Costimulation as a Platform for the Development of Vaccines: A Peptide-Based Vaccine Containing a Novel Form of 4-1BB Ligand Eradicates Established Tumors

Institute for Cellular Therapeutics, Department of Microbiology and Immunology, and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Cancer Research (Impact Factor: 9.33). 06/2009; 69(10):4319-26. DOI: 10.1158/0008-5472.CAN-08-3141
Source: PubMed


Vaccines represent an attractive treatment modality for the management of cancer primarily because of their specificity and generation of immunologic memory important for controlling recurrences. However, the efficacy of therapeutic vaccines may require formulations that not only generate effective immune responses but also overcome immune evasion mechanisms employed by progressing tumor. Costimulatory molecules play critical roles in modulating innate, adaptive, and regulatory immunity and have potential to serve as effective immunomodulatory components of therapeutic vaccines. In this study, we tested the function of a novel soluble form of 4-1BB ligand (4-1BBL) costimulatory molecule in modulating innate, adaptive, and regulatory immunity and assessed its therapeutic efficacy in the HPV-16 E7-expressing TC-1 cervical cancer and survivin-expressing 3LL lung carcinoma mouse models. Vaccination with 4-1BBL activated dendritic cells and enhanced antigen uptake, generated CD8(+) T-cell effector/memory responses, and endowed T effector cells refractory to suppression by CD4(+)CD25(+)FoxP3(+) T regulatory cells. Immunization with 4-1BBL in combination with an E7 peptide or survivin protein resulted in eradication of TC-1 and 3LL tumors, respectively. 4-1BBL was more effective than TLR agonists LPS, MPL, and CpG and an agonistic 4-1BB antibody as a component of E7 peptide-based therapeutic vaccine for the generation of immune responses and eradication of TC-1 established tumors in the absence of detectable toxicity. Therapeutic efficacy was associated with reversal of tumor-mediated nonresponsiveness/anergy as well as establishment of long-term CD8(+) T-cell memory. Potent pleiotropic immunomodulatory activities combined with lack of toxicity highlight the potential of 4-1BBL molecule as an effective component of therapeutic cancer vaccines.

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    • "CTL generation was determined by in vivo killing assays as described previously (Sharma et al., 2009). Briefly, antigen-loaded DCs were injected i.p. into C57BL/6 WT recipients 24 h after adoptive transfer of OT-I cells. "
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    ABSTRACT: Epidemiologic studies discovered an inverse association between immunoglobulin E (IgE)-mediated allergies and cancer, implying tumor-protective properties of IgE. However, the underlying immunologic mechanisms remain poorly understood. Antigen cross-presentation by dendritic cells (DCs) is of key importance for anti-tumor immunity because it induces the generation of cytotoxic CD8(+) T lymphocytes (CTLs) with specificity for tumor antigens. We demonstrate that DCs use IgE and FcεRI, the high-affinity IgE receptor, for cross-presentation and priming of CTLs in response to free soluble antigen at low doses. Importantly, IgE/FcεRI-mediated cross-presentation is a distinct receptor-mediated pathway because it does not require MyD88 signals or IL-12 induction in DCs. Using passive immunization with tumor antigen-specific IgE and DC-based vaccination experiments, we demonstrate that IgE-mediated cross-presentation significantly improves anti-tumor immunity and induces memory responses in vivo. Our findings suggest a cellular mechanism for the tumor-protective features of IgE and expand the known physiological functions of this immunoglobulin. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(9). DOI:10.1016/j.celrep.2015.02.015 · 8.36 Impact Factor
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    • "Immune responses to E7 expressing TC-1 tumors are driven by CD8+ T cells responding to a dominant E7 epitope (E749–57). Immunization with a synthetic peptide representing this epitope has shown therapeutic efficacy against HPV-16 E7 expressing tumors [24], providing indirect evidence for the critical role of CD8+ T cells. As a direct evidence, physical depletion of CD8+ T cells results in the abrogation of vaccine efficacy as demonstrated in this study and by others [32]. "
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    PLoS ONE 09/2013; 8(9):e73145. DOI:10.1371/journal.pone.0073145 · 3.23 Impact Factor
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    • "However, the E6/E7 peptides themselves are not often antigenic enough to induce an effective antitumor immune response. Adjuvant must be administered simultaneously [8,9,11]. "
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