Publications (6)41.06 Total impact
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Article: Apoptosis of CD4(+)CD25(high) T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2.
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ABSTRACT: Targeted molecular therapies inhibit proliferation and survival of cancer cells but may also affect immune cells. We have evaluated the effects of Sirolimus and Sorafenib on proliferation and survival of lymphoid cell subsets. Both drugs were cytotoxic to CD4(+)CD25(high) T cells, and were growth inhibitory for CD4(+) and CD8(+) T cells. Cytotoxicity depended on CD3/CD28 stimulation and was detectable within 12 h, with 80-90% of CD4(+)CD25(high) cells killed by 72 h. Cell death was due to apoptosis, based on Annexin V and 7AAD staining. Addition of IL-2 prevented the apoptotic response to Sirolimus, potentially accounting for reports that Sirolimus can enhance proliferation of CD4(+)CD25(high) cells. These results predict that Sirolimus or Sorafenib would reduce CD4(+)CD25(high) cells if administered prior to antigenic stimulation in an immunotherapy protocol. However, administration of IL-2 protects CD4(+)CD25(high) T cells from cytotoxic effects of Sirolimus, a response that may be considered in design of therapeutic protocols.Cancer Immunology and Immunotherapy 11/2008; 58(6):867-76. · 3.70 Impact Factor -
Article: Helper T-cell responses and clinical activity of a melanoma vaccine with multiple peptides from MAGE and melanocytic differentiation antigens.
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ABSTRACT: A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel melanoma vaccine comprising six melanoma-associated peptides defined as antigenic targets for melanoma-reactive helper T cells. Source proteins for these peptides include MAGE proteins, MART-1/MelanA, gp100, and tyrosinase. Thirty-nine patients with stage IIIB to IV melanoma were vaccinated with this six-peptide mixture weekly at three dose levels, with a preceding phase I dose escalation and subsequent random assignment among the dose levels. Helper T-lymphocyte responses were assessed by in vitro proliferation assay and delayed-type hypersensitivity skin testing. Patients with measurable disease were evaluated for objective clinical response by Response Evaluation Criteria in Solid Tumors. Vaccination with the helper peptide vaccine was well tolerated. Proliferation assays revealed induction of T-cell responses to the melanoma helper peptides in 81% of patients. Among 17 patients with measurable disease, objective clinical responses were observed in two patients (12%), with response durations of 1 and 3.9+ years. Durable stable disease was observed in two additional patients for periods of 1.8 and 4.6+ years. Results of this study support the safety and immunogenicity of a vaccine comprised of six melanoma helper peptides. There is also early evidence of clinical activity.Journal of Clinical Oncology 10/2008; 26(30):4973-80. · 18.37 Impact Factor -
Article: Immunity to melanoma antigens: from self-tolerance to immunotherapy.
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ABSTRACT: The development of effective immune therapy for cancer is a central goal of immunologists in the 21st century. Our laboratories have been deeply involved in characterization of the immune response to melanoma and translation of laboratory discoveries into clinical trials. We have identified a cohort of peptide antigens presented by Major Histocompatibility Complex (MHC) molecules on melanoma cells and widely recognized by T cells from melanoma patients. These have been incorporated into peptide-based vaccines that induce CD8(+) and CD4(+) T-cell responses in 80-100% of patients. Major objective clinical tumor regressions have been observed in some patients, and overall survival in vaccinated patients exceeds expected stage-specific survival. New clinical trials will determine the value of combination of melanoma helper peptides (MHP) into multipeptide vaccines targeting CD8 cells. New trials will also evaluate new approaches to modulating the host-tumor relationship and will develop new combination therapies. Parallel investigations in murine models are elucidating the immunobiology of the melanoma-host relationship and addressing issues that are not feasible to approach in human trials. Based on the fact that the largest cohort of melanoma antigens are derived from normal proteins concerned with pigment production, we have evaluated the mechanisms of self-tolerance to tyrosinase (Tyr) and have determined how T cells in an environment of self-tolerance are impacted by immunization. Using peptide-pulsed dendritic cells as immunogens, we have also used the mouse model to establish strategies for quantitative and qualitative enhancement of antitumor immunity. This information creates opportunities for a new generation of therapeutic interventions using cancer vaccines.Advances in Immunology 02/2006; 90:243-95. · 5.76 Impact Factor -
Article: Progenipoietin-generated dendritic cells exhibit anti-tumor efficacy in a therapeutic murine tumor model.
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ABSTRACT: Progenipoietin (ProGP-4) is a chimeric molecule, exhibiting both Flt-3 and granulocyte-colony stimulating factor (G-CSF) receptor agonist activities. Subcutaneous administration of ProGP-4 to BALB/c mice at a dose of 40-100 microg/day for up to 12 consecutive days induces both CD11c(+) dendritic cells (DCs) and CD11c(-)/CD11b(+) granulocytes in spleen, blood and lymph nodes of treated animals. Peak numbers of all cell populations were observed on day 7 of treatment, with CD11c(+) DCs representing approximately 8% of total splenocytes at that time. Approximately 40-50% of these CD11c(+) cells were also able to endocytose and process the exogenous fluorescent antigen DQ-BSA. As a test of their therapeutic utility, freshly prepared CD11c(+) DCs were pulsed with a defined tumor-associated peptide epitope (murine p53(232-240)) and injected as a vaccine into BALB/c mice bearing day 7 established CMS4 sarcomas. Similarly prepared DCs were injected again 1 week later. Based on our results, we conclude that (i) both peptide-pulsed CD11c(+) DCs (harvested directly from ProGP-4 treated mice) and pulsed bone marrow-derived DCs effectively slow the growth of or mediate the regression (in 25 of 89 [28%] cases) of CMS4 tumors, and (ii) nonpulsed DCs mediated minimal or no therapeutic effect. These data support the ability of ProGP-4 to enhance the peripheral frequencies of DCs that exhibit therapeutic efficacy when applied as a vaccine to treat tumor-bearing animals.International Journal of Cancer 09/2002; 100(5):586-91. · 5.44 Impact Factor -
Article: Differentiation of immunostimulatory stem-cell- and monocyte-derived dendritic cells involves maturation of intracellular compartments responsible for antigen presentation and secretion.
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ABSTRACT: Dendritic cells (DCs) are important for the induction of primary T-cell responses and may serve as "biologic adjuvants" in therapeutic protocols. However, given the "plasticity" of this antigen-presenting cell, it remains unclear which DC type (source, subtype, and stage of differentiation) should be applied clinically. To provide additional insight in this selection process, we have, for the first time, analyzed the in vitro differentiation of CD34(+) precursor-derived and monocyte-derived DCs for ultrastructure, phenotype, and function. The ultrastructural intracytoplasmic differentiation of DCs correlated with increasing T-cell stimulatory activity of these cells. "Early-stage"-DCs proliferate, exhibit high levels of soluble antigen uptake, and moderate T-cell stimulatory capacity, and are characterized by centrally located nuclei and numerous enlarged mitochondria. "Intermediate-stage"-DCs are enlarged cells with enhanced T-cell stimulatory activity and pronounced cytoplasmic protein synthesis machinery. "Late-stage" (LS)-DCs exhibit a mature secretory cell phenotype and low proliferative index. They express high levels of the HLA-DR, CD40L, B7-1, and B7-2 molecules and CD83, a specific marker of mature DCs, and appear maximally stimulatory to T cells. Ultrastructurally, LS-DCs feature an accentric nucleus, an enlarged cytoplasm, containing numerous secretory storage vesicles, along with a fully developed Golgi complex. LS-DCs exhibited numerous multivesicular and multilaminar structures containing major histocompatibility complex class II molecules, consistent with the MIIC (peptide-loading) compartment. In extended studies, cultured CD14(+) monocyte-derived DCs displayed a similar, but accelerated, temporal differentiation staging pattern.Stem Cells 02/2002; 20(5):380-93. · 7.78 Impact Factor -
Article: Immunity to Melanoma Antigens: From Self‐Tolerance to Immunotherapy
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ABSTRACT: The development of effective immune therapy for cancer is a central goal of immunologists in the 21st century. Our laboratories have been deeply involved in characterization of the immune response to melanoma and translation of laboratory discoveries into clinical trials. We have identified a cohort of peptide antigens presented by Major Histocompatibility Complex (MHC) molecules on melanoma cells and widely recognized by T cells from melanoma patients. These have been incorporated into peptide‐based vaccines that induce CD8+ and CD4+ T‐cell responses in 80–100% of patients. Major objective clinical tumor regressions have been observed in some patients, and overall survival in vaccinated patients exceeds expected stage‐specific survival. New clinical trials will determine the value of combination of melanoma helper peptides (MHP) into multipeptide vaccines targeting CD8 cells. New trials will also evaluate new approaches to modulating the host–tumor relationship and will develop new combination therapies. Parallel investigations in murine models are elucidating the immunobiology of the melanoma–host relationship and addressing issues that are not feasible to approach in human trials. Based on the fact that the largest cohort of melanoma antigens are derived from normal proteins concerned with pigment production, we have evaluated the mechanisms of self‐tolerance to tyrosinase (Tyr) and have determined how T cells in an environment of self‐tolerance are impacted by immunization. Using peptide‐pulsed dendritic cells as immunogens, we have also used the mouse model to establish strategies for quantitative and qualitative enhancement of antitumor immunity. This information creates opportunities for a new generation of therapeutic interventions using cancer vaccines.Advances in Immunology.
