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.     

Necitumumab for non-small cell lung cancer

Introduction: Targeting the EGFR pathway is a rational approach to treat patients with advanced NSCLC. Necitumumab, a second-generation recombinant fully human immunoglobulin G1 monoclonal antibody directed against EGFR, has recently been assessed in combination with first-line cisplatin-based chemotherapy.

Areas covered: This article reviews literature on necitumumab development, from preclinical data to results of Phase III clinical trials, either published or presented in international scientific conferences. Ongoing clinical trials were searched with the clinical-trials.gov website.

Expert opinion: During the last decade, advances in treatment of metastatic NSCLC have been exclusively achieved in patients with non-squamous histology. In this context, any treatment improvement, even modest, was eagerly awaited for patients with squamous NSCLC. In this patient’s population, the SQUIRE Phase III study demonstrated a relatively small, but statistically significant survival benefit in patients treated with necitumumab in combination with standard chemotherapy (cisplatin and gemcitabin) compared with those treated with chemotherapy alone. However, the identification of predictive biomarker for treatment outcome is still needed to select the patients who will experience a large benefit from the targeted treatment.     

The role of talactoferrin alfa in the treatment of non-small cell lung cancer

Importance of the field: Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in recent years.

Areas covered in this review: Talactoferrin alfa is an oral immunomodulatory agent currently in late-stage clinical trials that acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue.

What the reader will gain: Talactoferrin is a recombinant human lactoferrin that is a member of the transferrin family of iron-binding glycoproteins. Lactoferrins have multiple known biological activities including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties. This review discusses the proposed mechanism of action of talactoferrin-alfa and outlines the pre-clinical, Phase I and II data in NSCLC. The ongoing Phase III trials are discussed.

Take home message: The current role of Talactoferrin alpha in the treatment of NSCLC is described and we explore potential future roles for this drug in both early stage and advanced stage disease.     

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.     

Oncolytic vaccinia virus for the treatment of cancer

Introduction: Gene therapy offers promising approaches for the development of anticancer agents with new modes of action. Among gene therapy vectors, vaccinia virus has emerged as an attractive agent especially when used as an oncolytic virus.

Areas covered: This review describes the use of vaccinia virus in cancer therapy as a gene therapy vector, as an oncolytic virus and in the generation of oncolysates. The main achievements of each field are summarized with a special emphasis on vaccinia as an oncolytic vector and its combination therapies. The virus that has advanced furthest in clinical trials, GM-CSF expressing JX-594, is described in detail and its preclinical and clinical data are reviewed.

Expert opinion: Vaccinia virus has great potential in cancer gene therapy, especially when used as an oncolytic virus. In particular, JX-594 has shown promising preclinical and clinical data, and a multi-continental randomized Phase III trial in hepatocellular carcinoma is expected to start soon.     

The immunological era in melanoma treatment: new challenges for heat shock protein-based vaccine in the advanced disease

Introduction: Tumor-derived heat shock protein (HSP)–peptide complexes (HSPPCs) induced immunity against malignancies in preclinical trials, working across tumor types and bypassing the need to identify single immunogenic peptides. These results paved the way for the use of human gp96 obtained from autologous tumor samples as an anti-cancer vaccine.

Areas covered: Autologous tumor-derived HSP gp96 peptide complex (HSPPC-96) vaccine is emerging as a tumor- and patient-specific cancer vaccine, with confirmed activity in several malignancies. It has been tested in Phase III clinical trials in advanced melanoma and kidney cancer with evidence for efficacy in patients with earlier stage disease. HSPPC-96-based vaccine demonstrated an excellent safety profile, thus emerging as a novel therapeutic approach with a suggestive role in cancer therapy. This review summarizes work on the use of HSPPC-96 as an autologous anti-tumor vaccine in advanced melanoma. Data were retrieved by PubMed and Medline research and using the authors' personal experience.

Expert opinion: Further investigations are needed to understand the biological basis of immune functions in order to improve the clinical outcome of HSP-based cancer therapy. In the near future, the combination of HSP-based vaccines with other biological compounds might represent a successful strategy in the therapy of advanced melanoma.     

Role of MetMAb (OA-5D5) in c-MET active lung malignancies

Introduction: MetMAb (OA-5D5) is a one-armed monoclonal antibody developed to bind to and inhibit c-MET receptor tyrosine kinase. Though only in early clinical testing, this agent holds great promise in diseases thought to be driven by c-MET activation, as evidenced by the Phase II results in NSCLC where a benefit in overall survival was observed in patients with MET-diagnostic-positive disease. Thus far, both alone and in combination with other targeted agents, this drug has been well tolerated and no new significant safety signals have been identified.

Areas covered: This review summarizes the structure and function of the c-MET receptor and its ligand hepatic growth factor (HGF), provides an overview of select targeted monotherapies developed to interfere in the MET–HGF signaling pathway, discusses pre-clinical and clinical data surrounding MetMAb, and concludes with an expert opinion regarding this novel agent.

Expert opinion: MetMAb has been well tolerated and based on Phase II data testing it, in combination with erlotinib in advanced NSCLC, may have a role in improving survival in patients with disease driven by c-MET activation. However, Phase III validation is underway and the results of these studies will help elucidate which patients will benefit most from this novel agent.     

Farletuzumab in epithelial ovarian carcinoma

Importance of the field: Ovarian cancer is the leading cause of death from a gynecologic malignancy. Recurrence is both common and lethal, necessitating the development of novel targeted therapies. Farletuzumab (MORAb-003) is a humanized mAb with high affinity for folate receptor α (FRα), a 38 kDa GPI-anchored protein that is overexpressed in 90% of epithelial ovarian cancers.

Areas covered in this review: Preclinical and clinical trials, published or presented at national meetings from 2006 to the present, are presented in this review.

What the reader will gain: Preclinical studies have demonstrated robust antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro, inhibition of tumor growth in ovarian tumor xenografts and a safe toxicology profile in non-human primates. Phase I and II studies have demonstrated single agent and combination therapy efficacy with minimal drug-specific toxicity. The Phase III development plan in ovarian cancer patients includes combination chemotherapy studies in both platinum-sensitive (recently launched) and platinum-resistant (planned) recurrent disease.

Take home message: FRα is overexpressed in ovarian cancers but largely absent from normal tissue, making it an attractive therapeutic target. Farletuzumab is a novel inhibitor of FRα and has shown clinical efficacy in early phase trials.     

Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development

Introduction: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity.

Areas covered: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing.

Expert opinion: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC.     

Modification and Initial Psychometric Evaluation of the Physical Health Attitude Scale for Use in the Canadian Mental Health and Addictions Context

Introduction: The Physical Health Attitude Scale (PHASe) tool was developed to better understand mental health nurses’ attitudes towards their involvement and confidence in physical health care. This tool has been used in the United Kingdom and Australia; however, it has not been used in Canada.

Aim: This study aims to modify and provide an initial psychometric evaluation of the PHASe tool for use in a Canadian mental health and addictions context.

Methods: In Phase 1, clinical experts (n?=?8) were consulted to provide feedback on the content and face validity of the PHASe tool. In Phase 2, the PHASe tool was piloted with nurses at a large urban mental health and addiction organization in Ontario, Canada (n?=?77).

Results: In Phase 1, 4 items were added and 5 items were removed from the tool based on feedback provided by experts. In Phase 2, 12 poorly correlated items were removed. A two-factor solution was identified, with subscales “confidence” and “barriers and attitudes”.

Discussion: Initial psychometric evaluation suggests that a revised 15-item version of the PHASe tool is valid and reliable in a Canadian mental health and addictions context; however, more testing is recommended in larger, more diverse samples.     

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.     

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.     

Trastuzumab emtansine in breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)–targeted antibody–drug conjugate (ADC) composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine). Administration of T-DM1 leads to limited systemic exposure of free DM1, with no evidence of DM1 accumulation after repeated dosing.

Areas covered: Phase I and Phase II clinical trials with T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown substantial clinical activity and a favorable safety profile. A randomized, open-label, first-line trial comparing trastuzumab and docetaxel with single agent T-DM1 showed a significant improved progression-free survival for T-DM1.

Expert opinion: T-DM1 has successfully completed second-line Phase III development for advanced HER2-positive breast cancer. The Phase III EMILIA study demonstrated an overall survival benefit for T-DM1 compared to the combination of lapatinib and capecitabine in taxane-trastuzumab pretreated patients. T-DM1 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner.     

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.     

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.     

Monoclonal antibodies in neuroinflammatory diseases

Introduction: Monoclonal antibodies (mAbs) represent an emerging and rapidly growing field of therapy in neuroinflammatory diseases. Adhesion molecule blockade by natalizumab represents the first approved mAb therapy in neurology, approved for therapy of highly active multiple sclerosis (MS). Removal of immune cells by anti-CD52 mAb alemtuzumab or anti-CD20 mAb rituximab are other prime examples with existing positive Phase II and Phase III trials. MS clearly represents the neuroinflammatory disease entity with the largest body of evidence. However, some of these approaches are currently investigated or translated for use in other, rare neuroinflammatory diseases, such as neuromyelitis optica (NMO), inflammatory neuropathies and (neuro)-muscular disorders.

Areas covered: This review will highlight the most relevant therapeutic approaches involving mAbs in the field of neuroinflammatory diseases as published in peer-reviewed journals and presented on international meetings.

Expert opinion: There is continuously growing evidence on the therapeutic relevance of mAbs in neuroinflammatory disorders. In MS meanwhile several studies have provided evidence for efficacy: In addition to natalizumab, approved in 2006, several other candidates are under development, the most eminent examples with the most advanced study programs being anti-CD52 alemtuzumab, anti-CD20 principles and anti-CD25 daclizumab. Other intriguing candidates are anti-IL-17 strategies, and interference with the complement pathway, partly also developed for other neuroinflammatory disorders.     

Oral salmon calcitonin – pharmacology in osteoporosis

Importance of the field: Osteoporosis is a slow progressive disease which develops over decades, and where intervention is needed for an extended number of years. This highlights the need for safe intervention possibilities, which have sustained beneficial effects post-treatment.

Areas covered in this review: Articles on salmon calcitonin appearing on Pubmed from 1960 until today, with focus on a newly developed oral formulation showing increased exposure and efficacy compared with nasal formulation is reviewed. The second half focuses on long-term phenomena, such as bone quality and resolution effects. The final part discusses potential additional benefits of salmon calcitonin.

What the reader will gain: Insight into the clinical development of an orally formulated peptide, as well as a detailed understanding of why this approach could revive salmon calcitonin as a treatment for osteoporosis.

Take home message: The oral formulation of salmon calcitonin provides additional benefits and increased efficacy on bone based on Phase I and II clinical trials data, as compared with the nasal formulation. Hence, the results on the ongoing Phase III fracture trial are awaited with great interest.     

An update on vaccines for tuberculosis – there is more to it than just waning of BCG efficacy with time

Introduction: Apart from better diagnostics and new anti-microbial drugs, an effective vaccine for tuberculosis is urgently needed to halt this poverty-related disease, afflicting millions of people worldwide.

Areas covered: After a general introduction on the global threat of tuberculosis, the pros and cons of the existing M. bovis BCG vaccine are discussed. As the correlates of protection against tuberculosis remain largely unknown, new findings in biomarker research are described. Next, an update on the ongoing Phase I and Phase II clinical trials is given. Finally, some of the most promising novel pre-clinical developments using live attenuated vaccines, sub-unit vaccines, prime-boost strategies, and new vaccination routes are discussed. The field has made considerable progress and 12 vaccine candidates have now actually entered Phase I or Phase IIa and IIb clinical trials.

Expert opinion: It is argued that the variable protection conferred by the existing BCG vaccine against reactivation of latent TB is caused not only by waning of its efficacy with time but also by its weak induction of MHC class I restricted responses. Prime-boost strategies based on the actual BCG vaccine may not be sufficient to overcome this hurdle. The use of plasmid DNA vaccination might offer a solution.     

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.