No Effect of Vitamin C Administration on Neutrophil Recovery in Autologous Stem Cell Transplantation for Myeloma or Lymphoma: A Blinded, Randomized Placebo-Controlled Trial.

Vitamin C is an important micronutrient for various immune cells. It increases phagocytic cell function and is necessary for T and natural killer (NK) cell development. Patients in need of an autologous hematopoietic stem cell transplantation (HSCT) are often vitamin C-depleted.

Phase 1/2 study of subcutaneous and intradermal immunization with a recombinant MAGE-3 protein in patients with detectable metastatic melanoma.

The purpose of this phase 1/2 study was to evaluate toxicity, tumor evolution and immunologic response following administration of a fixed dose of a recombinant MAGE-3 protein by subcutaneous and intradermal routes in the absence of immunologic adjuvant. Thirty-two patients with detectable metastatic melanoma expressing gene MAGE-3 were included and 30 received at least one injection with a fixed dose of a ProtD-MAGE-3 fusion protein. The immunization schedule included 6 intradermal and subcutaneous injections at 3-week intervals.

Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy.

Epidermal growth factor receptor (EGF-R) overexpression is common in a large number of solid tumors and represents a negative prognostic indicator. Overexpression of EGF-R is strongly tumor associated, and this tyrosine kinase type receptor is considered an attractive target for Ab therapy. In this study, we describe the evaluation of mAb 2F8, a high avidity human mAb (IgG1kappa) directed against EGF-R, developed using human Ig transgenic mice.

Serum activity of prolyl endopeptidase, but not of dipeptidyl peptidase IV, is decreased by immunotherapy with IFN-alpha in high-risk melanoma patients.

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.

Pegylated interferon-alpha2b treatment in melanoma patients: influence on amino acids, 5-hydroxyindolacetic acid and pteridine plasma concentrations.

Our objective was to study the influence of pegylated interferon-alpha2b (PEG-IFN-alpha) on the metabolism of amino acids and pteridines. We used an exploratory study into plasma concentrations of large neutral amino acids, 5-hydroxyindolacetic acid (5-HIAA), total biopterin (BIOP) and neopterin (NEOP) in 40 high-risk melanoma patients. Patients were randomized to treatment with PEG-IFN-alpha once a week in a dose of 6 microg/kg/week s.

CpG oligodeoxynucleotides enhance FcgammaRI-mediated cross presentation by dendritic cells.

Dendritic cells (DC) can trigger naive CD8(+) T cell responses by their capacity to cross-present exogenous antigens via the major histocompatibility complex class I pathway. The myeloid class I IgG receptor, FcgammaRI (CD64), is expressed on DC, and in vivo targeting of antigens to FcgammaRI induces strong humoral and cellular immune responses. We studied the capacity of human FcgammaRI (hFcgammaRI) to facilitate DC-mediated cross presentation and T cell activation, and assessed the effect of CpG oligodeoxynucleotides on this process.

Phase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI x anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer.

A phase I study of the bispecific antibody MDX-H210 in combination with granulocyte colony-stimulating factor (G-CSF) was performed in stage IV breast carcinoma patients, overexpressing HER-2/neu. MDX-H210, constructed by crosslinking antigen binding fragments (F(ab') fragments) of monoclonal antibody (mAb) H22 to Fc gamma receptor I (FcgammaRI), and mAb 520C9 to HER-2/neu, respectively, mediates the lysis of tumour cells in vitro, and in human FcgammaRI transgenic mouse models. The proto-oncogene HER-2/neu is overexpressed in approximately 30% of breast cancer patients, and represents a promising target for antibody-based immunotherapy.

CpG-A and B oligodeoxynucleotides enhance the efficacy of antibody therapy by activating different effector cell populations.

Immunostimulatory CpG oligodeoxynucleotides (ODNs) can enhance the therapeutic effect of monoclonal antibodies (mAbs) by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). Distinct classes of CpG ODNs have been found recently to stimulate different effector cell populations. We used murine cancer models to explore the role of various effector cell populations in the antitumor activity seen with mAbs combined with CpG ODNs of the A and B classes.

IL-12: a promising adjuvant for cancer vaccination.

The clinical development of interleukin 12 (IL-12) as a single agent for systemic cancer therapy has been hindered by its significant toxicity and disappointing anti-tumor effects. The lack of efficacy was accompanied by, and probably related to, the declining biological effects of IL-12 in the course of repeated administrations at doses approaching the maximum tolerated dose (MTD). Nevertheless, IL-12 remains a very promising immunotherapeutic agent because recent cancer vaccination studies in animal models and humans have demonstrated its powerful adjuvant properties.

Mac-1 (CD11b/CD18) is crucial for effective Fc receptor-mediated immunity to melanoma.

Antibody-reliant destruction of tumor cells by immune effector cells is mediated by antibody-dependent cellular cytotoxicity, in which Fc receptor (FcR) engagement is crucial. This study documents an important role for the beta(2) integrin Mac-1 (CD11b/CD18) in FcR-mediated protection against melanoma. CD11b-deficient mice, those that lack Mac-1, were less protected by melanoma-specific monoclonal antibody TA99 than wild-type (WT) mice.

FcgammaRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses, and protection from bacterial infection.

The high-affinity receptor for IgG, FcgammaRI, shares its capacity to bind IgG2a immune complexes (IgG2a-IC) with the low-affinity receptor FcgammaRIII and complement factors, hampering the definition of its biological role. Moreover, in vivo, FcgammaRI is occupied by monomeric IgG2a, reducing its accessibility to newly formed IgG2a-IC. By using a variety of FcgammaR(-/-) mice, we demonstrate that in the absence of FcgammaRI, the IgG2a-IC-induced cellular processes of phagocytosis, cytokine release, cellular cytotoxicity, and antigen presentation are impaired.

Preclinical and clinical data with bispecific antibodies recruiting myeloid effector cells for tumor therapy.

Bispecific antibodies constitute a novel approach to improve antibody efficacy. In vitro, constructs to recruit myeloid effector cells have been extensively investigated, and first animal data in human Fc receptor transgenic mice confirmed their promising therapeutic potential. Clinical experience with these constructs demonstrated acceptable toxicity, and support therapeutic efficacy in subgroups of patients.

Immunotherapeutic perspective for bispecific antibodies.

Bispecific antibodies (BsAb) can, by virtue of combining two binding specificities, improve the selectivity and efficacy of antibody-based treatment of human disease. Recent studies underline the importance of both the 'anti-trigger' and 'anti-target' modalities of BsAb for therapeutic efficacy. Several BsAb induce effective cytotoxicity as well as 'vaccine effects' in vivo.

Generation of HER-2/neu-specific cytotoxic neutrophils in vivo: efficient arming of neutrophils by combined administration of granulocyte colony-stimulating factor and Fcgamma receptor I bispecific antibodies.

Abs are able to induce inflammatory antitumor responses by recruiting IgG Fc receptor (FcgammaR)-bearing cytotoxic effector cells. We recently described the capacity of the high affinity FcgammaRI (CD64) to trigger cytotoxic activity of neutrophils (PMN) during granulocyte CSF (G-CSF) treatment. To take advantage of FcgammaRI as a cytotoxic trigger molecule on PMN, two Ab constructs were prepared.

Cyclosporin for thrombotic thrombocytopenic purpura after autologous bone marrow transplantation.

Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) is a serious complication that, in contrast to classic TTP, is generally not responsive to therapeutic plasma exchange. We describe the remission of TTP after autologous BMT by administration of cyclosporin in four patients, either after failure of plasmapheresis (two patients) or as primary treatment modality (two patients). Cyclosporin may be an attractive drug for post autologous BMT-TTP.