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1.
Mol Cancer Ther ; 20(12): 2457-2468, 2021 12.
Article in English | MEDLINE | ID: mdl-34625505

ABSTRACT

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. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE potential against pancreatic cancer. Our study demonstrates the notable expression of FceRI (receptor for IgE antibody) in tumors from PDAC patients. Our study showed that administration of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust antitumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that the antigen specificity of the IgE antibody plays a vital role in executing the antitumor response as nonspecific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.


Subject(s)
Adenocarcinoma/drug therapy , Carcinoma, Pancreatic Ductal/drug therapy , Immunoglobulin E/therapeutic use , Animals , Humans , Immunoglobulin E/pharmacology , Mice
2.
Am J Clin Oncol ; 42(10): 755-760, 2019 10.
Article in English | MEDLINE | ID: mdl-31513018

ABSTRACT

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). Thereafter, nelfinavir was delivered (1250 mg bid) for 5 weeks, with SBRT (40 Gy/5 fractions) occurring during the third week of nelfinavir. Following another cycle of CIT, pancreaticoduodenectomy was performed if resectable. Three more cycles of CIT were then delivered (total 7 cycles). In subjects with high (≥10 U/mL) CA-125, oregovomab (2 mg) was administered for 7 total doses (3 pre-SBRT, 1 between SBRT and resection, and 3 postoperatively). The enzyme-linked immunospot assay evaluated the development of CA-125-specific CD8 T-lymphocytes. RESULTS: The trial was prematurely closed because gemcitabine/leucovorin/fluorouracil was replaced by FOLFIRINOX and gemcitabine/nab-paclitaxel as the standard of care. Median follow-up was 13 months. Of 11 enrolled patients, 10 had high CA-125; 1 patient suffered an unexpected cardiac-related death, so 9 subjects received oregovomab. Ten received SBRT and 4 underwent resection. Overall, 6/11 patients experienced any grade ≥3 event. The median survival and time to progression were 13 and 8.6 months, respectively. Five patients had samples available for immunospot testing, of whom 2 (40%) developed CA-125-specific CD8 T-lymphocytes. CONCLUSION: A combined pancreatic cancer multimodality approach using CIT and radiosensitized radiotherapy is feasible and safe; delivery of immunotherapy can lead to T-cell immunity. Re-evaluation with modern systemic paradigms is recommended.


Subject(s)
Adenocarcinoma/therapy , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Nelfinavir/therapeutic use , Neoadjuvant Therapy/methods , Pancreatic Neoplasms/therapy , Radiosurgery/methods , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CA-125 Antigen/blood , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Combined Modality Therapy , Disease-Free Survival , Female , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Leucovorin/adverse effects , Leucovorin/therapeutic use , Magnetic Resonance Imaging/methods , Male , Membrane Proteins/blood , Middle Aged , Nelfinavir/adverse effects , Neoplasm Invasiveness/pathology , Organoplatinum Compounds/adverse effects , Organoplatinum Compounds/therapeutic use , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreaticoduodenectomy/methods , Proportional Hazards Models , Risk Assessment , Survival Analysis , Time Factors , Tomography, X-Ray Computed/methods , Treatment Outcome
3.
Cancer Immunol Immunother ; 67(3): 445-457, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29204701

ABSTRACT

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-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5 + anti-PD-L1 + PolyICLC induced rejection of human MUC1 expressing tumors and provided a long-lasting, MUC1-specific cellular immune response, which could be adoptively transferred and shown to provide protection against tumor challenge in human MUC1 transgenic (MUC.Tg) mice. Furthermore, antibody depletion studies revealed that CD8 cells were effectors for the MUC1-specific immune response generated by the mAb-AR20.5 + anti-PD-L1 + PolyICLC combination. Multichromatic flow cytometry data analysis demonstrated a significant increase over time in circulating, activated CD8 T cells, CD3+CD4-CD8-(DN) T cells, and mature dendritic cells in mAb-AR20.5 + anti-PD-L1 + PolyICLC combination-treated, tumor-bearing mice, as compared to saline-treated control counterparts. Our study provides a proof of principle that an effective and long-lasting anti-tumor cellular immunity can be achieved in pancreatic tumor-bearing hosts against their own antigen (MUC1), which can be further potentiated using a vaccine adjuvant and an immune checkpoint inhibitor.


Subject(s)
Antibodies, Monoclonal/administration & dosage , B7-H1 Antigen/antagonists & inhibitors , Carboxymethylcellulose Sodium/analogs & derivatives , Deoxycytidine/analogs & derivatives , Mucin-1/genetics , Pancreatic Neoplasms/mortality , Poly I-C/administration & dosage , Polylysine/analogs & derivatives , Animals , Antimetabolites, Antineoplastic/administration & dosage , Carboxymethylcellulose Sodium/administration & dosage , Cytotoxicity, Immunologic , Deoxycytidine/administration & dosage , Humans , Immunity, Cellular , Mice , Mice, Transgenic , Mucin-1/chemistry , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/prevention & control , Polylysine/administration & dosage , Survival Rate , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Gemcitabine
4.
Immunotherapy ; 7(8): 923-39, 2015.
Article in English | MEDLINE | ID: mdl-26314410

ABSTRACT

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. The clinical success of the checkpoint inhibitors has validated immune modulation and mobilization as a therapeutic approach. Solid cancers are distinguished from hematologic malignancies because the solid tumor stroma contains significant tumor promoting and immune dampening elements less prominent in hematologic cancer. This review highlights how engineered monoclonal antibody products are emerging as potential cornerstones of new more personalized cancer treatment paradigms that target both tumor and the stromal environment.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunotherapy/methods , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Antibodies, Monoclonal/immunology , Homeostasis/drug effects , Homeostasis/immunology , Humans , Immune System/cytology , Immune System/drug effects , Immune System/immunology , Immunotherapy/trends , Models, Immunological , Molecular Targeted Therapy/trends , Neoplasms/blood supply , Neoplasms/immunology , Neovascularization, Pathologic/immunology , Neovascularization, Pathologic/prevention & control
5.
Am J Pathol ; 184(4): 1062-1072, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24486326

ABSTRACT

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. All TLRs, with the exception of TLR3, use an MyD88 adapter to Toll/IL-1 to initiate a proinflammatory cascade. TLR3 uses the toll receptor 3/4 induction factor adapter to initiate a different cytosolic adapter cascade with double-stranded RNA agonists. This non-MyD88 pathway induces both NF-κB and type 1 interferon responses. By using a TLR3-restricted double-stranded RNA agonist, rintatolimod, we demonstrate significant unexpected differences in toxic responses between rats and primates. The mechanism of this differential response is consistent with a relative down-regulation of the NF-κB inflammatory cytokine induction pathway in the cynomolgus monkey and humans, but not observed systemically in rat. Our findings suggest evaluation of TLR3 agonists in drug therapy.


Subject(s)
Inflammation/metabolism , Poly I-C/pharmacology , Poly U/pharmacology , Species Specificity , Toll-Like Receptor 3/antagonists & inhibitors , Amino Acid Sequence , Animals , Dogs , Fatigue Syndrome, Chronic/drug therapy , Humans , Inflammation/immunology , Macaca fascicularis , Maximum Tolerated Dose , Molecular Sequence Data , Rabbits , Rats , Rats, Sprague-Dawley
6.
BMC Cancer ; 13: 195, 2013 Apr 17.
Article in English | MEDLINE | ID: mdl-23594731

ABSTRACT

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 AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 and CD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa. METHODS: Binding characteristics of the antibody were determined by ELISA and flow cytometry. In vitro degranulation was determined by the release of ß-hexosaminidase from effector cells. In vivo degranulation was monitored in human FcεRIα transgenic mice using the passive cutaneous anaphylaxis assay. These mice were also used for a vaccination study to determine the in vivo anti-cancer effects of this antibody. Significant differences in survival were determined using the Log Rank test. In vitro T-cell activation was studied using human dendritic cells and autologous T cells. RESULTS: The anti-PSA IgE, expressed in murine myeloma cells, is properly assembled and secreted, and binds the antigen and FcεRI. In addition, this antibody is capable of triggering effector cell degranulation in vitro and in vivo when artificially cross-linked, but not in the presence of the natural soluble antigen, suggesting that such an interaction will not trigger systemic anaphylaxis. Importantly, the anti-PSA IgE combined with PSA also triggers immune activation in vitro and in vivo and significantly prolongs the survival of human FcεRIα transgenic mice challenged with PSA-expressing tumors in a prophylactic vaccination setting. CONCLUSIONS: The anti-PSA IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection. Further studies on this antibody as a potential PCa therapy are warranted.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Cell Degranulation/drug effects , Immunoglobulin E/therapeutic use , Immunologic Factors/therapeutic use , Prostate-Specific Antigen/immunology , Prostatic Neoplasms/therapy , Receptors, IgE/immunology , Animals , Cell Degranulation/immunology , Dendritic Cells , Humans , Immunoglobulin E/pharmacology , Kaplan-Meier Estimate , Lymphocyte Activation/drug effects , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , T-Lymphocytes , Vaccination
7.
Cancer Immunol Immunother ; 61(7): 991-1003, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22127364

ABSTRACT

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. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FcεRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECD(HER2)) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FcεRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECD(HER2). Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FcεRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers.


Subject(s)
Breast Neoplasms/immunology , Breast Neoplasms/therapy , Immunization, Passive/methods , Immunoglobulin E/pharmacology , Receptor, ErbB-2/immunology , Animals , Antibody Specificity , Breast Neoplasms/enzymology , CHO Cells , Cell Line, Tumor , Cricetinae , Female , Humans , Immunoglobulin E/immunology , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , Rats , Xenograft Model Antitumor Assays
9.
Am J Obstet Gynecol ; 202(6): 608.e1-8, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20080226

ABSTRACT

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. Dendritic cell maturation and antigen-specific immune responses were evaluated in vitro and in a murine model. The potential for polyI:C(12)U to enhance antibody-dependent cellular cytotoxicity against tumor was also evaluated. RESULTS: Dendritic cells are matured and T-cell stimulation is enhanced in the presence of polyI:C(12)U. In addition, polyI:C(12)U induced the release of proinflammatory chemokines and cytokines. Prostate-specific antigen-specific T-cell and antibody responses were enhanced significantly in a BALB/c prostate-specific antigen transgenic mouse model. Finally, rituximab-mediated antibody-dependent cellular cytotoxicity against tumor targets was improved significantly by the addition of polyI:C(12)U. CONCLUSION: PolyI:C(12)U shows promise as a potential agent for selective enhancement of effect with currently available and future cancer immunotherapies.


Subject(s)
Dendritic Cells/immunology , Immunotherapy/methods , Toll-Like Receptor 3/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , Cancer Vaccines/immunology , Cell Line, Tumor , Cells, Cultured , Cytokines/immunology , Dendritic Cells/cytology , Humans , Mice , Prostate-Specific Antigen/immunology , Rituximab , T-Lymphocytes/immunology
10.
J Immunother ; 32(1): 54-65, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19307994

ABSTRACT

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. The primary end point was antibody response to oregovomab. Secondary end points included cellular immune response, response rate to front-line treatment, and progression-free survival. A different immune response pattern was observed between the SIM arm and the OWD arm, baseline plasma cytokines were balanced. Humoral immunity occurred more rapidly (P=0.0033) and with greater magnitude in the SIM arm. Absolute lymphocyte counts decreased in the SIM arm at cycles 3 and 5 compared with baseline. Treatment emergent CA125-specific cellular immunity was measured more commonly with SIM (P=0.04) and clinical parameters directionally favored this schedule. The immune responses were stronger than those measured in a previous maintenance monoimmunotherapy protocol. Immunotherapy-associated toxicity was minimal in this study. Front-line chemotherapy with carboplatin-paclitaxel has immune adjuvant properties when combined with oregovomab immunotherapy; however, schedule is important. SIM strategies of carboplatin and paclitaxel should be further studied with oregovomab and other antigen-specific cancer immunotherapy approaches.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols , Carboplatin/administration & dosage , Ovarian Neoplasms/drug therapy , Paclitaxel/administration & dosage , Adjuvants, Immunologic/adverse effects , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/adverse effects , CA-125 Antigen/blood , Carboplatin/adverse effects , Cytokines/immunology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Drug Administration Schedule , Female , Humans , Immunotherapy , Interferon-gamma/immunology , Interferon-gamma/metabolism , Kaplan-Meier Estimate , Middle Aged , Ovarian Neoplasms/mortality , Paclitaxel/adverse effects
11.
J Clin Oncol ; 27(3): 418-25, 2009 Jan 20.
Article in English | MEDLINE | ID: mdl-19075271

ABSTRACT

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. Patients were evaluated with serial imaging and clinical evaluation for evidence of recurrence at quarterly visits. TTR was the primary end point. RESULTS: Three hundred seventy-three patients were accrued at more than 60 centers; 251 patients were assigned to oregovomab and 120 patients were assigned to placebo. The treatment arms were well balanced. There were no differences in the clinical outcomes between treatment groups. Median TTR measured from randomization after completion of chemotherapy for the integrated study was 10.3 months (95% CI, 9.7 to 13.0 months) for oregovomab and 12.9 months (95% CI, 10.1 to 17.4 months) for placebo (P = .29, log-rank test). The treatment was well tolerated. Grade 3 to 4 toxicity was reported in 24.6% of patients in the placebo group and 20.1% of patients in the oregovomab group, respectively. CONCLUSION: Although oregovomab has demonstrated bioactivity, the strategy of monoimmunotherapy is not effective as maintenance therapy after front-line treatment of a favorable subset of patients with advanced ovarian cancer. Future studies of this or other tumor-antigen specific immunization strategies should seek ways to further augment induced immunity.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunotherapy/methods , Ovarian Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Murine-Derived , Antibodies, Neoplasm/adverse effects , Antibodies, Neoplasm/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , CA-125 Antigen/immunology , Carboplatin/therapeutic use , Female , Humans , Immunotherapy/adverse effects , Middle Aged , Neoplasm Recurrence, Local , Ovarian Neoplasms/mortality , Paclitaxel/therapeutic use , Treatment Outcome
12.
J Immunother ; 31(2): 207-14, 2008.
Article in English | MEDLINE | ID: mdl-18481390

ABSTRACT

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. One hundred forty-five patients in the intent-to-treat population and the hypothesis generating subset of 67 patients (debulked to < or =2 cm, CA125 < or =65 U/mL before cycle 3, normal CA125 and no evidence of disease postchemotherapy) previously reported were evaluated for long-term outcomes. Patterns of relapse and survival were consistent in both groups for the intent-to-treat population. Median survival time was 57.5 months for oregovomab and 48.6 months for placebo with an adjusted hazard ratio of 0.72 (95% confidence interval, 0.41-1.25). Median survival has not been reached in the hypothesis generating subset of patients receiving oregovomab. Cox multivariate regression analysis identified velocity of CA125 rise at relapse to be a highly statistically significant predictor of postrelapse outcome (P = 0.006). Although time-to-relapse may be a useful surrogate of survival in ovarian cancer immunotherapy studies, 5 years of follow-up has proved insufficient to permit a definitive survival analysis and it has been extended in ongoing phase III studies of oregovomab. Velocity of CA125 rise at relapse is a highly significant predictor of survival after relapse.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunotherapy/methods , Ovarian Neoplasms/therapy , Proteins/analysis , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived , Cohort Studies , Female , Follow-Up Studies , Humans , Immunotherapy/statistics & numerical data , Intracellular Signaling Peptides and Proteins , Kaplan-Meier Estimate , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Prognosis , Proportional Hazards Models , Recurrence , Survival Analysis
14.
Expert Opin Biol Ther ; 7(3): 331-43, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17309325

ABSTRACT

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.


Subject(s)
Antibodies, Monoclonal/immunology , Neoplasms/immunology , Antibodies, Anti-Idiotypic/immunology , Antigen-Presenting Cells/immunology , Cytotoxicity, Immunologic , Humans
15.
Expert Rev Anticancer Ther ; 5(1): 87-96, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15757441

ABSTRACT

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. Antibodies can be used to stimulate the immune response, target tumor-specific receptors to induce antibody-dependent cellular cytotoxicity or interfere with biologic pathways. They can also be used to deliver therapeutic radioisotopes to malignant cells. Oregovomab is in Phase III clinical trials as a consolidation treatment post front-line therapy to trigger tumor-specific cellular immunity. Bevacizumab, which blocks vascular endothelial growth factor, will be entering Phase III as an adjuvant to front-line chemotherapy with a direct effect on angiogenesis. Additional immunostimulating, immune counter-regulatory and receptor-targeting approaches are also reviewed. The family of epidermal growth factor receptors including epidermal growth factor receptor 1 (HER-1) and 2 (HER-2) are both expressed in ovarian cancer and are the subject of ongoing research and development. The recent disappointing results with 90-yttrium-labeled anti-HMFG by single intraperitoneal administration have left the radiopharmaceutical field without a Phase III candidate. Identification of novel targets may advance this therapeutic area in the future. The rapid advances in the fields of immunoregulation and tumor biology should permit an accelerated introduction of antibodies for the treatment of ovarian cancer. These antibodies could complement novel small molecules that are also in development.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/immunology , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , ErbB Receptors/drug effects , ErbB Receptors/physiology , Female , Humans
16.
J Clin Oncol ; 22(17): 3507-16, 2004 Sep 01.
Article in English | MEDLINE | ID: mdl-15337799

ABSTRACT

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). RESULTS: One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P =.71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation. CONCLUSION: Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.


Subject(s)
Antibodies, Monoclonal/therapeutic use , CA-125 Antigen/immunology , Ovarian Neoplasms/therapy , Adult , Aged , Antibodies/analysis , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Agents/therapeutic use , CA-125 Antigen/analysis , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Recurrence, Local , Ovarian Neoplasms/immunology , Placebos
17.
Gynecol Oncol ; 94(2): 340-51, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15297171

ABSTRACT

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. Clinical outcomes were recorded. RESULTS: Twenty patients were enrolled; median follow-up was 15.8 months. Oregovomab was well tolerated and did not produce drug-related serious adverse reactions. In 15/19 (79%) patients, robust treatment-emergent humoral responses were observed to the constant (HAMA) and variable region (Ab2) of oregovomab, and 2/19 (11%) patients developed anti-CA125 antibodies. Significant increases in T-cell responses were measured in 7/18 (39%) patients in response to CA125, in 5/8 (63%) patients in response to autologous tumor and in 9/18 (50%) patients in response to oregovomab. Immune responses appeared by week 12 (four doses) and were generally maintained or augmented in patients continuing combined treatment with oregovomab and chemotherapy. Median survival was 70.4 weeks (4.6-141.6 weeks), and the median progression-free interval was 11 weeks (2.6-114.6 weeks). Patients who mounted a T-cell response to CA125 and/or autologous tumor showed significantly improved survival (median not reached vs. 51.9 weeks, P = 0.002) compared to patients who did not. CONCLUSIONS: Oregovomab was well tolerated and induced multiple antigen-specific immune responses, maintained during concomitant chemotherapy. A significant survival benefit was observed in patients mounting a T-cell response to CA125 and/or autologous tumor.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , CA-125 Antigen/immunology , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/therapy , Ovarian Neoplasms/immunology , Ovarian Neoplasms/therapy , T-Lymphocytes/immunology , Aged , Female , Humans , Immunization, Passive/methods , Infusions, Intravenous , Middle Aged
18.
Expert Opin Biol Ther ; 4(8): 1265-84, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15268661

ABSTRACT

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. The biology of antigen processing and recent advances in the field of dendritic cell biology are critical to understanding the potent immune response induction. Future directions include combination therapies to manipulate immune regulatory mechanisms and to enhance clinical effects. Additional applications of antibodies targeting costimulatory or regulatory receptors on antigen-presenting cells and T cells, neutralising immune suppressive cytokines, and depleting T regulatory cells hold promise for future mono- and particularly combination therapies.


Subject(s)
Antibodies/therapeutic use , Immunotherapy , Neoplasms/therapy , Animals , Antibodies, Anti-Idiotypic/immunology , Antibodies, Anti-Idiotypic/therapeutic use , Antibodies, Bispecific/immunology , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/biosynthesis , Antibodies, Neoplasm/immunology , Antigen-Antibody Complex/immunology , Antigen-Presenting Cells/immunology , Antigens, Neoplasm/immunology , Cancer Vaccines/therapeutic use , Clinical Trials as Topic , Cytokines/antagonists & inhibitors , Cytokines/immunology , Dendritic Cells/immunology , Growth Substances/immunology , Humans , Immunotherapy/methods , Immunotherapy, Active , Lymphocyte Activation , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/immunology , Neoplasms/immunology , T-Lymphocytes/immunology
19.
Am J Obstet Gynecol ; 189(1): 28-36, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12861134

ABSTRACT

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-B43.13, a murine monoclonal antibody that is directed against the tumor-associated antigen CA125. Most patients were pretreated heavily. Biologic activity was quantified by the assay of immune responses to the human anti-murine antibodies against the monoclonal antibody-B43.13 variable region (Ab(2)) and antibodies that target the CA 125 antigen itself (anti-CA 125 antibody). RESULTS: More than one half of patients (56.8%) survived for >12 months after the first dose of monoclonal antibody B43.13; 34.1% of the patients survived >24 months. To date, 6 of the 44 patients are alive, with survival times of 4 to 7.5 years after the start of the antibody treatment. More than 60% of the evaluable patients met predefined criteria for robust, treatment-emergent human anti-murine antibodies and Ab(2) responses, and these responses were associated with improved survival rates. Median survival time increased approximately 3-fold for human anti-murine antibody responders (22.6 months) versus nonresponders (7.2 months; P <.0016, log-rank test) and 2-fold for Ab(2) responders (18.3 months) versus nonresponders (9.3 months). No serious drug-associated adverse events were reported. CONCLUSION: The associations between multiple types of immune response and improved clinical outcomes suggest that monoclonal antibody-B43.13 should be further evaluated for potential use as an immunotherapy for CA125-expressing malignancies.


Subject(s)
Antibodies, Monoclonal/immunology , CA-125 Antigen/immunology , Ovarian Neoplasms/immunology , Ovarian Neoplasms/therapy , Survival Rate , Adult , Aged , Animals , Antibodies, Anti-Idiotypic/blood , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Female , Humans , Kinetics , Mice , Middle Aged , Neoplasm Recurrence, Local , Ovarian Neoplasms/mortality , Retrospective Studies , Technetium
20.
J Clin Oncol ; 21(10 Suppl): 168s-174s, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12743131

ABSTRACT

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. Phase II and III trials are ongoing with MAbs directed against CA-125 (MAb B43.13) and an antibody directed against HMFG1 (anti-HMFG1-yttrium-90-labeled antibody). The trials have shown that these agents are well tolerated and that immunologic responses occur, although the ultimate clinical value of these agents remains to be determined. Prolonged survival after MAb B43.13 treatment has been correlated with changes in several immune parameters, including human antimurine antibody, Ab2, anti-CA-125 antibody development, and induced T-cell immunity. Clinical trials using a MAb directed toward the encoded products of her2/neu have shown minimal activity against ovarian cancer in a phase I and II trial conducted by the Gynecologic Oncology Group. Cytokine therapies have been administered systemically and intraperitoneally. Intracavitary interferon alfa, interferon gamma, and interleukin-2 alone or in combination with cytotoxic therapy in phase I and II trials demonstrated intraperitoneal lymphoid cell stimulation and produced antitumor responses. A randomized trial of chemotherapy with or without interferon gamma in primary treatment produced a response and a progression-free survival advantage in the arm that incorporated the interferon gamma, without a statistically significant benefit in overall survival. A phase III study of interferon gamma in combination with first-line chemotherapy is currently ongoing.


Subject(s)
Antineoplastic Agents/therapeutic use , Biological Products/therapeutic use , Genetic Therapy , Immunotherapy , Ovarian Neoplasms/therapy , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal, Murine-Derived , CA-125 Antigen/immunology , Combined Modality Therapy , Female , Humans , Interferon-alpha/therapeutic use , Interferon-gamma/therapeutic use , Mucin-1/immunology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/immunology , Radiopharmaceuticals/therapeutic use , Receptor, ErbB-2/immunology , Recurrence , Trastuzumab , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Yttrium Isotopes/therapeutic use
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