Recent developments on immunotherapy for brain cancer

INTRODUCTION: Brain tumors are a unique class of cancers since they are anatomically shielded from normal immunosurveillance by the blood-brain barrier, lack a normal lymphatic drainage system and reside in a potently immunosuppressive environment. Of the primary brain cancers, glioblastoma multiforme (GBM) is the most common and aggressive in adults. Although treatment options include surgery, radiation and chemotherapy, the average lifespan of GBM patients remains at only 14.6 months post-diagnosis. AREAS COVERED: A review of key cellular and molecular immune system mediators in the context of brain tumors including TGF-β, cytotoxic T cells, Tregs, CTLA-4, PD-1 and IDO is discussed. In addition, prognostic factors, currently utilized immunotherapeutic strategies, ongoing clinical trials and a discussion of new or potential immunotherapies for brain tumor patients are considered. EXPERT OPINION: Current drugs that improve the quality of life and overall survival in patients with brain tumors, especially for GBM, are poorly effective. This disease requires a reanalysis of currently accepted treatment strategies, as well as newly designed approaches. Here, we review the fundamental aspects of immunosuppression in brain tumors, new and promising immunotherapeutic drugs as well as combinatorial strategies that focus on the simultaneous inhibition of immunosuppressive hubs, both in immune and brain tumor cells, which is critical to consider for achieving future success for the treatment of this devastating disease.     

Update on bevacizumab and other angiogenesis inhibitors for brain cancer

Introduction: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years.

Areas covered: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab.

Expert opinion: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival – a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.     

Challenges and strategies for successful clinical development of immune checkpoint inhibitors in glioblastoma

ABSTRACT

Introduction: Glioblastoma (GBM) remains an incurable tumor with median overall survival of 15 months with the best standard of care. Immune checkpoint inhibitors (CPI) have been the forefront of immunotherapy advances for treatment of various solid cancers. However, clinical development of CPI in GBM has been challenging due to factors associated with intracranial tumors such as limited space for an inflammatory response, difficulties with repeated sampling, and low tumor mutation burden and immunosuppressive mechanisms unique to GBM.

Areas covered: Herein, the authors review the clinical development of CPI in GBM, the challenges involved for their successful implementation, and discuss approaches to overcome these challenges.

Expert opinion: Strategies to improve clinical development of CPI in GBM need to carefully address multiple steps that are needed for successful activation and maintenance of tumor-specific immune responses. Multi-modality approaches are needed to achieve this goal and should focus on augmenting tumor T-cell infiltration, activating cytotoxic T-cells, and maintaining their effector function. CPI have been the most successful immunotherapy approach in the treatment of solid cancers and optimization of combinatorial approaches are needed for their successful implementation in GBM.     

The Safety of available immunotherapy for the treatment of glioblastoma

Introduction: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM.

Areas covered: Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM.

Expert opinion: Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM.     

Advances in malignant glioma drug discovery

Introduction: Outcome for patients with glioblastoma (GBM), the most common malignant primary brain tumor among adults, remains poor. However, two key treatment options have recently generated meaningful improvements in outcome for GBM patients. The addition of temozolomide (a methylating chemotherapeutic agent) to surgical resection and radiation therapy increases survival and is the first evidence that systemic chemotherapy can benefit GBM patients. Also, bevacizumab (a humanized mAb against VEGF) has significant antitumor activity among recurrent GBM patients. Additional areas of ongoing research are generating more therapeutic options that offer exciting potential to build on these results and further improve the outcome for malignant glioma patients.

Areas covered: This review describes three foci of advanced clinical research aimed at improving the outcome of GBM patients: protracted temozolomide dosing, VEGF-inhibiting agents and integrin inhibitors. This review also discusses potential clinical trial strategies to evaluate irreversible EGFR inhibitors as well as therapeutics targeting PI3K and the hedgehog signaling pathway.

Expert opinion: Several factors limit the efficacy of therapeutics targeting GBM. However, significant advances from basic science laboratories have recently generated important insights into the pathophysiology and molecular genetic abnormalities of these tumors. Efforts to translate these findings into innovative treatment strategies offer substantial promise to overcome therapeutic hurdles and treat individual patients more effectively. Improved understanding of malignant glioma biology and factors associated with treatment response will probably lead to improved therapeutic options and a better patient outcome.     

Emerging immunotherapies for glioblastoma

Introduction: Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA’s approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM.

Areas covered: Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy.

Expert opinion: Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.     

Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions

Introduction: The survival of patients with glioblastoma (GBM), which is the most common primary brain malignancy, remains poor with current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes.

Areas covered: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) initiate key signaling pathways in GBM; however, trials with anti-EGFR agents have failed to show improved outcomes. Bevacizumab, a monoclonal antibody targeting VEGF, remains the only FDA-approved molecular drug in GBM; yet its use has only improved progression-free survival without any improvement in overall survival. We review the evidence supporting the continued evaluation of targeted molecular therapies in recurrent GBM. In addition, newer potential therapies targeting other signaling pathways, heat shock proteins and proteosomes, as well as the concept of targeting glioma stem cells are discussed.

Expert opinion: The complex genetic origin of GBM makes it challenging to identify molecular subsets that may benefit from specific targeted therapies. Pathway inhibition, via multisite kinase inhibitors or a carefully selected combination of molecular drugs with or without cytotoxic agents, is currently undergoing evaluation in clinical trials and may improve outcomes in these patients.     

Irinotecan and bevacizumab in recurrent glioblastoma multiforme

Introduction: Glioblastoma multiforme (GBM) is the most common high grade primary brain tumor in adults. Despite significant advances in treatment, the prognosis remains poor. Bevacizumab (BVZ) and irinotecan (CPT-11) are currently being investigated in the treatment of GBM patients. Although treatment with BVZ and irinotecan provides impressive response rates (RR), it is still uncertain if this treatment translates into improved clinical benefit in GBM patients.

Areas covered: This review discusses the clinical efficacy, safety and difficulties regarding response evaluation when treating with BVZ and CPT-11 in recurrent GBM. Particular attention is placed on the literature and a discussion on whether treatment with BVZ and CPT-11 improves clinical outcome. Antiangiogenic treatment has led to difficulties when evaluating objective response by the conventional MacDonald criteria. In the present paper the authors discuss selected key aspects of this treatment modality. A literature search was performed using PubMed in February 2011.

Expert opinion: BVZ + irinotecan leads to high RR and to an increased 6-month progression-free survival. However, no improvement in median overall survival has been observed compared with conventional chemotherapy. Nevertheless, the GBM patients who respond to treatment with BVZ and irinotecan have survived significantly longer than non-responders, indicating that it could be beneficial for a selection of patients to receive this treatment.     

Sustainable release of carmustine from biodegradable poly[(d,l)-lactide-co-glycolide] nanofibrous membranes in the cerebral cavity: in vitro and in vivo studies

Objective: Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. The only interstitial chemotherapy pharmaceutical approved to date for GBM treatment is the Gliadel® wafer. Despite the safety and efficacy of this approach that have been demonstrated in patients undergoing resection of both newly diagnosed and recurrent malignant gliomas, the wafer provides an effective release of the anticancer 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for only 5 days.

Methods: In this study, the authors developed biodegradable poly[(d,l)-lactide-co-glycolide] nanofibrous membranes via electrospinning that provided a sustained release of BCNU. An elution method and a HPLC assay were employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the electrospun membranes.

Results: The experimental results show that the biodegradable, nanofibrous membranes released high concentrations of BCNU for more than 6 weeks in the cerebral cavity of rats. Furthermore, the membranes can better conform to the geometry of the brain tissue and can cover more completely the tissue after the removal of tumors, achieving better drug transport without interfering with the normal function of the brain. Histological examination showed no obvious inflammation reactions of the brain tissues.

Conclusion: Adopting the electrospinning technique will help in manufacturing biodegradable, nanofibrous membranes for the long-term deliveries of various anticancer drugs in the cerebral cavity, which will further enhance the therapeutic efficacy of GBM treatment.     

Role of microRNAs in gliomagenesis: targeting miRNAs in glioblastoma multiforme therapy

Introduction: Gliomas consist of a very heterogeneous group of malignant tumors, accounting for 50 – 60% of primary brain tumors. Despite all the efforts of cytoreductive surgery in combination with intense chemoradiotherapy, glioblastoma multiforme (GBM, glioma grade IV) still has a dismal prognosis. Current research is focused on molecular targeting to overcome resistance to conventional therapy. MicroRNAs (miRNAs), small non-coding RNAs, represent endogenous agents of RNA interference, dramatically changing expression of target proteins. Their role in brain physiology as well as GBM development has attracted intense research efforts pointing toward therapeutic potential and immediate targeting for sensitization of glioma cells to chemo and/or radiotherapy.

Areas covered: This review is focused on the variable role of miRNAs in gliomagenesis and their possible clinical relevance in patient's survival and prognosis. It further addresses the potential application of selected miRNAs as therapeutic targets or agents in GMB, including data from clinical studies in other central nervous system tumors.

Expert opinion: Although miRNA-targeted therapy is still in its initial stage and clinical trials with glioma/brain tumor patients are under recruitment or currently running, several miRNAs have been selected as promising tumor biomarkers, with increased potential to reduce disease progression in combination to conventional first-line therapy for gliomas.     

Systemic treatment in breast-cancer patients with brain metastasis

Importance of the field: Breast cancer is the second most common cause of CNS metastasis, following lung cancer. With better control of systemic disease, the CNS is emerging as a sanctuary site of relapse in patients with otherwise controlled cancer.

Areas covered in this review: Standard therapy for brain metastasis is currently whole-brain radiotherapy. Other treatment modalities include surgery and radiosurgery in selected cases, corticosteroids, and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of brain metastases, partly because tumors develop brain metastases at a stage when they become totally chemoresistant. Nevertheless, new treatment choices have emerged considering cytotoxic and biological agents for the treatment of CNS metastases in patients with breast cancer.

What the readers will gain: In this review, we aimed to review current and future treatment options in the systemic treatment of brain metastases of breast cancer.

Take home message: Corticosteroids, anti-epileptic drugs, and radiotherapy remain the cornerstones of management. The efficacy of conventional cytotoxic chemotherapeutics is limited. Novel biologic agents, lapatinib being the most promising, are currently investigated in the treatment of brain metastases of breast cancer with promising results.     

Emerging drugs for neuroblastoma

Introduction: Neuroblastoma accounts for 8 – 10% of pediatric cancers and is responsible for 15% of childhood cancer deaths. Despite multimodality treatment, the overall survival (OS) and event-free survival (EFS) in high-risk patients remain suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment.

Areas covered: This review discusses about the unmet medical needs for new therapeutic options against high-risk neuroblastoma. New drugs and therapeutic strategies that are under development in clinical trials, which are currently recruiting patients.

Expert opinion: There is a need to improve the response rate of induction chemotherapy, which is not effective in a third of patients and also the other components of the current treatment, little efficacious in avoiding the relapses. Few drugs have been introduced as upfront therapy in the last years. Topotecan, irinotecan and temozolomide are expected to improve the response in high-risk neuroblastoma, but their impact on OS and EFS is unknown. Anti-GD2 antibodies combined with other immunomodulators (IL-2, GM-CSF) are an important advance in the treatment of these children. Nevertheless, the hope is put in the new drugs directed to molecular targets of neuroblastoma. Anti-angiogenic drugs, ALK antagonist and PI3K/Akt/mTOR inhibitors are among the most promising.     

Harnessing nanomedicine for therapeutic intervention in glioblastoma

ABSTRACT

Introduction: Glioblastoma is a type of brain cancer arises from glial cells. Glioblastoma multiforme (GBM), a subtype of glioblastoma, is the most common and most aggressive primary brain tumor. Currently, GBM therapy includes surgery and post-operative high-doses of radiation and chemotherapy. This therapeutic strategy has a limited contribution in extending the survival rate of GBM patients.

Areas covered: Herein, we focus on harnessing nanoscale drug delivery strategies to treat brain malignancies. Specifically, we briefly discuss the challenges facing GBM therapy such as restricted passage across the blood-brain barrier (BBB) and low enhanced permeability and retention effect. Next, we describe different pathways to address these challenges. Finally, we discuss the field of nanomedicine, which emerged as a promising platform for drug delivery to brain malignancies.

Expert opinion: Countless strategies have been applied in preclinical and clinical settings to treat GBM. Among them is the use of different types of nanoparticles (NPs) and viruses with different approaches to cross or bypass the BBB. We suggest here a paradigm shift in thinking about crossing the BBB and tumor penetration as fundamental issues that need to be address in order to improve the therapeutic outcome in GBM     

Preclinical models for pediatric solid tumor drug discovery: current trends,challenges and the scopes for improvement

Introduction: The enhancement in pediatric cancer survival achieved in the past few decades has been confined to low- and moderate-risk cancers, whereas no notable improvement in survival was observed in high-risk and advanced-stage childhood cancers. High attrition rate of candidate drugs in clinical trials is a major hurdle in the development of effective therapies for pediatric solid tumors. In order to reduce the failure rate of candidate drugs in clinical trials, more effective strategies are needed to enhance the predictability of preclinical testing.

Areas covered: The authors have described the current trends in preclinical drug development for treating pediatric solid tumors. Furthermore, the authors review their limitations and the available remedies, with regards to choice of models, pharmacokinetic considerations and the criteria for assessing the long-term efficacy of a candidate drug.

Expert opinion: In many solid tumors, common differences between pediatric and adult cancers have been observed, and therefore, clinical trials for pediatric solid tumors must be conducted on the basis of preclinical observations in pediatric solid tumor models. There is a need to invest in extensive preclinical testing on pediatric solid tumor models. None of the preclinical models can fully recapitulate the human cancers. Therefore, these limitations must be considered while conducting a preclinical trial. The dose and schedule of drugs used for preclinical testing must be clinically relevant. While testing the efficacy of drugs, the markers of apoptosis, drug resistance, hypoxia and tumor-initiating cells can inform us about the long-term therapeutic response of a cancer.     

Pharmacological management of autoimmune hepatitis

Introduction: Without prompt immunosuppressive treatment, autoimmune hepatitis is a devastating, albeit rare, liver disease. It affects both adults and children, being particularly aggressive in the latter. Eighty per cent of patients respond satisfactorily to treatment; the other 20% progress to end-stage liver disease and require transplantation.

Areas covered: This review emphasizes the importance of a timely diagnosis of autoimmune hepatitis and provides a practical guide for its treatment. The authors summarize the treatment options available for autoimmune hepatitis and stress that most patients respond successfully to standard treatment with prednisolone and azathioprine, two well-tried and inexpensive drugs. The authors also review the options for difficult-to-treat patients (non-responders and frequent relapsers), for whom newer immunosuppressive agents – usually employed as anti-rejection drugs – have been tried with variable success.

Expert opinion: Autoimmune hepatitis is exquisitely responsive to immunosuppression but treatment must be started as soon as possible to achieve full remission and halt progression of liver disease. New strategies aiming at treating the unresponsive patients and at specifically curbing the liver autoimmune attack, without provoking unwanted systemic side effects, are being investigated and may be available within the next 5 years.     

Development of transplant immunosuppressive agents – considerations in the use of animal models

ABSTRACT

Introduction: The development of all immunosuppressant agents to date has involved the experimental use of large and small animal models. Over the last half-century, immunosuppressive drugs have extended the lives of transplant patients worldwide. However, the use of animal models in the development of these drugs is not perfect, and this has brought to light a number of issues including idiosyncratic reactions that are found in animal models but not in humans. The 2006 highly publicized case of the ‘elephant man’ TGN 1412 drug trial highlights the importance of being cogent of the limitations of animal models.

Areas covered: This review covers the utility and limitations of the use of animal models for the development of immunosuppressant agents. This includes both large and small animal models, particularly rodent models in the transplant setting.

Expert opinion: The use of animal models represents a critical stage in the development of immunosuppressive drugs. Limitations include physiological differences to humans; this is especially true of immunologically naïve lab rodents with small memory cell populations. Toxic drug levels may differ widely between species. Animal models are also costly and raise ethical concerns. However, there is currently no way to recreate the complex environment of the human immune system purely in vitro.     

Standard of care and future pharmacological treatment options for malignant glioma: an urgent need for screening and identification of novel tumor-specific antigens

Introduction: Malignant gliomas (MGs) represent the most common primary brain tumors in adults, the most deadly of which is grade IV glioblastoma. Patients with glioblastoma undergoing current standard-of-care therapy have a median survival of 12 – 15 months.

Areas covered: Over the past 25 years, there have been modest advancements in the treatment of MGs. Assessment of therapeutic responses has continued to evolve to account for the increasing number of agents being tested in the clinic. Currently approved therapies for primary tumors have been extended for use in the setting of recurrent disease with modest efficacy. Agents initially approved for recurrent gliomas have begun to demonstrate efficacy against de novo tumors but will ultimately need to be evaluated in future studies for scheduling, timing and dosing relative to chemotherapy.

Expert opinion: Screening and identification of tumor-specific mutations is critical for the advancement of effective therapy that is both safe and precise for the patient. Two unique antigens found in glioblastoma are currently being employed as targets for immunotherapeutic vaccines, one of which has advanced to Phase III testing. Whole genome sequencing of MGs has yielded two other novel mutations that offer great promise for the development of molecular inhibitors.     

What is novel in the clinical management of pemphigus

ABSTRACT

Introduction: Pemphigus, an autoimmune disease group characterized by blisters and erosions of the skin and/or mucosal membranes has been treated with systemic corticosteroids (CS) and immunosuppressive therapies for the past few decades.

Areas Covered: However, common adverse effects and complications of long-term CS and immunosuppressive drugs are limiting their long-term use. The disease results in death if not treated. Thus, currently, researchers are trying to develop new and safer therapeutic approaches. Specifically, targeted therapies to pathogenic immune pathways are under investigation. The B cell inhibitors which block CD20 and CD19 are the main new drugs investigated in clinical trials as alternatives to systemic steroids.

Expert Opinion: Randomized controlled trial (RCT) Level evidence shows that rituximab and short course CSs are more effective and safer than standard CS treatment. Specific BTK inhibitors have shown promise in data from a phase II international open-label study. Further studies are ongoing.     

Potential chemotherapeutic targets for Japanese encephalitis: current status of antiviral drug development and future challenges

Introduction: Japanese encephalitis (JE) remains a public health threat in Asia. Although several vaccines have been licensed, ～ 67,900 cases of the disease are estimated to occur annually, probably because the vaccine coverage is low. Therefore, effective antiviral drugs are required to control JE. However, no licensed anti-JE drugs are available, despite extensive efforts to develop them.

Areas covered: We provide a general overview of JE and JE virus, including its transmission cycle, distribution, structure, replication machinery, immune evasion mechanisms and vaccines. The current situation in antiviral drug development is then reviewed and future perspectives are discussed.

Expert opinion: Although the development of effective anti-JE drugs is an urgent issue, only supportive care is currently available. Recent progress in our understanding of the viral replication machinery and immune evasion strategies has identified new targets for anti-JE drug development. To date, most candidate drugs have only been evaluated in single-drug formulations, and efficient drug delivery to the CNS has virtually not been considered. However, an effective anti-JE treatment is expected to be achieved with multiple-drug formulations and a targeted drug delivery system in the near future.