Immune alterations in malignant melanoma and current immunotherapy concepts

Introduction: Malignant melanoma is a highly aggressive, immunogenic tumor that has the ability to modulate the immune system to its own advantage. Patients with melanoma present numerous cellular immune defects and cytokine abnormalities, all leading to suppression of the host anti-tumor immune response. Innovative treatment strategies can be achieved through employing our knowledge of the melanoma-induced immune alterations.

Areas covered: The authors review comprehensively the immune abnormalities in individuals with melanoma, and provide a summary of currently available melanoma immunotherapy agents that are currently on the market or undergoing clinical trials.

Expert opinion: Ipilimumab, a monoclonal antibody directed against the CTLA-4, is one of the current forefront treatment strategies in malignant melanoma. Novel immunomodulating agents have shown clear activity in patients with malignant melanoma. These include anti-PD-1 and anti-PD-1 ligand antibodies that may soon become important items in the anti-melanoma armamentarium. Combinations of different immunotherapy agents, between themselves or with other agents, are currently being studied in an attempt to further enhance the antineoplastic effect in patients with malignant melanoma.     

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.     

Intralesional and systemic immunotherapy for metastatic melanoma

ABSTRACT

Introduction: Immunotherapy has revolutionized the treatment of metastatic melanoma and dramatically improved patient outcomes. Ipilimumab, an inhibitor of cytotoxic T-lymphocyte antigen-4 (CTLA-4), was the first immunotherapeutic agent to demonstrate improved survival in advanced melanoma. More recently, other immune checkpoint inhibitors, including the programmed death-1 (PD-1) inhibitors pembrolizumab and nivolumab, have demonstrated efficacy in locally advanced unresectable and metastatic melanoma. In addition to systemically delivered immunotherapies, intralesional therapies such as talimogene laherparepvec (TVEC) play an important role in the treatment of locoregionally advanced and metastatic melanoma.

Areas covered: This review provides an overview of the mechanisms behind immune checkpoint inhibitors. Clinical evidence of their efficacy is presented and discussion of new patterns of response and associated immune related adverse events associated with immunotherapy are provided.

Expert opinion: Treatment options for locally advanced and metastatic melanoma are expanding with new developments in immunotherapy and immune checkpoint inhibitors. The utility of these novel therapies in the adjuvant setting is currently being explored. The ideal treatment of metastatic melanoma continues to be multimodal, combining systemic treatments, intralesional and regional therapies, surgery and radiotherapy to achieve optimal outcomes.     

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.     

Naptumomab estafenatox: a new immunoconjugate

Importance of the field: New agents that specifically engage the immune system are being tested in a variety of malignancies. This review provides an overview of naptumomab, an immunotoxin, with encouraging clinical activity in Phase I trials.

Areas covered in this review: This review examines the preclinical and the published clinical data with regards to naptumomab.

What the reader will gain: This review provides the reader with an understanding of the mechanism of action, immunology, pharmacokinetics and clinical activity of this agent.

Take home message: Naptumomab has a unique mechanism of action and appears to be an active agent in the treatment of refractory solid tumors such as renal cell carcinoma.     

Allovectin-7 therapy in metastatic melanoma

Background: Patients with metastatic melanoma are immunosuppressed by the growing tumor. Allovectin-7 therapy is a form of active immunotherapy that aims at immunization of the host with substances designed to elicit an immune reaction that will eliminate or slow down the growth and spread of the cancer. Objective: to describe the rationale for immunotherapy with Allovectin-7 and assess its safety profile and efficacy based on the results of completed melanoma clinical trials. Methods: we reviewed both the published medical literature and the results of trials pending publication. Results/conclusion: Allovectin-7 is a safe and active immunotherapeutic agent. It induces local and systemic durable responses in patients with metastatic melanoma.     

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.     

Inhibiting the inhibitors: evaluating agents targeting cancer immunosuppression

Importance of the field: Immunotherapy of cancer has not improved disease-free or overall patient survival. The lack of concordance between immunological and clinical responses in cancer immunotherapy trials is thought to result from the pervasive presence of tumor-driven immune suppression that allows tumor to escape and that has not been adequately targeted by current therapies.

Areas covered in this review: Because multiple mechanisms of tumor induced suppression have been identified and shown to contribute to tumor escape, the opportunity arises to interfere with these mechanisms. A range of known tumor-derived inhibitors can now be blocked or neutralized by biologic or metabolic agents. Used alone or in combination with each other or with conventional cancer therapies, these agents offer novel therapeutic strategies for the control of tumor escape.

What the reader will gain: This review deals with currently available inhibitors for counteracting tumor immune escape. The restoration of effective anti-tumor immunity in patients with cancer will require new approaches aiming at: i) protection of immune cells from adverse effects of myeloid-derived suppressor cells, regulatory T cells or inhibitory factors thus enhancing effector functions; and ii) prolonging survival of central memory T cells, thus ensuring long-term protection.

Take home message: Inhibitors of mechanisms responsible for tumor escape could restore anti-tumor immune responses in patients with cancer.     

Tremelimumab for the treatment of malignant mesothelioma

Introduction: Tremelimumab demonstrated therapeutic activity in different malignancies, including malignant pleural mesothelioma (MPM); however, continued research could improve the therapeutic index of this agent.

Areas covered: This review describes tremelimumab’s clinical efficacy, administration and safety in patients affected with MPM and reports the state of the art clinical trials of tremelimumab. A literature search using the PubMed database was conducted using the search terms tremelimumab, MPM, current therapy, immune checkpoint blockage and cytotoxic T lymphocyte-associated antigen-4. Data was also obtained from meeting abstracts and clinical trial registries.

Expert opinion: The use of immunotherapy has been extended from melanoma to thoracic malignancies or lung cancer and MPM. The first clinical trials for MPM with drugs modulating immune checkpoints have been tested or are currently being tested with the first results now under critical consideration. Among these drugs, tremelimumab has been attracting attention as a potential new treatment for MPM. Nevertheless, even though clinical efficacy has been preliminarily demonstrated, the cost/benefit ratio of this drug for this neoplasm is yet to be ascertained.     

Targeting B cells with biologics in systemic lupus erythematosus

Importance of the field: The use of biologics as immune modulators in several autoimmune diseases has provided new tools to the physician's therapeutic armamentiarium and has led to improved patients' outcomes and quality of life. By producing autoantibodies, B cells in systemic lupus erythematosus (SLE) are key players in the pathogenesis of the disease and in its clinical manifestations. Therefore, biologics that target B cells in SLE aim at reducing the activity of these cells for the induction of remissions and/or amelioration of disease activity, reduction of organ involvement, and limitation of the complications and side effects caused by immunosuppressive therapies.

Areas covered in this review: This review describes the past and current clinical trials with B-cell-targeted biologics in SLE, to provide a historical perspective and the state-of-the-art on the topic.

What the reader will gain: We review how the disappointment in the field from promising agents has been instrumental in providing valuable lessons leading to an improved design of new trials that are now giving encouraging results.

Take home message: In systemic lupus erythematosus (SLE), the use of B-cell-based biologics in clinical trials has shown both disappointment and promise.     

Efficacy and safety of ustekinumab and etanercept for the treatment of psoriasis

Importance of the field: TNF-α inhibitors such as etanercept have been used for psoriasis for years. A fairly well defined efficacy and safety profile has developed. A new biologic agent, ustekinumab, an IL-12 and IL-23 inhibitor, has recently been released in the US for the treatment of moderate-to-severe psoriasis. The purpose of this article is to compare the efficacy and safety profiles of ustekinumab and etanercept.

Areas covered in this review: We examined safety and efficacy data regarding ustekinumab and etanercept from clinical reports, a head-to-head trial, review articles, and databases and registries from the last 20 years.

What the reader will gain: Evidence is reviewed about the efficacy for the treatment of psoriasis as well as the safety profiles for both agents, ustekinumab and etanercept.

Take home message: Both drugs have data to confirm efficacy and safety in patients with moderate-to-severe psoriasis in the short-term. The limited long-term data on the safety profile of ustekinumab requires careful judgment on the clinician's part, weighing well-defined benefits and potential unknown risks.     

Synergy of molecular targeted approaches and immunotherapy in melanoma: preclinical basis and clinical perspectives

Introduction: Targeted therapy and immunotherapies are the novel pharmacologic treatment strategies for metastatic melanoma. BRAF and MEK inhibitors effectively block the hyperactivation of the MAPK pathway in BRAF mutant melanomas and also have several other effects on melanoma cells and on the immune response. The aim of this work is to discuss the rationale, evidence and perspectives of approaches combining target and immunotherapy against melanoma.

Areas covered: We first review the effects of BRAF and MEK inhibitors on melanoma cells and on the different components of the immune system. Afterwards, we summarize the results of the preclinical and clinical studies that have combined targeted therapy and immunotherapy for the treatment of melanoma.

Expert opinion: Clinical applications of immunotherapy strategies have recently changed the therapeutic mainstay for metastatic melanoma. Biologic and initial preclinical data support their integration with innovative molecular targeted therapies, opening enormous perspectives for researchers in the effort of finding a definitive cure. Main open challenges are the definition of reliable research models, assessment of effective schedules, safety issues and designing of personalized approaches.     

Costimulatory blockade with belatacept in clinical and experimental transplantation – a review

Background: Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade. However, long-term follow-up has revealed that these agents are associated with troublesome side effects and chronic toxicity, contributing to graft loss and death. Objectives: Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation. Belatacept, a high-affinity chimeric fusion protein that binds to CD80/CD86 on antigen-presenting cells, has shown great promise in renal transplantation and is now in Phase III trials. Methods: This review explores the development and efficacy of belatacept, compared with currently approved immunosuppressive agents used in transplantation. Results: Belatacept seems to be an effective alternative to current maintenance immunosuppressive therapies, with no apparent end organ toxicity and a minimal side-effect profile. This agent works best when used in combination with therapies that target different pathways of T-cell activation, but the optimal regimen has not yet been identified. Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept-based combinatorial strategies.     

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.     

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.     

Immune alterations and emerging immunotherapeutic approaches in lung cancer

Introduction: Subjects with lung cancer were shown to present a variety of immune abnormalities including cellular immune dysfunction, cytokine alterations, and antigen presentation defects. As discouraging results are commonly seen with the existing therapies in lung cancer, more innovative treatment strategies are needed.

Areas covered: The authors review comprehensively the immune abnormalities in individuals with lung cancer, describe the lung cancer immunotherapy candidates that are most advanced in their clinical development, and summarize recent data from clinical trials of these agents.

Expert opinion: Enhancing the immune system represents an appealing avenue for lung cancer therapy. Several immunomodulating agents have activity in this regard including ipilimumab, a monoclonal antibody against the CTLA-4, and talactoferrin, a dendritic cell activator. In addition, a significant activity was shown with belagenpumatucel-L, a whole-cell-based vaccine that blocks the action of TGF-β2. Other promising vaccines are protein-specific vaccines against tumor antigens such as MAGE-A3, EGF, and MUC1. Although some of these immunotherapies may have lackluster performance as single agents in advanced disease, more impressive results are seen in combination with chemotherapy agents. Given their proven activity in lung cancer, these immunotherapies may soon become a powerful addition to the oncologist's toolbox.     

Monoclonal antibodies currently in Phase II and III trials for multiple myeloma

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option.

Areas covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options.

Expert opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.     

New era of biologic therapeutics in atopic dermatitis

Introduction: Atopic dermatitis (AD) is a common inflammatory skin disease regulated by genetic and environmental factors. Both skin barrier defects and aberrant immune responses are believed to drive cutaneous inflammation in AD. Existing therapies rely largely on allergen avoidance, emollients and topical and systemic immune-suppressants, some with significant toxicity and transient efficacy; no specific targeted therapies are in clinical use today. As our specific understanding of the immune and molecular pathways that cause different subsets of AD increases, a variety of experimental agents, particularly biologic agents that target pathogenic molecules bring the promise of safe and effective therapeutics for long-term use.

Areas covered: This paper discusses the molecular pathways characterizing AD, the contributions of barrier and immune abnormalities to its pathogenesis, and development of new treatments that target key molecules in these pathways. In this review, we will discuss a variety of biologic therapies that are in development or in clinical trials for AD, perhaps revolutionizing treatment of this disease.

Expert opinion: Biologic agents in moderate to severe AD offer promise for controlling a disease that currently lacks good and safe therapeutics posing a large unmet need. Unfortunately, existing treatments for AD aim to decrease cutaneous inflammation, but are not specific for the pathways driving this disease. An increasing understanding of the immune mechanisms underlying AD brings the promise of narrow targeted therapies as has occurred for psoriasis, another inflammatory skin disease, for which specific biologic agents have been demonstrated to both control the disease and prevent occurrence of new skin lesions. Although no biologic is yet approved for AD, these are exciting times for active therapeutic development in AD that might lead to revolutionary therapeutics for this disease.     

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.