Biomedical subjects

Theresa J Goletz

Publications and source records attributed to Theresa J Goletz.

4 recordsLinked to original sources

PubMed2006

A MUC1/IL-18 DNA vaccine induces anti-tumor immunity and increased survival in MUC1 transgenic mice.

MUC1 (mucin 1) is a tumor-associated antigen that is overexpressed in many adenocarcinomas. Active immunotherapy targeting tumors expressing MUC1 could have great treatment value. MUC1 DNA vaccines were evaluated in MUC1 transgenic (MUC1.Tg) mice challenged with MC38/MUC1+ tumor cells. Vaccination with MUC1 plasmid DNA (pMUC1) alone was insufficient to induce tumor protection. However, co-administration of pMUC1 with a plasmid encoding murine interleukin-18 (pmuIL-18) resulted in significant tumor protection and survival after tumor challenge. Protection was durable in the absence of additional vaccination, as demonstrated by continued protection of vaccinated mice following tumor rechallenge. Mice surviving challenges with MC38/MUC1+ cells showed significant protection after challenge with MUC1(-) MC38 tumor cells, suggesting that these mice had developed immune responses to epitopes shared between the tumor cell lines. Antibody-mediated depletion of lymphocyte subsets demonstrated that protection was due largely to CD4+ T cells. This work demonstrates that a naked DNA vaccine can break tolerance to MUC1 and induce an immune response capable of mediating both significant protection from tumor challenge and increased survival.

Adjuvants, Immunologic↗

PubMed2006

Engineering human IL-18 with increased bioactivity and bioavailability.

Cytokines in plasmid form can act as potent adjuvants when co-administered with DNA vaccines, resulting in an enhanced immune response to the DNA-encoded antigen. This is true of interleukin-18 (IL-18), which has been shown to serve as an adjuvant in conjunction with certain DNA vaccines. To determine if the properties of IL-18 could be optimized for use as a DNA vaccine adjuvant, a model of IL-18/IL-18R binding was developed to identify variants of human IL-18 that were predicted to improve receptor interactions and potentially bioactivity. The linkage of mature IL-18 to a secretion signal sequence provided improved protein expression from mammalian cells and signal peptidase cleavage of this protein produced the authentic N-terminus. The IL-18 variant proteins secreted this way were bioactive, as demonstrated by their ability to induce interferon gamma (IFNgamma) expression by human peripheral blood mononuclear cells (PBMCs) and to bind to IL-18R, as demonstrated by BIAcore analysis. The IL-18 variants were inhibited by IL-18 binding protein (IL-18BP), the soluble inhibitor of IL-18, as measured by neutralization of the IFNgamma response in PBMCs. One variant, V11I/T63A, demonstrated increases both in bioactivity and mammalian cell expression as compared to native IL-18, indicating that this molecule may be particularly well suited for use as a DNA-encoded vaccine adjuvant.

Amino Acid Sequence↗

PubMed2004

Induction of dendritic cell maturation by IL-18.

IL-18 is a pluripotent proinflammatory cytokine produced primarily by antigen presenting cells involved in numerous aspects of immune regulation most notably on lymphoid cells. The effect of IL-18 stimulation on cells in the myeloid compartment, however, has been poorly studied. Human monocytes did not respond to IL-18. However, the human myelomonocytic cell line KG-1 and monocyte-derived dendritic cells (generated by GM-CSF+IL-4) showed a marked increase in CD83, HLA-DR, and several costimulatory molecules upon stimulation with IL-18. Furthermore, IL-18 decreased pinocytosis of these cells and increased their ability to stimulate alloreactive T cell proliferation, all characteristics of mature dendritic cells. These results suggest that IL-18 is involved in the maturation of myeloid DCs, but not differentiation of monocytes into DCs. The finding that IL-18 is involved in the maturation of dendritic cells is both novel and unexpected and indicates another important role for IL-18 as a key regulator of immune responses.

Cell Line↗

PubMed2002

Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study.

BACKGROUND: Patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma have poor prognoses and limited therapeutic options. We have investigated the use of peptide pulsed vaccination in an attempt to immunologically target the breakpoint region of tumor specific fusion proteins expressed in these tumors. PROCEDURE: Sixteen patients with recurrent, translocation positive, Ewing sarcoma, and alveolar rhabdomyosarcoma underwent apheresis for collection of peripheral blood mononuclear cells. Following countercurrent centrifugal elutriation, an apheresis product comprised predominantly of monocytes but containing small numbers of circulating immature dendritic cells was pulsed with peptides derived from the breakpoint region of the fusion proteins. Vaccines were administered intravenously concomitant with continuous intravenous rhIL-2 at 9 x 10(6) IU/m(2)/day. RESULTS: Toxicity was limited to IL-2 related effects and was generally mild. Following vaccination, all patients showed progressive disease, most in a rapid fashion following the first vaccine. One patient showed evidence of an immunologic response and another showed a mixed clinical response. Patients enrolled on this tumor vaccine trial showed significant immunosuppression and large bulky tumors. CONCLUSIONS: Peptide vaccination as administered in this trial did not alter the dismal clinical outcome for patients with recurrent pediatric sarcomas. Future trials of tumor vaccines in this population should target patient populations with improved immune competence and smaller tumor burdens. Furthermore, optimization of the antigen presenting cell populations may be important for inducing immune responses to peptide antigens.

Adolescent↗