DiaPep277 peptide therapy in the context of other immune intervention trials in type 1 diabetes

INTRODUCTION: Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β-cells. The aim of immune intervention is to arrest this autoimmune attack. DiaPep277, a major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective in the modulation of the immune response in recent onset T1D and is the main focus of this review in the context of other ongoing trials using different approaches. AREAS COVERED: The authors performed a literature search of Pubmed listed publications (from the last 10 years) and a website search of the company licensing DiaPep277. DiaPep277 has been investigated in Phase I - III trials in humans. Phase II trials showed a significant preservation of β-cell function in adult T1D patients (but not children) with an absence of adverse effects and not accompanied by lower glycosylated haemoglobin (HbA1c) levels or reduced daily insulin requirement compared with placebo-treated patients. EXPERT OPINION: Administration of DiaPep277 is safe and represents a promising therapeutic strategy in patients with recent-onset T1D. The results of two large Phase III trials will tell us whether this therapy may change our current approach to treating T1D patients at diagnosis.     

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.     

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.     

Otelixizumab: a novel agent for the prevention of type 1 diabetes mellitus

Introduction: Type 1 diabetes mellitus is a chronic, progressive autoimmune disorder linked to numerous genetic and environmental factors. Insulin is the only treatment and preventative strategies do not currently exist. An obvious need exists to develop a safe regimen that suppresses the progression of the disease.

Areas covered: A MEDLINE search (1966–June 2011) was conducted for English-language articles using the terms ‘otelixizumab’, ‘anti-CD3 antibody’ and ‘prevention of type 1 diabetes mellitus’. Relevant literature on otelixizumab, an anti-CD3 monoclonal antibody, currently in Phase III clinical trials for prevention of T1DM is discussed.

Expert opinion: Studies suggest that a monoclonal antibody directed against CD3 mitigates the deterioration in insulin production and decreases the rise in insulin requirement in recent onset T1DM for up to five years. The benefit was most pronounced in younger patients and in those with higher initial β-cell function. Adverse effects were significant but transient. Otelixizumab shows great promise but leaves room for improvement. Results of ongoing trials will help define its role in the prevention of T1DM.     

Emepepimut-S for non-small cell lung cancer

Introduction: Immunotherapy as a possible therapeutic option for cancer has been of great importance due to the innovative development of vaccines. Various molecules have been tested and emepepimut-S (Biomira Liposomal Peptide 25 (BLP 25)) has emerged as an option, particularly in lung cancer.

Areas covered: A PubMed literature and ClinicalTrials.gov search was conducted using the terms: emepepimut, BLP25, NSCLC, cancer immunotherapy, cancer vaccine and MUC1. This review covers how emepepimut-S acts against the mucin 1 (MUC1) tumor-associated antigen producing a cellular immune response against the cells that express MUC1 and the most important clinical data available that led to the ongoing Phase III trial.

Expert opinion: The results obtained in the Phase I/II trials are promising, showing a favorable toxicity with a benefit in survival in NSCLC patients. As future trials develop, demonstration of the long-term survival benefit, understanding of the various mechanisms of immune response initiated by the drug and the selection of patients that will highly benefit from the immunotherapy will be elucidated. The safety and extension in survival makes emepepimut-S a very interesting drug and could, therefore, offer a possibility of treatment and maintenance, particularly for good performance status patients with locally advanced NSCLC.     

Amyloid-directed monoclonal antibodies for the treatment of Alzheimer’s disease: the point of no return?

Introduction: Two humanized monoclonal antibodies, bapineuzumab and solanezumab, directed against the N terminus and mid-region of β-amyloid (Aβ), respectively, were recently tested in large, long-term Phase III trials in patients with mild-to-moderate Alzheimer’s disease (AD).

Areas covered: This review discusses current clinical data on solanezumab, bapineuzumab and their failure in Phase III trials to show significant clinical benefits, as well as other monoclonal antibodies under investigation for AD.

Expert opinion: Solanezumab showed some beneficial cognitive effects in mildly affected AD patients and this subgroup of AD patients is currently being tested in another Phase III trial to this subgroup of AD patients to confirm previous encouraging observations. Two other monoclonal antibodies, gantenerumab, which preferentially binds to fibrillar Aβ, and crenezumab, which preferentially binds to soluble, oligomeric and fibrillar Aβ deposits, are being tested in secondary prevention trials in presymptomatic subjects with autosomal dominant AD mutations. Solanezumab is also being tested in a prevention study in asymptomatic older subjects, who have positive positron emission tomography scans for brain amyloid deposits. These ongoing secondary prevention trials will tell us if Aβ really plays a crucial role in the pathophysiology of AD.     

Bapineuzumab and solanezumab for Alzheimer's disease: is the ‘amyloid cascade hypothesis' still alive?

Introduction: The ‘amyloid cascade hypothesis' remains the leading hypothesis to explain the pathophysiology of Alzheimer's disease (AD). Immunotherapeutic agents have been developed to remove the neurotoxic amyloid β42 protein and prevent the hypothesized amyloid β42-induced neurotoxicity and neurodegeneration. The most notable of these immunotherapies are bapineuzumab and solanezumab.

Areas covered: This article briefly reviews the experimental agents in development for treatment of AD and then discusses the results of bapineuzumab and solanezumab in AD patients, as reported in preclinical studies, clinical trials and press releases.

Expert opinion: Phase III trials showed that bapineuzumab failed to improve cognitive and functional performances in AD patients, and was associated with a high incidence of amyloid-related imaging abnormalities (ARIA). Solanezumab's two Phase III trials in AD patients failed to meet endpoints when analyzed independently. However, analysis of pooled data from both trials showed a significant reduction in cognitive decline in mild AD patients. The improvement was associated with an increase in plasma amyloid-β (Aβ) levels and a low incidence of ARIA in solanezumab-treated patients. The marginal benefits of solanezumab are encouraging to support continued evaluation in future studies, and offer small support in favor of the ongoing viability of the ‘amyloid cascade hypothesis' of AD.     

5T4-modified vaccinia Ankara: progress in tumor-associated antigen-based immunotherapy

Importance of the field: The expression and biology of the tumor-associated antigen (TAA) 5T4 suggest it is an effective target for cancer immunotherapy.

Areas covered in this review: Development of a vaccine comprising highly attenuated modified vaccinia Ankara virus encoding 5T4 (MVA-5T4, a.k.a. TroVax^®).

What the reader will gain: Preclinical studies demonstrated that MVA-5T4 is safe and effective in prophylactic and active treatment of syngeneic murine tumor models. Over 700 doses of MVA-5T4 have been administered to over 200 patients to date. Results from clinical trials on metastatic colorectal, metastatic renal and hormone-refractory prostate cancer patients demonstrate that MVA-5T4 is safe and immunogenic as a monotherapy and in combination with standard-of-care therapies. MVA-5T4 induced potent and sustained immune responses in approximately 95% of tested patients. Post hoc analyses have noted a correlation between anti-5T4 immune responses and indicators of clinical benefit. A Phase III randomized, placebo controlled study, which investigated MVA-5T4 added to first line standard of care to evaluate whether vaccination prolonged survival of patients with metastatic clear cell renal cell cancer did not meet the primary endpoint (overall survival).

Take home message: With its minimal side effects and ability to produce immune responses MVA-5T4 is a promising addition to the cancer therapy arsenal.     

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.     

Efficacy and safety of otelixizumab use in new-onset type 1 diabetes mellitus

ABSTRACT

Introduction: Type 1 diabetes (T1DM) is an immune-mediated disease induced by antigen-specific T cells infiltrating pancreatic beta cells leading to the progressive loss of endogenous insulin secretion.

Areas covered: The identification of specific components of the autoimmune response favoured the implementation of several immunomodulatory therapies including antiCD3 monoclonal antibody (mAb) called otelixizumab. Otelixizumab is a chimeric monoclonal antibody that targets the ε-chain of the CD3T-lymphocyte surface receptor that has been developed with the aim of short therapeutic courses capable of inducing a remission of T1DM. Clinical trials have been carried out with otelixizumab to evaluate its safety and efficacy, but despite positive results of Phase I and II studies, the results of Phase III studies have been contradictory.

Expert opinion: High doses of otelixizumab have shown beneficial effects on beta cell function whereas a lower dose, which was tested to avoid the adverse effects associated with higher doses, was not effective on beta cells preservation. We believe that otelixizumab is a drug of potential interest for treating new onset T1DM patients and its use in combination with other immunomodulatory agents should be considered as a solution to circumvent adverse effects while maintaining efficacy.     

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.     

Solanezumab for Alzheimer's disease

Introduction: Alzheimer's disease (AD) is a debilitating neurodegenerative illness affecting over 35 million people worldwide. Solanezumab is a monoclonal antibody that binds to β-amyloid (Aβ), a protein that plays a key role in the pathogenesis of AD. The drug is currently being investigated in Phase III trials as a disease-modifying treatment for AD.

Areas covered: This paper reviews literature on solanezumab that is available in PubMed from 2008 to 2010, other treatment trials in clinicaltrials.gov and published abstracts from conferences. The article also provides a discussion of the early trials of AN1792 and an overview of the immunotherapies currently in development. The authors provide the reader with a critical appraisal of the to-date clinical trial data on solanezumab and its implications for the broader field of immunotherapies for AD.

Expert opinion: Solanezumab can neutralize soluble Aβ peptides, which may represent the more neurotoxic of the Aβ species. Phase II findings support the compound's safety, which has been a concern for some Aβ immunotherapies. Cerebrospinal and plasma biomarker changes with solanezumab treatment are encouraging. Results of the ongoing Phase III trials will be instrumental in determining the drug's clinical significance.     

Combination immune checkpoint blockade with ipilimumab and nivolumab in the management of advanced melanoma

ABSTRACT

Introduction: The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies such as ipilimumab and nivolumab to combination strategies involving both. This combination approach results in response rates around 60% and superior progression-free survival compared with ipilimumab monotherapy (median 11.5 versus 2.9 months).

Areas covered: A comprehensive literature search was undertaken including search terms of ‘ipilimumab and nivolumab’ and ‘combination immune checkpoint therapy’. Relevant information contained in abstracts and conference presentations was included. This article summarizes the mechanism of action, efficacy and safety of combination ipilimumab and nivolumab across Phase I, II and III clinical trials. It also describes the place of combination therapy in the current market of advanced melanoma treatment options.

Expert Opinion: Efficacy for the combination approach is seen across a wide array of subgroups and occurs regardless of BRAF mutation status. Counterbalancing the apparent advantages, combination ipilimumab with nivolumab is associated with a high rate (55%) of grade 3/4 adverse events leading to discontinuation in a third of those treated. Most of these are manageable and do not appear to compromise durability of response. Overall survival information is currently immature but appears promising.     

Cell therapy for type 1 diabetes

ABSTRACT

Introduction

Type 1 diabetes (T1D) is a lifelong condition resulting from autoimmune destruction of insulin-producing β-cells. Islet or whole-pancreas transplantation is limited by the shortage of donors and need for chronic immune suppression. Novel strategies are needed to prevent β-cell loss and to rescue production of endogenous insulin.     

Gemtuzumab ozogamicin in non-acute promyelocytic acute myeloid leukemia

Introduction: Gemtuzumab ozogamicin (GO) has been used in relapsed, refractory and newly diagnosed acute myeloid leukemia (AML) as a single agent and in combination with intensive chemotherapy. Results of recent Phase III trials have led to its withdrawal in the USA although a beneficial effect of GO in genetically defined AML subgroups was evident.

Areas covered: This review examines the use of GO as a single agent or in combination with intensive chemotherapy in non-acute promyelocytic AML. The literature search was based on publications on GO indexed in the PubMed electronic database and selected meeting abstracts. GO has shown moderate activity as a single agent but promising activity in combination with intensive chemotherapy in refractory or relapsed AML. Relapsed AML defined molecularly by mutant nucleophosmin-1 without concurrent fms-related tyrosine kinase 3 (FLT3) internal tandem duplication seems to benefit most from GO. In newly diagnosed AML two up-front randomized Phase III trials evaluating GO in induction therapy failed to demonstrate an improvement in response and survival. Again, genetically defined subgroups may benefit.

Expert opinion: Future challenges of personalized therapy in AML will be to integrate the signals from current subgroup analyses underlining the role of GO in genetically defined AML entities.     

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.     

Heat-shock proteins-based immunotherapy for advanced melanoma in the era of target therapies and immunomodulating agents

Introduction: Heat-shock proteins (HSPs) are highly conserved, stress-induced proteins that function as chaperones, stabilizing proteins and delivering peptides. Tumor-derived HSP peptide complexes (HSPPCs) induced immunity against several malignancies in preclinical models, exhibiting activity across tumor types.

Areas covered: HSPPC-based vaccination showed clinical activity in subsets of patients with different malignancies (e.g., gastric, colorectal, pancreatic, ovarian cancer, and glioblastoma). In Phase III clinical trials for advanced melanoma and renal cell carcinoma patients, HSPPC-based vaccine demonstrated an excellent safety profile, thus emerging as a flexible tumor- and patient-specific therapeutic approach.

Expert opinion: Melanoma, renal clear cell carcinoma, and glioblastoma are among suitable targets for HSP-based treatment as demonstrated by immune responses and clinical activity observed in subsets of patients, mainly those with early stage of disease and limited tumor burden. In order to further improve clinical activity, combinations of HSPPC-based vaccines with mutation-driven therapies, antiangiogenic agents, or immunomodulating monoclonal antibodies should be tested in controlled clinical trials.     

Velimogene aliplasmid

Importance of the field: Immunotherapy for cancer has been investigated for several decades, achieving limited success. The development of effective new immunotherapeutic agents has reignited interest in the filed. Intralesional injection of plasmids in order to transfect genes capable of stimulating or augmenting immune recognition and destruction of tumors is a relatively new approach.

Areas covered in this review: Our objective is to discuss the role velimogene aliplasmid (Allovectin-7^®, Vical Incorporated), a plasmid–lipid complex containing the DNA sequences encoding HLA-B7 and β2 microglobulin, as an immunotherapeutic agent.

What the reader will gain: Intralesional velimogene aliplasmid induces anti-tumor responses in a proportion of melanoma patients with locoregional and limited distant metastases. Preclinical data and the results of Phase I, II and III clinical trials with this drug are reviewed. The limited data in other malignancies is also reviewed. Velimogene aliplasmid in humans appears safe, with minimal drug-related adverse events.

Take home message: Velimogene aliplasmid has activity in melanoma with local and limited distant disease associated with an excellent safety profile. The activity of this approach is also being investigated in other malignancies.     

Albiglutide: a new GLP-1 analog for the treatment of type 2 diabetes

Importance of the field: Despite the wide array of treatments available, a significant number of patients with type 2 diabetes continue to remain uncontrolled. The discovery of the incretin hormones and their role in glucose homeostasis has brought about a new class of medications called the glucagon-like peptide-1 (GLP-1) analogs. This new class of medications provides the benefits of weight loss as well as a lack of hypoglycemia. However, the currently available agents require once or twice daily injections.

Areas covered in this review: Relevant literature will be discussed on albiglutide, a new GLP-1 analog in Phase III clinical trials. Several clinical trials examining the use of albiglutide as combination therapy are currently ongoing.

What the reader will gain: To date, results of clinical trials suggest that albiglutide may provide a more attractive dosing profile compared with the currently available GLP-1 analogs.

Take home message: The results of ongoing trials will help define the role of albiglutide in treating patients with type 2 diabetes.     

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.