Albinterferon-alfa 2b: a new treatment option for hepatitis C

Importance of the field: HCV infection affects 180 million people worldwide. Standard therapy combines weekly injections of pegIFN and daily ribavirin (RBV). Albinterferon (albIFN)-α2b is the most advanced in the development of an IFN-based compound.

Areas covered in this review: The rationale for albIFN-α2b is to combine IFN-α antiviral activity with prolonged presence of human serum albumin in human blood. Initial experimental studies on albIFN-α2b were published in 2002. This review provides results of preclinical and subsequent clinical trials. Results of two Phase III clinical trials were presented in 2009 and will be published shortly.

What the reader will gain: This review discusses the current status of knowledge on the efficacy and safety of albIFN-α2b. Phase III clinical trials demonstrated comparable efficacy of albIFN-α2b given every 2 weeks to weekly pegIFN-α2a, both in combination with RBV. However, the most promising seems to be every 4 weeks dosage.

Take home message: Treatment with albIFN-α2b combined with RBV can provide comparable efficacy with the current standard of care medication with a reduced number of injections. Lower frequency of some adverse events and improved quality of life can be expected in patients receiving albIFN-α2b every 4 weeks.     

Herpes simplex virus oncolytic vaccine therapy in melanoma

Importance of the field: Advanced melanoma is a devastating disease with a five year survival for Stage IV disease of 10 – 20% and a median survival of 6 – 18 months depending on sub-stage. Current FDA approved therapies demonstrate limited response rates, few complete remissions and no proven survival benefit. New therapies are clearly needed. JSI/34.5-/47-/GM-CSF is a herpes simplex virus-1 (OncoVEX^GM-CSF) oncolytic vaccine therapy designed to induce local and systemic anti-tumor immune responses.

Areas covered in this review: Evolution of current herpes simplex virus oncolytic vaccines from preclinical to clinical studies from 1994 to 2010.

What the reader will gain: Preclinical studies have shown that herpes simplex virus-1 oncolytic vaccines generate local tumor destruction through the lytic action of the virus and local and systemic immune responses. Phase I studies demonstrated limited toxicities with no neurotoxicty. Phase II studies demonstrated durable regressions in patients with metastatic melanoma. A Phase III trial in melanoma is ongoing to determine clinical effectiveness, and a Phase III trial in head and neck cancer will initiate during 2010.

Take home message: JSI/34.5-/47-/GM-CSF is a new generation herpes simplex virus-1 oncolytic vaccine that demonstrates direct tumor lysis and systemic immune responses. Early clinical studies have yielded preliminary evidence of activity.     

TNFα gene delivery therapy for solid tumors

Importance of the field: Multimodality therapy, including adjuvant and neoadjuvant chemotherapy and radiotherapy, is now the mainstay of treatment for the majority of non-hematologic cancers. Host toxicity can, however, be significant, which may contribute to local and/or systemic failures. Novel adjunctive treatments that can limit systemic exposure while synergizing with standard therapy hold promise in the fight against an increasing number of cancers.

Areas covered in this review: We discuss a TNFα gene delivery system used to generate high levels of intratumoral TNFα, while limiting systemic exposure. The delivery system utilizes a replication-deficient adenoviral vector. When injected intratumorally and activated by external beam radiation, infected cells synthesize and locally secrete large amounts of TNFα.

What the reader will gain: This review will provide the reader with a thorough understanding of the gene-based TNFα delivery system with special emphasis on product characteristics, mechanisms of action, clinical efficacy, safety and tolerability.

Take home message: The TNFα gene delivery system holds promise as an adjunctive agent for improved local control and increasing resectability rates for many solid tumors. The completion of several ongoing randomized trials will help to better define the role for TNFα gene delivery therapy in the treatment of solid tumors.     

Kinoid of human tumor necrosis factor-alpha for rheumatoid arthritis

Introduction: Anti-TNF-α drugs have dramatically changed treatment of rheumatoid arthritis (RA) in terms of both clinical control and articular damage prevention. Despite this, they hold some important drawbacks, such as frequent therapeutic failures and high costs. Anti-TNF-α active immunization, with a therapeutic vaccine against TNF-α, is a promising alternative anti-TNF-α targeting strategy, potentially devoid of treatment limitations of some of current anti-TNF blocking agents.

Areas covered: This review covers the preclinical proof-of-concept of anti-TNF-α vaccination with the kinoid of human TNF-α (TNFK) and analyzes the body of evidence forming the rationale for the application of this strategy in RA and other TNF-α-dependent diseases. We describe the theoretical bases of anti-TNF-α active immunization and of experimental data supporting the applicability of TNFK to human disease in terms of both safety and efficacy.

Expert opinion: Based on preclinical efficacy and safety data supporting its feasibility in a Phase I – II trial in Crohn's disease, anti-TNF-α vaccination with TNFK has entered the phase of clinical development and promises to be a valuable anti-TNF-α targeting strategy in human disease. The focus is made in the first clinical trial in RA (Phase II) on the efficacy in active RA patients having developed antibodies against anti-TNF mAbs.     

VB-111 for cancer

Introduction: Antibody, small molecule and protein inhibitors of angiogenesis are used in the management of several cancers. These do not specifically target tumor vascularity, and resistance can be problematic. VB-111 is a vascular-targeting agent consisting of a non-replicating adenovirus vector with a pre-proendothelin-1 promoter that encodes an apoptotic receptor.

Areas covered: The rationale and design of VB-111, its mechanism of action, and preclinical studies examining antitumor activity, toxicology and pharmacodynamics are reviewed. Phase I and Phase II clinical trials are also reviewed.

Expert opinion: VB-111 is a vascular-targeting gene therapeutic that is both tissue- and condition-specific, with effects limited to endothelial cells undergoing angiogenesis. Systemic administration produces selective destruction of tumor vascularity. Synergistic antitumor activity can be observed when combined with chemotherapy. VB-111 has been found to be safe and well tolerated in a Phase I clinical trial in patients with advanced solid tumors. Phase II clinical trials are in progress. VB-111 is novel agent for cancer that may have application as monotherapy and in combination with other therapies.     

Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that combines intracellular delivery of the potent cytotoxic agent, DM1 (a derivative of maytansine) with the antitumor activity of trastuzumab. While there are several ADCs in Phase III development, T-DM1 is the only one in which the targeting antibody has antitumor properties. T-DM1 is also the only ADC that is directed toward the human EGFR 2 (HER2). Effective therapies are limited in HER2-positive advanced or metastatic breast cancer (MBC), particularly following progression on available HER2-targeted therapies.

Areas covered: The mechanisms of action, preclinical efficacy and clinical profile of T-DM1 are reported. The latest preclinical and clinical data for T-DM1 are examined.

Expert opinion: T-DM1 has significant antitumor potency in vitro and in vivo, which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor responses and was well tolerated across various lines of therapy in patients with HER2-positive MBC. In addition, it showed similar efficacy to trastuzumab plus docetaxel in first-line MBC. Ongoing trials (including two Phase III studies) are investigating T-DM1 as single-agent therapy or combined with other chemotherapeutic or biologic agents, and the results should help to define the place of T-DM1 within current treatment algorithms for HER2-positive disease.     

Adecatumumab: an anti-EpCAM monoclonal antibody,from the bench to the bedside

Importance of the field: In developing new anticancer drugs, the identification of relevant targets is a key issue of growing importance. Ideally, an anticancer drug target should be specific to cancer cells, in order to both increase efficacy and decrease toxicity of the compound.

Areas covered in this review: Epithelial cell adhesion molecule (EpCAM) is a membrane protein with proto-oncogenic properties that is expressed in a number of endothelium-derived cancers and is a promising anticancer drug target. Adecatumumab is a monoclonal, fully human IgG1 antibody that targets EpCAM, development of which is at present reaching Phase III trials.

What the reader will gain: From a review of literature, we here update the rationale for using EpCAM as an anticancer target for monoclonal antibodies, with a special focus on adecatumumab. The fully human nature of adecatumumab is also discussed to put the drug in perspective with other related anti-EpCAM monoclonal antibodies, such as edrecolomab and catumaxomab. Adecatumumab studies are recapitulated, in order to provide the reader with a comprehensive view of the development of this promising anticancer agent.

Take home message: Adecatumumab is a promising fully human monoclonal antibody targeting EpCAM which is expressed in almost all adenocarcinomas and its activity is not dependent of K-Ras status.     

Conatumumab: a novel monoclonal antibody against death receptor 5 for the treatment of advanced malignancies in adults

Introduction: Advanced malignancies that are refractory to standard chemotherapy have few treatment options. Conatumumab is an investigational, fully human monoclonal agonist antibody directed at human death receptor DR5, which is expressed in multiple advanced cancers.

Areas covered: The rationale for the use of conatumumab based on in vitro, in vivo, Phase I, and Phase II data will be discussed.

Expert opinion: Conatumumab, at a dose of 20 mg/kg every 2 weeks, has demonstrated acceptable safety and tolerability in patients with advanced tumors based on available and published data. Further clinical trials are underway evaluating the use of conatumumab in combination with chemotherapeutic and targeted agents.     

Teplizumab therapy for type 1 diabetes

Importance of the field: Type 1 diabetes mellitus (T1D) is a T-cell mediated autoimmune disease with selective destruction of β cells. Immunological interventions are directed at arresting the loss of β-cell function with the promise that this will make it easier for patients to control their glucose levels.

Areas covered in this review: This review provides a summary of the preclinical and clinical research published between 1992 and 2009 using teplizumab and other anti-CD3 antibodies to arrest the loss of β-cell function in new onset T1D. Data from animal and human studies on the probable mechanism of action of teplizumab are also reviewed.

What the reader will gain: A broad perspective on the use of teplizumab in inducing disease specific tolerance.

Take home message: In Phase I/II randomized control trials, in patients with new onset T1D, teplizumab slowed the rate of loss of β-cell function over 2 years of follow-up. Treated patients had better glycemic control and lower insulin requirements. Adverse events so far are mild and of limited duration. Phase III clinical trials are underway to confirm these results and to determine if two courses of drug have greater efficacy in arresting loss of β-cell function.     

Immunomodulation with heat shock protein DiaPep277 to preserve beta cell function in type 1 diabetes – an update

Importance of the field: Type 1 diabetes is a chronic autoimmune disease in which pancreatic beta cells are selectively destroyed. Ultimately hyperglycemia develops and insulin substitution becomes necessary. Immunomodulation aims at arresting this autoimmune attack. DiaPep277, the major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective as a modulator of the immune system in type 1 diabetes and is the focus of this review.

Areas covered in this review: A literature search of Pubmed listed publications covering 1990 – 2009 and a website search of the licensing company were performed.

What the reader will gain: DiaPep277 has been successfully employed in animal models and has been investigated in Phase I – III studies in humans. A combined analysis of the Phase II trials showed a significant preservation of beta cell function in adults without adverse effects, but HbA1c was not changed. A Phase III clinical trial is ongoing, and a second Phase III trial will start in early 2010. Addressing the underlying autoimmune process is the call of the future in type 1 diabetes.

Take home message: Use of Diapep277 is a promising therapeutic strategy currently being tested in Phase III trials.     

Immunotherapy for metastatic prostate cancer: where are we at with sipuleucel-T?

Importance of the field: Prostate cancer is the leading malignancy in North American men and despite improvements in treatments 20 – 30% of patients will relapse. Immunotherapy using activated mononuclear cells is a way to harness the body's adaptive immune response to fight metastatic prostate cancer.

Areas covered in this review: In 2005, at least 10 therapeutic cancer vaccines, designed to confer active, specific immunotherapy against tumor-associated antigens, were in clinical trials. These covered potential fields of immunological strategy to overcome castration-resistant prostate cancer.

What the reader will gain: A literature review was performed using the search terms sipuleucel-T, Provenge and APC8015 or APC-8015, and restricted to English language articles from 2000 to 2010. The immunological design and development of sipuleucel-T are summarized. The efficacy and safety of sipuleucel-T are discussed based on current data from clinical trials. Ongoing clinical trials involving sipuleucel-T are summarized.

Take home message: Efficacy and safety with sipuleucel-T has been demonstrated in Phase I/II trials. The latest data from a Phase III trial shows that sipuleucel-T has met the primary endpoint of survival benefit. Further work is needed to understand the mechanisms behind cancer vaccine failure and elucidate the population for whom this vaccine will be suitable.     

Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer.

Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed.

Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.     

Tralokinumab for uncontrolled asthma

Introduction: Asthma is a chronic inflammatory disease of the airways mainly related to allergen exposure, in which various cytokine-specific pathways interact among themselves to promote IgE hyperproduction, bronchial hyperresponsiveness, eosinophil local recruitment and airways remodeling. IL-13 is known for its prominent pathogenic role in this disease and therapeutic blocking approaches are underway.

Areas covered: Anti-IL-13 antibodies are currently investigated in clinical studies in uncontrolled asthma. Tralokinumab is a human IgG4 anti IL-13 antibody which was recently evaluated in a Phase II study demonstrating the maximal efficacy in a subset of asthma patients characterized by the highest sputum IL-13 levels. The results of this study are discussed in this paper.

Expert opinion: The IL-13 blockade with various therapeutic approaches such as tralokinumab has the potential to improve the asthma control in patients subsets in whom the blocked cytokine is demonstrated to be overexpressed.     

Mavrilimumab,a human monoclonal GM-CSF receptor-α antibody for the management of rheumatoid arthritis: a novel approach to therapy

Introduction: Mavrilimumab, formerly known as CAM-3001, a GM-CSF receptor-α antibody, is the first human monoclonal antibody to be used in Phase II studies (2011) to modulate the innate immunity pathway targeting GM-CSF signaling in moderate rheumatoid arthritis (RA).

Areas covered: Analysis of available clinical trial data on GM-CSF receptor-α antibody and medical literature search using MEDLINE for molecular mechanisms of pathogenesis of RA and its treatment forms the basis of this expert opinion review. The mavrilimumab Phase II double blind, randomized, placebo-controlled ascending dose trial demonstrated statistically significant achievement of primary and secondary end points in patients with moderate RA. The trial demonstrated significant clinical benefit in the 100 mg mavrilimumab cohort compared to the placebo group.

Expert opinion: The novel molecular targeting mechanism of mavrilimumab together with its demonstrated clinical efficacy, tolerability and safety profile in Phase II clinical trials in moderate RA, suggests significant potential utility for this drug to induce clinical remission, reduce flares and improve morbidity and mortality in patients with RA.     

Recent advances and future of immunotherapy for glioblastoma

ABSTRACT

Introduction: Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM.

Areas covered: Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies.

Expert opinion: Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.     

Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure

ABSTRACT

Introduction: Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an “off the shelf” therapy, with consistent potency and less variability than autologous cells.

Areas covered: Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial—DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients.

Expert opinion: The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.     

Molecular target therapy for bone metastasis: starting a new era with denosumab,a RANKL inhibitor

Introduction: The skeleton is generally the primary, and sometimes the only, site of metastasis in patients with advanced solid tumors. Bone metastases are the most frequent cause of cancer-related pain and the origin of severe morbidity in patients. Among the treatment options available for the prevention of skeletal-related events (SREs) associated with bone metastasis, zoledronic acid, an antiresorptive treatment from the group of bisphosphonates, is currently the standard of care in this setting.

Areas covered: Zoledronic acid, together with denosumab (a monoclonal antibody against the receptor activator of nuclear factor kappa B ligand), is the most frequent approach for the prevention of cancer-related events in skeleton. This paper reviews several trials evaluating the efficacy of denosumab in comparison with zoledronic acid in patients with solid osteotropic tumors. In this setting of skeleton-invading cancers, denosumab was demonstrated to be superior to zoledronic acid in preventing or delaying SREs. In comparison with zoledronic acid, denosumab significantly delayed the time to first SRE by 17%.

Expert opinion: Current research on denosumab is addressed to prove the immunomodulator effect of this agent in humans. Other avenue of research is focused on its antitumor activity observed in some Phase III trials.