IgE-Based Therapeutic Combination Enhances Antitumor Response in Preclinical Models of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC.

Phase I/II Trial of Neoadjuvant Oregovomab-based Chemoimmunotherapy Followed by Stereotactic Body Radiotherapy and Nelfinavir For Locally Advanced Pancreatic Adenocarcinoma.

Objective: Cancer antigen (CA)-125 influences progression, metastasis, and outcomes in pancreatic cancer. This phase I/II trial (NCT01959672) evaluated the safety, efficacy, and immunologic correlates of chemoimmunotherapy (CIT) with oregovomab (anti-CA-125), followed by stereotactic body radiotherapy (SBRT) with the radiosensitizer nelfinavir.

Materials And Methods: Following imaging, pathologic confirmation, and staging laparoscopy, subjects received three 3-week cycles of CIT (gemcitabine/leucovorin/fluorouracil/oregovomab).

Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors.

A substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.

Antibody-based immunotherapy of solid cancers: progress and possibilities.

Monoclonal antibodies remain a primary product option for novel cancer treatment. The properties of an antibody are a function of the antigen specificity and constant region incorporated. The rapid advance in molecular understanding of cancer biology and the host-tumor interaction has defined a new range of targets for antibody development.

Discordant biological and toxicological species responses to TLR3 activation.

Toll-like receptors (TLRs) are highly conserved type 1 membrane proteins that initiate a multiplicity of transient gene transcriptions, resulting in innate and adaptive immune responses. These essential immune responses are triggered by common TLR pattern recognition receptors of microbial products expressed through the cytoplasmic carboxy-terminal Toll/IL-1 domain. Toll/IL-1 adapter protein cascades are induced by an activated Toll/IL-1 to induce transient transcription responses.

A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy.

Background: Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.

Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells.

Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu.

Toll-like receptor-3 as a target to enhance bioactivity of cancer immunotherapy.

Objective: The purpose of this study was to explore the potential of toll-like receptor-3 stimulation, with polyI:C(12)U (poly[l].poly[C(12),U]; rintatolimod [Ampligen; Hemispherx Biopharma, Philadelphia, PA]) to enhance bioactivity of cancer immunotherapies.

Study Design: Several models of immune activation were assessed with polyI:C(12)U at concentrations that were achieved clinically.

The Immune adjuvant properties of front-line carboplatin-paclitaxel: a randomized phase 2 study of alternative schedules of intravenous oregovomab chemoimmunotherapy in advanced ovarian cancer.

Oregovomab is a monoclonal antibody that recognizes CA125 and forms circulating immune complexes that can elicit immunity against both tumor antigen and tumor. This study was designed to assess combining this immunotherapy at 2 dosing schedules with front-line chemotherapy in patients with advanced ovarian cancer. Forty patients with stage III/IV carcinomas were randomized to receive a 2 mg oregovomab infusion either the same day [simultaneous infusion (SIM)] or 1 week after [1-week delayed (OWD)] standard carboplatin-paclitaxel chemotherapy at cycles 1, 3, and 5, then quarterly for up to 11 antibody doses.

Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer.

Purpose: This phase III study tested the hypothesis that the CA-125-specific murine monoclonal antibody, oregovomab, administered as a monoimmunotherapy after front-line therapy in a selected ovarian cancer population would prolong time to relapse (TTR) and, ultimately, survival.

Patients And Methods: Patients with stage III to IV ovarian cancer with preoperatively elevated CA-125 and objectively defined characteristics were randomly assigned 4 to 12 weeks after front-line carboplatin and paclitaxel chemotherapy to maintenance monoimmunotherapy in a fully blinded protocol. Two mg of oregovomab or placebo was infused over 20 minutes at weeks 0, 4, and 8 and then 12 weeks until recurrence or up to year 5.

CA125 velocity at relapse is a highly significant predictor of survival post relapse: results of a 5-year follow-up survey to a randomized placebo-controlled study of maintenance oregovomab immunotherapy in advanced ovarian cancer.

This report presents final survival survey results from a previously reported study using oregovomab immunotherapy in patients with advanced ovarian epithelial cancer. Follow-up surveys to 5 years from randomization were collected for the cohort of stage III/IV ovarian cancer patients achieving initial remission who received subsequent maintenance immunotherapy with oregovomab or placebo. The relationship of time-to-relapse, survival postrelapse, and overall survival was analyzed.

Role of monoclonal antibodies in tumor-specific immunity.

Monoclonal antibodies, considered to be 'magic bullets' 20 years ago, may finally be realizing their full potential, particularly in the area of oncology, where > 10 monoclonal antibodies are approved for treatment. Monoclonal antibodies are being used to modulate tumor-specific immunity through several approaches: antibodies that direct cytotoxicity against the tumor through cellular or complement-mediated pathways; antibodies that directly modulate immune regulation; antibodies that alter tolerance to tumor antigens; and antibodies that act as antigen mimetics through the anti-idiotype network. Therapeutic progress in these areas is reviewed as well as the potential to combine these approaches with standard therapies.

Monoclonal antibody therapy of ovarian cancer.

Despite advances in understanding and treatment, ovarian cancer remains a major cause of cancer mortality worldwide. Debulking surgery and paclitaxel/carboplatin chemotherapy induce good initial responses in most patients, although most cases of advanced disease are not controlled. Monoclonal antibodies hold promise as a potential incremental advance for the treatment of the disease.

Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer.

Purpose: To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study.

Patients And Methods: Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR).

CA125- and tumor-specific T-cell responses correlate with prolonged survival in oregovomab-treated recurrent ovarian cancer patients.

Objective: To evaluate immune responses and clinical outcomes for combined oregovomab and chemotherapy treatment of patients with recurrent ovarian cancer.

Methods: Patients with advanced recurrent ovarian cancer were administered oregovomab over 12 weeks before chemotherapy, then optionally concurrent with chemotherapy x 2. Antibody responses, including human anti-mouse antibody (HAMA), anti-idiotypic antibody (Ab2) and anti-CA125, were assessed by ELISA; T-cell responses to CA125, autologous tumor and oregovomab by interferon (IFN)-gamma enzyme-linked immunoSPOT (ELISPOT) were also evaluated.

Using antibodies in tumour immunotherapy.

The role of antibodies as therapeutic cancer vaccines includes two distinct approaches, which are summarised in this review, namely anti-idiotypic vaccines and antigen-antibody complex therapies. Bispecific antibodies directed against T cells or antigen-presenting cells are also referenced. The report focuses on theoretical issues, laboratory data on the mechanism of action, examples of humoral and cellular immune induction, and novel therapeutic advances in vaccine development.

Immunomodulation with antibodies: clinical application in ovarian cancer and other malignancies.

This review identifies the role of antibodies in the field of therapeutic cancer vaccines. Ovarian cancer is used as a model to review advances in therapeutic vaccine development with a focus on antibodies as immunomodulators and antigen mimetics, highlighting research on B43.13 and ACA125.

Immune responses to murine monoclonal antibody-B43.13 correlate with prolonged survival of women with recurrent ovarian cancer.

Objective: We evaluated the therapeutic efficiency of the murine monoclonal antibody-B43.13 in the treatment of patients with recurrent ovarian cancer.

Study Design: This was a retrospective study of immune responses and survival in 44 patients who were treated with technetium 99m-labeled monoclonal antibody-B43.

Biologic and immunologic therapies for ovarian cancer.

Biologic therapy of ovarian cancer has been conducted using nonspecific biologic response modifiers, cytokines, monoclonal antibodies (MAbs), vaccines, and gene therapy. Antibodies directed toward her2/neu have also been studied. Phase I and II gene therapy trials using adenoviral vectors containing a wild-type or modified p53 have shown that the treatment is well tolerated.