The Experts below are selected from a list of 4125 Experts worldwide ranked by ideXlab platform

Craig L. Slingluff - One of the best experts on this subject based on the ideXlab platform.

  • pilot trial of an indoleamine 2 3 dioxygenase 1 ido1 inhibitor plus a multipeptide Melanoma Vaccine in patients with advanced Melanoma
    Journal of Clinical Oncology, 2018
    Co-Authors: Craig L. Slingluff, David H Lawson, Steven P Fling, Ileana S Mauldin, Marc S Ernstoff, Brent A Hanks, Keith A Delman, Brian R Gastman, Judith C Kaiser, Martin A Cheever
    Abstract:

    3033Background: Melanoma metastases limit infiltration and function of antitumor T cells in part by immunosuppression with IDO1. INCB024360 (epacadostat) is an IDO1 inhibitor that normalizes serum ...

  • vaccination with Melanoma helper peptides induces antibody responses associated with improved overall survival
    Clinical Cancer Research, 2015
    Co-Authors: Caroline M Reed, Craig L. Slingluff, Ileana S Mauldin, Nicole Cresce, Walter C. Olson
    Abstract:

    Purpose: A Melanoma Vaccine incorporating six peptides designed to induce helper T-cell responses to Melanoma antigens has induced Th1-dominant CD4 + T-cell responses in most patients, and induced durable clinical responses or stable disease in 24% of evaluable patients. The present study tested whether this Vaccine also induced antibody (Ab) responses to each peptide, and whether Ab responses were associated with T-cell responses and with clinical outcome. Experimental Design: Serum samples were studied from 35 patients with stage III-IV Melanomas vaccinated with 6 Melanoma helper peptides (6MHP). IgG Ab responses were measured by ELISA. Associations with immune response and overall survival were assessed by log-rank test and χ 2 analysis of Kaplan–Meier data. Results: Ab responses to 6MHP were detected by week 7 in 77% of patients, and increased to peak 6 weeks after the last Vaccine and persisted to 6 months. Ab responses were induced most frequently to longer peptides. Of those with T-cell responses, 82% had early Ab responses. Survival was improved for patients with early Ab response ( P = 0.0011) or with early T-cell response ( P P = 0.0002). Conclusions: Vaccination with helper peptides induced both Ab responses and T-cell responses, associated with favorable clinical outcome. Such immune responses may predict favorable clinical outcome to guide combination immunotherapy. Further studies are warranted to understand mechanisms of interaction of these Abs, T-cell responses, and tumor control. Clin Cancer Res; 21(17); 3879–87. ©2015 AACR .

  • Activation, dysfunction and retention of T cells in Vaccine sites after injection of incomplete Freund’s adjuvant, with or without peptide
    Cancer Immunology Immunotherapy, 2013
    Co-Authors: Elise P Salerno, Kimberly A. Chianese-bullock, Gina R. Petroni, Mark E. Smolkin, Walter C. Olson, Sofia M Shea, Chantel Mcskimming, Craig L. Slingluff
    Abstract:

    We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV Melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund’s adjuvant (IFA) alone, or a Melanoma Vaccine in IFA. At a primary Vaccine site, all patients received a multi-peptide Melanoma Vaccine in IFA. At a replicate Vaccine site, which was biopsied, group 1 received IFA only; group 2 received Vaccine in IFA. Lymphocytes isolated from replicate Vaccine site microenvironments (VSME) were compared to time-matched peripheral blood mononuclear cells (PBMC) in ELISpot and flow cytometry assays. Compared to PBMC, the VSME had fewer naïve and greater proportions of effector memory CD8^+ T cells (T_CD8). The vast majority of T_CD8 within the VSME were activated (CD69^+), with a concentration of antigen-specific (tetramer^pos) cells in the VSME, particularly in Vaccine sites with peptide (group 2). CXCR3^+ lymphocytes were concentrated in the VSME of all patients, suggesting IFA-induced chemokine recruitment. T_CD8 expression of retention integrins αEβ7 and α1β1 was elevated in VSME, with the highest levels observed in antigen-specific cells in VSME containing peptide (group 2). T_CD8 retained in the VSME of both groups were strikingly dysfunctional, with minimal IFN-γ production in response to peptide stimulation and few tetramer^pos cells producing IFN-γ. These data suggest that Vaccine-induced selective retention and dysfunction of antigen-specific T_CD8 within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide Vaccines administered in IFA.

  • activation dysfunction and retention of t cells in Vaccine sites after injection of incomplete freund s adjuvant with or without peptide
    Cancer Immunology Immunotherapy, 2013
    Co-Authors: Elise P Salerno, Gina R. Petroni, Mark E. Smolkin, Walter C. Olson, Sofia M Shea, Chantel Mcskimming, Kimberly A Chianesebullock, Craig L. Slingluff
    Abstract:

    We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV Melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund’s adjuvant (IFA) alone, or a Melanoma Vaccine in IFA. At a primary Vaccine site, all patients received a multi-peptide Melanoma Vaccine in IFA. At a replicate Vaccine site, which was biopsied, group 1 received IFA only; group 2 received Vaccine in IFA. Lymphocytes isolated from replicate Vaccine site microenvironments (VSME) were compared to time-matched peripheral blood mononuclear cells (PBMC) in ELISpot and flow cytometry assays. Compared to PBMC, the VSME had fewer naive and greater proportions of effector memory CD8+ T cells (TCD8). The vast majority of TCD8 within the VSME were activated (CD69+), with a concentration of antigen-specific (tetramerpos) cells in the VSME, particularly in Vaccine sites with peptide (group 2). CXCR3+ lymphocytes were concentrated in the VSME of all patients, suggesting IFA-induced chemokine recruitment. TCD8 expression of retention integrins αEβ7 and α1β1 was elevated in VSME, with the highest levels observed in antigen-specific cells in VSME containing peptide (group 2). TCD8 retained in the VSME of both groups were strikingly dysfunctional, with minimal IFN-γ production in response to peptide stimulation and few tetramerpos cells producing IFN-γ. These data suggest that Vaccine-induced selective retention and dysfunction of antigen-specific TCD8 within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide Vaccines administered in IFA.

  • Usefulness of prestudy assessment of patient willingness to undergo tissue biopsy for correlative studies in a Melanoma Vaccine trial
    Clinical trials (London England), 2012
    Co-Authors: Joshua M. Judge, Kimberly A. Chianese-bullock, Anneke T. Schroen, Craig L. Slingluff
    Abstract:

    BackgroundPerforming biopsies for correlative studies in cancer trials raises ethical and regulatory concerns and may impact trial accrual negatively. However, strategies to address these concerns remain largely unexplored.PurposeWe sought to assess the perceived risk of mandatory tissue biopsies to be performed for research purposes as part of a clinical trial of a Melanoma Vaccine by administering a pretrial accrual assessment questionnaire in the population of interest. Furthermore, we explored how such survey data may be used to address potential concerns of regulatory and funding organizations that may not be able to assess the risks of those biopsies.MethodA total of 91 Melanoma patients, similar to potential participants in a Melanoma Vaccine pilot study, scored their willingness, on a 9-point Likert scale, to participate in Vaccine trials involving no skin biopsy versus a skin biopsy resulting in a 3-, 6-, or 12-cm scar. The Vaccine trial was performed with skin biopsies leaving a 6-cm scar. Accru...

Andrzej Mackiewicz - One of the best experts on this subject based on the ideXlab platform.

  • Therapeutic Melanoma Vaccine with cancer stem cell phenotype represses exhaustion and maintains antigen-specific T cell stemness by up-regulating BCL6
    Oncoimmunology, 2020
    Co-Authors: Patrycja Czerwińska, Marcin Rucinski, Nikola Agata Wlodarczyk, Anna Maria Jaworska, Iga Grzadzielewska, Katarzyna Gryska, Lukasz Galus, Jacek Mackiewicz, Andrzej Mackiewicz
    Abstract:

    We developed a therapeutic, gene-modified, allogeneic Melanoma Vaccine (AGI-101H), which, upon genetic modification, acquired Melanoma stem cell-like phenotype. Since its initial clinical trial in ...

  • Re-induction using whole cell Melanoma Vaccine genetically modified to Melanoma stem cells-like beyond recurrence extends long term survival of high risk resected patients - updated results.
    Journal for immunotherapy of cancer, 2018
    Co-Authors: Jacek Mackiewicz, Tomasz Burzykowski, Dariusz Iżycki, Andrzej Mackiewicz
    Abstract:

    AGI-101H is an allogeneic gene modified whole cell therapeutic Melanoma Vaccine, evaluated in over 400 Melanoma patients in the adjuvant and therapeutic settings. We present updated long-term survival results from two single-arm, phase II adjuvant trials (Trial 3 and Trial 5) with the focus on treatment beyond recurrence of the disease. Patients with resected high-risk Melanoma (stage IIIB-IV) were enrolled to Trial 3 (n = 99) and Trial 5 (n = 97). The primary endpoint was disease-free survival (DFS), and the secondary was overall survival (OS). In the induction phase, the Vaccine was administered every 2 weeks (eight times), followed by the maintenance phase every month until progression. At progression, maintenance was continued or re-induction was applied with or without surgery. In Trial 3, the 10-year DFS was equal to 33.0% overall and to 52.4, 25.0, and 8.7% for stage IIIB, IIIC, and stage IV patients, respectively. In Trial 5, the overall 10-year DFS was equal to 24.2%, and to 37.5, 18.0, and 17.6% for stage IIIB, IIIC, and stage IV patients, respectively. In Trial 3, the 10-year OS was equal to 42.3% overall, and to 59.5, 37.5, and 17.4% for stage IIIB, IIIC, and stage IV patients, respectively. In Trial 5, the 10-year OS was equal to 34.3% overall and to 46.9, 28.0, and 29.4% for stage IIIB, IIIC, and stage IV patients, respectively. Among the 65 patients of Trial 3 who developed progression, 43 received re-induction with (n = 22) or without (n = 21) surgery. Two patients received surgery without re-induction. All the 22 progressing patients, who did not receive re-induction, died. Among the 75 patients of Trial 5 who experienced progression, 39 received re-induction with (n = 21) or without (n = 18) surgery. Among the 36 progressing patients who did not receive the re-induction, 35 died. Surgery and re-induction reduced (independently) the increase of mortality after progression in both trials, with the effect of re-induction reaching statistical significance in Trial 5. Vaccination beyond recurrence of the disease with additional re-induction combined with surgery or alone increased long term survival of Melanoma patients. However, further studies on larger patient cohorts are required. Central Evidence of Clinical Trials (EudraCT Number 2008–003373-40 )

  • whole cell therapeutic Vaccine modified with hyper il6 for combinational treatment of nonresected advanced Melanoma
    Medicine, 2015
    Co-Authors: Jacek Mackiewicz, Tomasz Burzykowski, Aldona Karczewskadzionk, Maria Laciak, Malgorzata Kapcinska, Maciej Wiznerowicz, Monika Zakowska, Stefan Rosejohn, Andrzej Mackiewicz
    Abstract:

    Active specific immunotherapy of cancer requires an efficient induction and effector phase. The induction covers potent activation of anti-tumor response, whereas effector breaks the immunosuppression. We report efficacy of therapeutic Melanoma Vaccine (AGI-101H) used alone in advanced disease as a candidate for further combined treatment. In adjuvant setting in patients with resected metastases AGI-101H combined with surgery of recurring disease demonstrated long-term survival. Seventy-seven patients with nonresectable Melanoma (8% IIIB, 21% IIIC, 71% IV) were enrolled. AGI-101H was administered 8× every 2 weeks, and then every month. At progression, maintenance was continued or induction was repeated and followed by maintenance. Median follow-up was 139.3 months. The median overall survival (OS) was 17.3 months; in patients with WHO 0-1 was 20.3 months. Complete response (CR) and partial response (PR) were observed in 19.4% and 9% of pts. Disease control rate was 54.5% of pts. The median CR+PR duration was 32 months. Reinduction was performed in 36.3% patients following disease progression with 46.6% of CR+PR. No grade 3/4 adverse events were observed. Treatment with AGI-101H of Melanoma patients is safe and effective. AGI-101H is a good candidate for combinatorial treatment with immune check-points inhibitors or tumor hypoxia normalizators. Trial registration: EudraCT Number 2008–003373-40.

  • cpg immunostimulatory oligodeoxynucleotide 1826 enhances antitumor effect of interleukin 12 gene modified tumor Vaccine in a Melanoma model in mice
    Clinical Cancer Research, 2004
    Co-Authors: Tomasz Switaj, Ahmad Jalili, Anna Jakubowska, Nadzieja Drela, Magdalena Stoksik, Dominika Nowis, Grzegorz W Basak, Jakub Golab, Piotr J Wysocki, Andrzej Mackiewicz
    Abstract:

    Purpose: The effectiveness of interleukin (IL)-12-secreting tumor Vaccines in the treatment of mouse tumors could be enhanced by concurrent application of cytokines and costimulatory molecules. We investigated the therapeutic potential of IL-12 gene-transduced Melanoma Vaccine in combination with CpG immunostimulatory oligodeoxynucleotide (ODN) 1826, an adjuvant known to favor development of Th1-biased immune response, in a B78-H1 (B78) Melanoma model in mice. Experimental Design: Mice injected with B78 Melanoma cells were treated with irradiated IL-12 gene-transduced B78 cells [B78/IL-12(X)] and/or ODN 1826. Mechanisms responsible for the antitumor effects of the treatment were investigated using fluorescence-activated cell sorter analysis, a standard 51 Cr releasing assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and ELISA. Results: Single injection of B78/IL-12(X) cells had no effect on tumor growth, whereas seven consecutive daily injections of ODN 1826 markedly inhibited tumor progression with occasional curative effects. When used in combination, B78/IL-12(X) cells and ODN 1826 caused additional tumor growth reduction and eradication of tumors in 62% of treated mice. The combined treatment activated local inflammatory response against tumor but also induced systemic antitumor immunity. In vitro studies have shown that when used together, B78/IL-12(X) cells and ODN 1826 induced a potent Th1 response and suggested the role of IFN-γ in activation of the host immune response. The antitumor effects in double-treated mice were accompanied by the development of cytotoxic effectors in the spleen and activation of macrophages. Conclusions: The results provided the evidence that the combination of IL-12 gene-modified Melanoma Vaccine and ODN 1826 induces synergistically systemic and local antitumor immunity.

Vernon K Sondak - One of the best experts on this subject based on the ideXlab platform.

  • adjuvant immunotherapy of resected intermediate thickness node negative Melanoma with an allogeneic tumor Vaccine impact of hla class i antigen expression on outcome
    Journal of Clinical Oncology, 2002
    Co-Authors: Jeffrey A Sosman, Joseph M Unger, Lawrence E Flaherty, Raymond A Kempf, J. A. Thompson, Paul I Terasaki, Min S. Park, Vernon K Sondak
    Abstract:

    PURPOSE: An association between expression of ≥ two of five HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3; collectively called M5) and response to an allogeneic Melanoma Vaccine (Melacine; Corixa Corporation, Seattle, WA) has been described in stage IV Melanoma. This study investigated whether class I antigen expression impacted relapse-free survival (RFS) after adjuvant therapy with this Vaccine. PATIENTS AND METHODS: We performed class I (HLA-A, HLA-B, and HLA-C) serotyping on patients enrolled onto Southwest Oncology Group Trial 9035, a randomized, observation-controlled, phase III trial of adjuvant Melacine. All patients had clinically node-negative cutaneous Melanoma (1.5 to 4.0 mm). Interactions between treatment and class I antigen expression were tested. Analyses involved all serotyped patients and were adjusted for tumor thickness, method of nodal staging, sex, ulceration, and primary tumor site. RESULTS: HLA typing was performed on 553 (80%) of the 689 enrolled patients (29...

  • adjuvant immunotherapy of resected intermediate thickness node negative Melanoma with an allogeneic tumor Vaccine overall results of a randomized trial of the southwest oncology group
    Journal of Clinical Oncology, 2002
    Co-Authors: Vernon K Sondak, Joseph M Unger, Raymond A Kempf, J. A. Thompson, Jeffrey A Sosman, P Y Liu, Ralph J Tuthill, Geoffrey R Weiss, Bruce G Redman, James G. Jakowatz
    Abstract:

    PURPOSE: Patients with clinically negative nodes constitute over 85% of new Melanoma cases. There is no adjuvant therapy for intermediate-thickness, node-negative Melanoma patients. PATIENTS AND METHODS: The Southwest Oncology Group conducted a randomized phase III trial of an allogeneic Melanoma Vaccine for 2 years versus observation in patients with intermediate-thickness (1.5 to 4.0 mm or Clark’s level IV if thickness unknown), clinically or pathologically node-negative Melanoma (T3N0M0). RESULTS: Six hundred eighty-nine patients were accrued over 4.5 years; 89 patients (13%) were ineligible. Surgical node staging was performed in 24%, the remainder were clinical N0. Thirteen eligible patients refused assigned treatment: seven on the observation arm and six on the Vaccine arm. Most Vaccine patients experienced mild to moderate local toxicity, but 26 (9%) experienced grade 3 toxicity. After a median follow-up of 5.6 years, there were 107 events (tumor recurrences or deaths) among the 300 eligible patien...

  • Treating colon cancer with a Melanoma Vaccine? Preposterous?
    Annals of surgical oncology, 2001
    Co-Authors: Vernon K Sondak, Alfred E. Chang
    Abstract:

    Dr. Donald Morton and his group have never been afraid to think outside the box. While the rest of us were debating whether to do elective node dissections for Melanoma, he developed a technique to identify nodal micrometastases in the “sentinel” node, revolutionizing the management of stage I and II Melanoma in the process. But has he gone too far this time? After all, giving patients with colon cancer a Melanoma Vaccine! 1 That’s crazy—isn’t it? Maybe not. It certainly bucks the current trend toward ever more precisely defined single antigen Vaccines, such as the rash of designer peptides that are not merely disease-specific but actually restricted to use in specific subsets of patients based on HLA expression. So giving patients a “gamish” of Melanoma cells in hope of engendering an immune response to colon cancer antigens would seem to be proceeding in the opposite direction: firing blindly at the immune system and hoping a ‘golden bullet’ magically hits the target. Nonetheless, the limitations of defined-antigen Vaccine strategies are becoming apparent, 2,3 and evidence that polyvalent, autologous, and allogeneic tumor Vaccines can mediate an effective antitumor immune response is growing. 4,5 The question is no longer “If?” but “How?” Limitations of Defined Antigen Vaccines Human tumors develop in a series of evolutionary steps, during which time they evade the immune system’s surveillance mechanisms. Thus, every clinically detectable tumor is already adept to some degree at disguising itself from the immune system. Antigenic heterogeneity is the rule in tumors: even within strongly antigen-rich tumors there are at least some cells that do not express the target antigen. Moreover, most tumors are eventually capable of down-modulating antigen expression in the face of sustained immune attack. Although it is clear that on occasion immunization with a single, defined antigen can result in regression of even extensive tumor, this is the exception and not the rule. So far, successes of immunotherapy with single antigen vaccinations have been virtually entirely restricted to malignant Melanoma patients. The possibility exists that Melanoma is a unique tumor arising in a regionally immunocompromised setting (ultraviolet radiation-exposed skin), not readily generalizable to other solid tumors. Even if a tumor lacks antigen expression on a subset of its cells, a defined antigen Vaccine can still induce regression of advanced disease by killing the majority population of antigen-expressors. Ultimately, unless a more generalized immune reaction occurs (“epitope spreading”), the antigen-negative population will grow out and cause clinical relapse. This limitation is particularly glaring in the adjuvant therapy setting, where cure and not transient reduction of tumor burden is the goal. It may be that this phenomenon explains the results of a recent phase III clinical trial in which a defined antigen Vaccine (purified GM2 ganglioside conjugated to keyhole limpet hemocyanin) that achieved high levels of IgG and IgM antibody induction failed to match standard therapy with high-dose interferon-alfa 2b in high-risk Melanoma patients. 2

Donald L. Morton - One of the best experts on this subject based on the ideXlab platform.

  • effect of granulocyte macrophage colony stimulating factor on vaccination with an allogeneic whole cell Melanoma Vaccine
    Clinical Cancer Research, 2009
    Co-Authors: Mark B. Faries, Eddy C. Hsueh, Mary Hoban, Donald L. Morton
    Abstract:

    Purpose: The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy, but it also leads to uncertainty in how to combine agents and how to assess those combinations. We sought to assess the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a Melanoma Vaccine. Experimental Design: Ninety-seven patients with resected Melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular Melanoma Vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response to Melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined. Results: The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes. This arm also had diminished antiMelanoma cell delayed-type hypersensitivity response. Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune changes were accompanied by an increase in early Melanoma deaths and a trend toward worse survival with GM-CSF. Conclusion: These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution. (Clin Cancer Res 2009;15(22):7029–35)

  • Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Vaccination with an Allogeneic Whole-Cell Melanoma Vaccine
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2009
    Co-Authors: Mark B. Faries, Eddy C. Hsueh, Mary Hoban, Donald L. Morton
    Abstract:

    Purpose: The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy, but it also leads to uncertainty in how to combine agents and how to assess those combinations. We sought to assess the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a Melanoma Vaccine. Experimental Design: Ninety-seven patients with resected Melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular Melanoma Vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response to Melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined. Results: The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes. This arm also had diminished antiMelanoma cell delayed-type hypersensitivity response. Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune changes were accompanied by an increase in early Melanoma deaths and a trend toward worse survival with GM-CSF. Conclusion: These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution. (Clin Cancer Res 2009;15(22):7029–35)

  • Molecular Tumor Markers in the Blood: Early Prediction of Disease Outcome in Melanoma Patients Treated With a Melanoma Vaccine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2003
    Co-Authors: Robert A. Wascher, Donald L. Morton, Christine Kuo, Robert Elashoff, He-jing Wang, Mehri Gerami, Dave S B Hoon
    Abstract:

    Purpose: Patients with American Joint Committee on Cancer (AJCC) stage III Melanoma are at high risk of recurrence and death. We hypothesized that a multiple-marker reverse transcriptase polymerase chain reaction (MM-RT-PCR) blood assay could predict, early in the course of therapy, those patients destined to experience treatment failure with a Melanoma Vaccine (MV) previously shown to improve survival in a phase II clinical trial. Patients and Methods: After complete surgical resection, prospectively collected cryopreserved peripheral-blood lymphocyte specimens (n = 90) from the serial bleeds of 30 patients with AJCC stage III Melanoma were studied by MM-RT-PCR, using the markers tyrosinase, Melanoma antigen recognized by T cells-1 (MART-1), and universal Melanoma antigen gene-A (uMAG-A). All patients were enrolled in a phase II MV trial during the period of blood draws, and were selected for this study in a blinded fashion. Median duration of clinical follow-up was 74 months for the 13 survivors and 11 ...

  • Androgen blockade enhances response to Melanoma Vaccine.
    The Journal of surgical research, 2003
    Co-Authors: Eddy C. Hsueh, Rishab K. Gupta, Alan T. Lefor, Gary Reyzin, Donald L. Morton
    Abstract:

    Abstract Background. Because preclinical studies suggest an interaction between androgens and the immune system, we used a murine model to determine whether androgen blockade with flutamide might enhance the immunogenicity of an irradiated Melanoma cell Vaccine. Materials and methods. Forty C57BL/6 male mice were randomly assigned to four treatment groups: flutamide + RPMI (Group A), flutamide + irradiated B16 murine Melanoma cells (Group B), placebo + RPMI (Group C), and placebo + irradiated B16 cells (Group D). Splenocyte proliferation and secretion of interleukin-2 and interferon-gamma were assayed after coculturing splenocytes with irradiated B16 cells. Antibody-dependent cellular cytotoxicity (ADCC) against B16 cells was determined using peripheral blood lymphocytes. To examine the effect of treatment on tumor growth, a second set of 40 mice assigned to Groups A, B, C, and D underwent tumor challenge 7 days after the last treatment. Results. Splenocyte proliferation was significantly higher in the two groups receiving flutamide at 50 mg/kg × 7 days (29% in Groups A and B vs 3% in Group C and 7% in Group D). Secretion of interferon was significantly higher in mice receiving flutamide + irradiated B16 cells (15.2 pg/ml in Group B vs 0, 1.7, and 4 pg/ml in Groups A, C, and D, respectively; P = 0.0024). Differences in interleukin secretion were not significant. ADCC was 26% in Group B vs 15, 8, and 22% in Groups A, C, and D, respectively ( P = 0.0001). In the tumor challenge experiment, the rate of survival was 10% higher in mice receiving irradiated B16 + flutamide than in mice receiving irradiated B16 alone. Conclusion. Flutamide can enhance immune responses to an irradiated whole-cell Melanoma Vaccine. A clinical study of immunotherapeutic androgen blockade is warranted.

  • Overview of Melanoma Vaccines: Active specific immunotherapy for Melanoma patients
    Seminars in surgical oncology, 1998
    Co-Authors: David W. Ollila, Mark C. Kelley, Guy Gammon, Donald L. Morton
    Abstract:

    Although a phase III trial has yet to show a statistically significant improvement in the disease-free or overall survival of Melanoma patients receiving Vaccine therapy, several phase II trials have shown enhanced disease-free and overall survival of patients who develop a humoral and/or cellular response to a Melanoma Vaccine. The challenge of active specific immunotherapy research is to determine which combination of humoral and cellular immune responses optimizes clinical outcome and how to monitor the immune response effectively. This review identifies key components of a successful Melanoma Vaccine, discusses new ways to modulate and stimulate the immune system, and summarizes some of the important clinical trials of active specific immunotherapy for patients with Melanoma. Semin. Surg. Oncol. 14:328–336, 1998. © 1998 Wiley-Liss, Inc.

Jean-claude Bystryn - One of the best experts on this subject based on the ideXlab platform.

  • Heterogeneous antibody response to polyvalent Melanoma Vaccines in syngeneic mice.
    Cancer immunology immunotherapy : CII, 2004
    Co-Authors: Dean Johnston, Jean-claude Bystryn
    Abstract:

    In this study, a human Melanoma Vaccine induced antibody responses in mice that varied significantly from animal to animal. BALB/c mice were immunized to a xenogenic human polyvalent Melanoma Vaccine that has been used in phase II clinical trials in over 600 patients. Mice were bled biweekly for up to 6 weeks to measure antibody responses. IgG antibody responses to the Melanoma Vaccine components were detectable within 2 weeks but were much stronger at 4 and 6 weeks. When the pooled sera were further analyzed by Western blot, a complex pattern of antigens was detected. When individual sera from identically immunized mice were assayed by Western blot, a consistent, reproducible pattern of antigen recognition was not seen. Rather, we found significantly different antibody responses among the mice. Both the intensity of antibody responses and the pattern of antigens recognized varied from animal to animal. Although there appeared to be immunodominant antigens that produced antibody responses in most mice, no single antigen induced antibody responses in all mice. These results demonstrate that polyvalent Vaccines induce heterogeneous antibody responses in mice treated identically. Analysis of the response of selected Melanoma patients immunized to the same Vaccine revealed similar antibody responses to the antigens in the Melanoma Vaccine. Heterogeneity may hamper interpretation of Vaccine immunogenicity and relevant tumor antigens in humans.

  • Emerging Melanoma Vaccines.
    Expert opinion on emerging drugs, 2002
    Co-Authors: Jean-claude Bystryn
    Abstract:

    No satisfactory treatment currently exists for Melanoma once it has spread beyond its original site. At present, the only FDA-approved treatment for advanced Melanoma is IFN-α2b. Vaccines are an experimental therapy intended to stimulate the immune system to react more strongly against patients’ own Melanoma cells, thereby destroying the tumour or slowing its progression. Unfortunately, the exact tumour antigens that can stimulate an effective tumour-protective response in humans remain unknown. The approach that is increasingly followed to circumvent this problem is to prepare polyvalent Vaccines containing a variety of Melanoma antigens, as the greater the number of antigens in a Vaccine, the greater the chance it will contain the correct antigen(s) to stimulate an antitumour response. Two recent randomised trials suggest that this approach results in Vaccines that can be clinically effective. One is a double-blind, placebo-controlled trial of a polyvalent, shed antigen Melanoma Vaccine developed by Bys...

  • Double-blind trial of a polyvalent, shed-antigen, Melanoma Vaccine.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2001
    Co-Authors: Jean-claude Bystryn, Ruth Oratz, Matthew N. Harris, Anne Zeleniuch-jacquotte, Richard L. Shapiro, Daniel F. Roses
    Abstract:

    A polyvalent Melanoma Vaccine prepared from shed antigens stimulates humoral and cellular immune responses and improves survival compared with historical controls. We conducted a double-blind, prospectively randomized, placebo-controlled trial to assess whether this Vaccine could slow the progression of resected Melanoma. Thirty-eight patients with resected Melanoma metastatic to regional nodes (American Joint Committee on Cancer stage III) who had a particularly poor prognosis on the basis of the nodes being clinically positive or two or more histologically positive nodes were randomly assigned in a 2:1 ratio to treatment with 40 μg of Melanoma or placebo (human albumin) Vaccine, both of which were bound to alum as an adjuvant. Immunizations were given intradermally into the extremities every 3 weeks × 4, monthly × 3, every 3 months × 2, and then every 6 months for 5 years or until disease progression. Twenty-four patients were treated with the Melanoma, and 14 patients were treated with the placebo Vaccine. The groups were evenly balanced with respect to prognostic factors. Median length of observation was 2.5 years. There was no local or systemic toxicity. By Kaplan-Meier analysis, median time to disease progression was two and a half times longer in patients treated with Melanoma Vaccine compared with that in patients treated with placebo Vaccine, i.e., 1.6 years (95% confidence interval, 1.0–3.0 years) compared with 0.6 year [95% confidence interval, 0.3–1.9 year(s)]. By Cox proportional hazards analysis, this difference was significant at P = 0.03. Overall survival was 40% longer in the Melanoma Vaccine-treated group (median overall survival of 3.8 years versus 2.7 years), but this difference was not statistically significant. In a double-blind and placebo-controlled trial, these results suggest that immunization with a Melanoma Vaccine may be able to slow the progression of Melanoma. Although statistically significant, these results must be interpreted with caution because they are based on a small number of patients.

  • hla independent heterogeneity of cd8 t cell responses to mage 3 melan a mart 1 gp100 tyrosinase mc1r and trp 2 in Vaccine treated Melanoma patients
    Journal of Immunology, 1998
    Co-Authors: Sandra R. Reynolds, Ruth Oratz, Richard L. Shapiro, Dean Johnston, Marilena Fotino, Esteban Celis, Alessandro Sette, Jean-claude Bystryn
    Abstract:

    An important element in Melanoma Vaccine construction is to identify peptides from Melanoma-associated Ags that have immunogenic potential in humans and are recognized by CD8+ T cells in vivo. To identify such peptides, we evaluated HLA-A*02+ Melanoma patients immunized to a polyvalent Vaccine containing multiple Ags, including MAGE-3, Melan-A/MART-1, gp100, tyrosinase, melanocortin receptor (MC1R), and dopachrome tautomerase (TRP-2). Using a filter spot assay, we measured peripheral blood CD8+ T cell responses, before and after immunization, to a panel of 45 HLA-A*0201-restricted peptides derived from these Ags. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*0201. Vaccine treatment induced peptide-specific CD8+ T cell responses to 22 (47.8%) of the peptides. The most striking finding was the HLA-independent heterogeneity of responses to both peptides and Ags. All responding patients reacted to different combination of peptides and Ags even though the responding patients were all A*0201+ and the peptides were all A*0201-restricted. From 9 to 27% of patients developed a CD8+ T cell response to at least one peptide from each Ag, but no more than 3 (14%) reacted to the same peptide from the same Ag. This heterogeneity of responses to individual peptides and Ags in patients with the same haplotype points to the need to construct Vaccines of multiple peptides or Ags to maximize the proportion of responding patients.

  • Stimulation of CD8+ T cell responses to MAGE-3 and Melan A/MART-1 by immunization to a polyvalent Melanoma Vaccine.
    International journal of cancer, 1997
    Co-Authors: Sandra R. Reynolds, Ruth Oratz, Richard L. Shapiro, Phyllis Hao, Zhang Yun, Marilena Fotino, Stanislav Vukmanovic, Jean-claude Bystryn
    Abstract:

    A critical requirement for cancer Vaccines is that they stimulate CD8+ T cell responses. In this study, we tested the ability of a polyvalent Melanoma Vaccine to induce CD8+ T cell responses to the Melanoma associated antigens MAGE-3 and Melan A/MART-1. Fifteen HLA-A2+ patients with resected malignant Melanoma were immunized with the Vaccine s.c. every 2–3 weeks. CD8+ T cells in peripheral blood reacting to HLA-A2 restricted epitopes on MAGE-3 (FLWGPRALV) and Melan A/MART-1/(AAGIGILTV) were quantitated using a filter spot assay at baseline and following 4 immunizations. Vaccine immunization induced CD8+ T cells reacting to one or both of these peptides in 9 of the 15 (60%) patients. These cells were CD8+ and HLA-A2 restricted, as reactivity was abrogated by monoclonal antibodies (MAbs) to CD8 and class I HLA, but not by anti-CD4. All responding patients remained recurrence-free for at least 12 months (median 15 months, range 12 to >21 months), whereas Melanoma recurred within 3–5 months in non-responders. The differences in outcome were unrelated to differences in disease severity or overall immunological competence between responders and non-responders. Our results demonstrate directly that MAGE-3 and Melan A/MART-1 can stimulate CD8+ T cell responses in humans, and suggest that these responses are protective and surrogate markers of Vaccine efficacy. Int. J. Cancer 72:972–976, 1997. © 1997 Wiley-Liss, Inc.