 μg of ovalbumin along with either irrelevant rat IgG2a (Ova+Isotype control) or rat anti-mouse C5a antibody (Ova+anti-C5a Ab). Results: In Vitro: In Vivo: Conclusions: Presence of C5a in the immune microenvironment results in increased generation of Treg cells and leads to dampening of antigen-specific immune responses. Absence or depletion of C5a results in a drop in the Tregs and a higher antigen-specific immune response. Ongoing studies are exploring the use of C5a depletion as a novel strategy to overcome the low immunogenicity of vaccines, such as cancer vaccines. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analysis of the Intratumoral Adaptive Immune Response in Well Differentiated and Dedifferentiated Retroperitoneal Liposarcoma

Sarcoma ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
William W. Tseng ◽  
Shruti Malu ◽  
Minying Zhang ◽  
Jieqing Chen ◽  
Geok Choo Sim ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Retroperitoneal Liposarcoma ◽  
Well Differentiated

Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease.

scholarly journals Using Natural Adjuvants to Stimulate Anti-Tumour Immune Responses

2021 ◽  
Author(s):  
◽  
Sabine Kuhn
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Tumour Growth ◽  
Tumour Site ◽  
Effector Cells ◽  
Draining Lymph Nodes

<p><b>The anti-tumour immune response is often not potent enough to prevent or eradicate disease. Dendritic cells (DCs) are professional antigen-presenting cells that are critical for the initiation of immune responses. While DCs frequently infiltrate tumours, lack of activation together with immuno-suppressive factors from the tumour can hamper an effective anti-tumour immune response.</b></p> <p>In this thesis, the ability of microbial stimuli and danger signals to overcome suppression and re-programme DCs and macrophages to an immuno-stimulatory phenotype was investigated. Whole live Mycobacterium smegmatis and BCG were used to provide multiple pathogen-associated molecular patterns. The intracellularly-recognised toll-like-receptor (TLR) ligands CpG and Poly IC, as well as the extracelullarly recognised TLR ligand LPS, and the danger signal monosodium-urate crystals (MSU) were also included.</p> <p>Bone-marrow derived DCs were found to respond to all adjuvants in vitro and DCs in tumour cell suspensions could be activated ex vivo. To assess the ability of adjuvants to enhance anti-tumour responses in vivo, immune-competent mice bearing established subcutaneous B16F1 melanomas were injected peri-tumorally with the different adjuvants. In line with previous reports, CpG treatment was effective in delaying tumour growth and increasing survival. A similar effect was found with Poly IC, but not with LPS, M. smegmatis, BCG or MSU alone. Combination of M. smegmatis + MSU, however, significantly delayed tumour growth and prolonged survival, while combinations of MSU + BCG or LPS were ineffective. Similar results were obtained using the B16.OVA melanoma and E.G7-OVA thymoma subcutaneous tumour models. In addition, Poly IC and MSU + M. smegmatis reduced primary tumour growth as well as lung metastases in the orthotopic 4T1 breast carcinoma model.</p> <p>Both Poly IC and MSU + M. smegmatis elicited an anti-tumour immune response that required CD8 T cells as well as NK cells. These treatments also resulted in increased proliferation of CD8 T cells and NK cells in tumour-draining lymph nodes, augmented infiltration of effector cells into the tumour, as well as enhanced production of in ammatory cytokines by effector cells and DCs in tumours. In addition, MSU + M. smegmatis also stimulated CD4 T cell proliferation, tumour-infiltrationand activation, while at the same time decreasing the frequency of regulatory T cells in tumours.</p> <p>Activation of a successful immune response to tumours was associated with early induction of IL-12 and IFNʸ, as well as moderate levels of pro-inflammatory cytokines at the tumour site and systemically. Furthermore, anti-tumour activity correlated with the induction of inflammatory monocyte-derived DCs in tumour-draining lymph nodes. These DCs were also observed in adjuvant treated tumours and their appearance was preceded by accumulation of inflammatory monocytes at the tumour site.</p> <p>These findings suggest that specific natural adjuvants can successfully modify the tumour environment and enhance the innate and adaptive anti-tumour immune response to delay tumour progression and increase survival.</p>

Immunological relevance of the tumor associated antigen (TAA) COA-1 in colorectal cancer (CRC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13590-13590
Author(s):  
D. C. Corsi ◽  
C. Maccalli ◽  
M. Ciaparrone ◽  
A. F. Scinto ◽  
G. Cucchiara ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Specific Antigen ◽  
Class Ii ◽  
Hla Typing ◽  
Class I ◽  
Mhc Molecules

13590 Background: Immunotherapy (IT) in CRC has often produced discouraging results. COA-1 is a new TAA recognized by CD4+ T cells from peripheral blood (PB) of a CRC pt; its immunogenic epitope is presented on the surface of tumor cells in association with DRβ1*1301 or *0402 HLA class II molecules. Our aim is verifying whether an immune response directed against COA-1 mediated by CD4+ T cells can be isolated from PB of CRC pts. To achieve a more efficient anti-tumor response a recognition of a specific antigen by both the CD4+ and CD8+ lymphocytes should be performed; so different epitopes deriving from the processing of the same antigen should be presented to the immune system in association with both class I and class II MHC molecules. We identified a list of COA-1 derived peptides with the calculated score for the binding to HLA-A2, the more common HLA class I molecule within the Caucasian population. A failure in generating COA-1 specific T cells was observed in stage I-II CRC pts. Methods: From Jan 04 to day PB samples from 36 CRC pts (14 stage III/ 22 stage IV) have been collected and the HLA typing has been performed. Pts. expressing HLA DRbβ*0402, HLA DRβ1*1301 or HLA-A2 have been selected to collect other blood drawns and verifying whether an immune response directed against COA-1 could be isolated from their PB. Results: 4 pts were positive for the expression of DRβ1*1301 and 2 for the expression of DRβ1*0402. PB lymphocytes have been in vitro stimulated with the COA-1 derived epitopes and tumor reactivity has been verified. An immune response directed to COA-1 was detected in the PB of these 6 pts; anti-COA-1 CD4+ T cells were in vitro isolated and their cytotoxicity measured by granzyme B release. 9 pts were positive for the expression of HLA-A2 and we are stimulating the lymphocytes isolated from these pts with 6 selected COA-1 derived peptides binding the HLA-A2. We observed specific CD8+ T cells for 2 peptides in 1 pt. Conclusions: Our data identify COA-1 like an immunogenic antigen that can evoke an anti-tumor immune response CD4+ mediated in CRC; the response correlates with disease progression. Experiments are ongoing to evaluate an immune response mediated by both CD4+ and CD8+ T cells. These results will determine whether COA-1 could be used for future protocols of IT in CRC. No significant financial relationships to disclose.

Anti-Leukemia Immune Responses in CML Patients Treated with Imatinib Mesylate.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1108-1108
Author(s):  
Christiane I.-U. Chen ◽  
Holden T. Maecker ◽  
Wesley H. Neal ◽  
Rhoda Falkow ◽  
Peter P. Lee
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Post Treatment ◽  
Leukemia Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Cytogenetic Remission ◽  
Pre Treatment

Abstract Imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, has revolutionized the treatment of patients with chronic myelogenous leukemia (CML). Most CML patients in chronic phase achieve hematologic remission with imatinib, while some achieve cytogenetic remission. As imatinib is an oral agent with few side effects, it has rapidly become the first-line therapy for most CML patients. However, this therapy does not represent a cure, as patients who discontinue the drug invariably relapse. Furthermore, imatinib resistance is beginning to emerge in some patients. Hence, the need to find alternate, potentially curative, therapies for CML remains. To date, the only curative treatment for CML is allogeneic bone marrow or stem cell transplantation (ABMT). A major mechanism of the curative potential of ABMT is immunological, as evidenced by the poor clinical outcome with T cell-depleted ABMT, and the efficacy of donor lymphocyte infusions (DLI) upon relapse. We hypothesized that an effective anti-leukemia immune response may emerge in patients entering remission on imatinib which may contribute to its clinical effectiveness. If so, strategies to further enhance this anti-leukemia immune response may lead to a potential cure. To determine if CML patients in remission on imatinib develop anti-leukemia immune responses, blood and bone marrow samples from patients before and after treatment were collected and analyzed. Pre-treatment samples were utilized as sources of autologous leukemic cells to detect anti-leukemia immune responses in post-treatment samples in IFN-g ELISPOT assays. Pre-treatment samples alone, post-treatment samples alone, and when available, serial post-treatment samples mixed together served as controls. In 9 of 14 patients investigated, IFN-g release was detected in pre- and post-treatment samples together with a median response of 22 spots above background (range 10 – 56 dots, p&lt;0.01), whereas serial post-treatment samples together in 8 patients yielded results similar to background (median 5, range 5 – 20). In 6 of these patients in hematologic (or cytogenetic) remission, sufficient cells were available to allow additional analyses via intracellular staining for IFN-g, TNF-a, and IL-2 in autologous leukemia stimulated T cells (CD4 and CD8) and NK cells. In 4 of 6 patients, leukemia-reactive T cells were detected, most prominently in CD4+ T cells expressing TNF-a (1.4 – 37%), followed by IL-2 (0.3 – 12%) and IFN-g (0.1 – 4.6%). NK cells did not show significant expression of these cytokines upon stimulation with autologous leukemia cells. In pre-treatment and post-treatment samples alone, IL-2, TNF-a, and IFN-g expression was not detectable (0 – 0.5%). These results suggest that a significant portion of CML patients in remission with imatinib develop an anti-leukemia immune response, most notably in CD4+ T cells. Mechanisms by which imatinib treatment leads to anti-leukemia immune responses, and the molecular targets to which these cells are directed, will be further investigated. This knowledge will be useful in the development of immunotherapy strategies against CML as well as other leukemias, and raises the hope that immunotherapy may be combined with imatinib to eradicate residual leukemia cells for a durable cure of the disease. intracellular cytokine staining CD4+ T Cells CD8+ T Cells IL-2 IFN- γ TNF- α IL-2 IFN- γ TNF- α pt 1 0.3 0 0.8 0.1 0.1 0.5 pt 1 0.3 0.1 1.4 0.1 0.1 0.4 pt 2 2.6 0.8 10.3 2.2 2.1 6.1 pt 3 21 2 37 2.3 0.7 1.7 pt 4 12 4.6 19 6.3 1.8 5.8

Immunomodulatory Effects of STI571 in Chronic Myeloid Leukaemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2198-2198
Author(s):  
Dagmar Bund ◽  
Ting Yang ◽  
Raymund Buhmann ◽  
Hans-Jochem Kolb
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cellular Immune Response ◽  
Myeloid Cells ◽  
Dependent Manner ◽  
Activation Markers ◽  
Cellular Immune ◽  
Antigen Presenting

Abstract Background: The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and Gleevec) is highly effective in the treatment of chronic myeloid leukaemia (CML) and has already been shown to be effective in the setting of allogeneic stem cell transplantation. But until now, less is known with respect to its immunomodulating effects. Objective: In the present survey we investigated, whether imatinib could modify the antigen-presenting capacity of myeloid cells and in turn affects the cellular immune response. Method: For this purpose, patient derived chronic myeloid cells were incubated with different concentrations of imatinib (0, 1, 2, or 5microM), characterized for their antigen-presenting profile and their stimulatory capacity in the context of HLA-matched and mismatched T-cells. After 5 days, the proliferative immune response was evaluated in presence or absence of different concentrations of imatinib and altered effector-to-target ratios. Thereby, proliferation was detected via a CFDA, SE (5,6-carboxyfluorescein diacetate succinimidyl ester) based assay. Result: The proliferative capacity of the T- cells (allogeneic, HLA-mismatched) was inhibited by imatinib in a dose-dependent manner. Also, the expression of the activation markers was reduced in the presence of the different STI571 concentrations. Moreover, myeloid blasts were sensitized for T cell mediated effector functions by pre-treatment with increasing concentrations of imatinib. Conclusion: Taken together, imatinib can interfere with the T cellular immune response in vitro, and its impact on graft-versus-leukemia (GvL) and graft-versus-host (GvH) reactions will be further investigated.

Peptide Vaccination Induces Dynamic Changes in CD4+ and CD8+ T Cell Subsets: Report on the First Peptide Vaccination Trial in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3159-3159 ◽  
Author(s):  
Krzysztof Giannopoulos ◽  
Malgorzata Kowal ◽  
Anna Dmoszynska ◽  
Jacek Rolinski ◽  
Kamila Mazurek ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Peptide Vaccination ◽  
Tetramer Staining ◽  
Induced Changes

Abstract There is an accumulation of in vivo (graft-versus-leukemia effect) and in vitro (spontaneous remissions after infections) data providing evidence that CLL might be effectively targeted by T-cell based immunotherapy. Earlier, we characterized the receptor for hyaluronic acid mediated motility (RHAMM) as antigen associated with proliferation and negative prognosis in CLL. We also demonstrated that RHAMM-derived epitope(R3)- primed T cells were able to lyse RHAMM+ target CLL cells. Therefore, we initiated a small phase I/II clinical trial with R3 peptide vaccination for patients with CLL. Six CLL patients in Binet stage 0 of the disease were vaccinated four times at a biweekly interval with HLA-A2 restricted RHAMM-derived epitope R3 (ILSLELMKL, 300μg/dose on day 3) emulsified in incomplete Freund’s adjuvant (IFA) with concomitant administration of GM-CSF (100μg/dose, days 1–5). R3-specific T-cell responses were assessed by tetramer staining and ELISPOT assays. T-cell subsets which play a role in regulation of immune responses including CD3+CD4+CD25hiCD127loFOXP3+ T regs, Th17, CD8+CD137+, CD8+CD103+ and IL-17 producing CD8+ T cells (CD8+IL-17+) were evaluated by flow cytometry. No severe adverse events greater than CTC Io skin toxicity could be observed. Four of six patients showed a reduction of WBC during vaccination. Although these WBC changes did not meet the NCI response criteria, we described these favorable hematological changes achieved in short period of immunotherapy as hematological improvement (defined as at least 20% reduction of WBC during vaccination). The immune responses were found in 5/6 patients as assessed by tetramer-staining (positive response defined as an increase of R3-specific CD8+ T cell frequency by more than 100% after vaccination) and confirmed in 4/5 as assessed by ELISPOT assay. Patients included in this study showed median Tregs frequency of 4.2%, range: 2.5–8%. There was no significant difference of Tregs percentages between patients who improved clinically when compared with non-responders (median 6.1% vs. 3.7%). Vaccination induced Tregs in 4 patients (2 non-responders and 2 responders). Two other patients who improved hematologically did not significantly change frequency of Tregs or even reduced it during vaccination (Figure 1). Median expression of CD103 on CD8+ T cells was 1.84%, range: 0.41–5.63%. In one non-responder, we observed an increase in frequency of CD103+CD8+ T-cells during vaccination from 1.46% to 2.56%. During vaccination, changes in CD8+CD103+ T cell subset did not correlate with the frequency of Tregs, nonetheless we could find an inverse correlation with inflammatory Th17 T cells (r2=−0.5, p&lt;0.05). We could find a correlation between the frequency of Tregs and activated CD8+CD69+ T cells (r2=0.51, p&lt;0.05). Interestingly, CD8+CD137+ cells correlated with CD8+IL-17+ T cells (r2=0.54, p&lt;0.05). In conclusion, peptide vaccination in CLL patients is safe and feasible to mount immune responses against the tumor antigen RHAMM. Most of patients benefited hematologically from vaccination. Although in some patients we observed an induction of tumor-specific T cells without induction of Tregs there is a rationale to add novel active agents against Tregs in future vaccination trials. Figure 1. Peptide vaccination induced changes in WBC, percentages of regulatory T cells (Tregs) as well as R3 specific tetramer ‘CD’ T cells (tetra) of A CLL patients. Patients B, C, E and F improved hematologically during vaccination. Figure 1. Peptide vaccination induced changes in WBC, percentages of regulatory T cells (Tregs) as well as R3 specific tetramer ‘CD’ T cells (tetra) of A CLL patients. Patients B, C, E and F improved hematologically during vaccination.

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