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

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

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

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

Systemic lupus erythematosus: an update on current pharmacotherapy and future directions

Introduction: In the last decade, the development of a number of potential drugs for lupus that target the pathogenesis of the disease at different levels has been witnessed. Despite a number of negative trials during this period, belimumab was recently approved for the treatment of adult seropositive lupus patients with mild-to-moderate disease activity.

Areas covered: This review summarizes the results of the most recent drug trials in lupus and highlights the aspects that require further refinement and modification in order to facilitate positive results in new drug trials for lupus.

Expert opinion: The success of a clinical trial depends on the efficacy of the study drug and its appropriate dosing. Several other factors play a major role in the success of trials, including the patient inclusion criteria, the choice of evidence-based study outcomes and endpoints and other aspects of study design that are described in this review.     

RNAi-mediated gene silencing in cancer therapy

Introduction: This review presents the intriguing success of RNA interference (RNAi)-mediated gene silencing and its advantages and obstacles in cancer therapy.

Areas covered: RNAi has implications in metabolic disease, viral hepatitis, cardiovascular and cerebrovascular diseases, HIV, neurodegenerative disorders and cancer. RNAi can enhance the specificity and efficacy of therapeutic intervention for human diseases while at the same time reducing toxicity. The existing research related to gene therapy suggests encouraging prospects of a new high-efficiency and low-toxicity anti-tumor therapy. Although gene therapy is still in the experimental research phase, in the near future, this method will become an important means for the treatment of cancer therapies and it will be widely used in clinical practice.

Expert opinion: RNAi-based drug development is still in preclinical trial and several challenges limit the use of RNAi in the clinic. It is believed that further investigation of the mechanisms of RNAi-based therapies will help overcome these limitations and provide powerful weapons in the oncology clinic.     

AAV-directed muscular dystrophy gene therapy

Importance of the field: Muscle-directed gene therapy for genetic muscle diseases can be performed by the recombinant adeno-associated viral (rAAV) vector delivery system to achieve long-term therapeutic gene transfer in all affected muscles.

Areas covered in this review: Recent progress in rAAV-vector-mediated muscle-directed gene transfer and associated techniques for the treatment of muscular dystrophies (MD). The review covers literature from the past 2 – 3 years.

What the reader will gain: rAAV-directed muscular dystrophy gene therapy can be achieved by mini-dystrophin replacement and exon-skipping strategies. The additional strategies of enhancing muscle regeneration and reducing inflammation in the muscle micro-environment should be useful to optimize therapeutic efficacy. This review compares the merits and shortcomings of different administration methods, promoters and experimental animals that will guide the choice of the appropriate strategy for clinical trials.

Take home message: Restoration of muscle histopathology and function has been performed using rAAV systemic gene delivery. In addition, the combination of gene replacement and adjuvant therapies in the future may be beneficial with regard to improving muscle regeneration and decreasing myofiber necrosis. The challenges faced by large animal model studies and in human trials arise from gene transfer efficiency and immune response, which may be overcome by optimizing the rAAV vectors utilized and the administration methods.     

An update on RNA interference-mediated gene silencing in cancer therapy

Introduction: Based on our previous review, this article presents the new progress in RNA interference (RNAi)-mediated gene silencing in cancer therapy, and reviews the hurdles and how they might be overcome.

Areas covered: RNAi-mediated gene silencing approaches have been demonstrated in humans, and ongoing clinical trials hold promise for treating cancer or providing alternatives to traditional chemotherapies. Here we describe the broad range of approaches to achieve targeted gene silencing for cancer therapy, discuss the progress made in developing RNAi as therapeutics for cancer and highlight challenges and emerging solutions associated with its clinical development.

Expert opinion: Although the field of RNAi-based cancer therapy is still an emerging one, we have yet to get solutions for overcoming all obstacles associated with its clinical development. The current rapid advances in development of new targeted delivery strategies and noninvasive imaging methods will be big steps to explore RNAi as a new and potent clinical modality in humans.     

Prospect of ultrasound-mediated gene delivery in cardiovascular applications

ABSTRACT

Introduction: The field of regenerative medicine has evolved over the years, investigating gene and stem/progenitor cell therapies to help address the increasing burden of cardiovascular disease (CVD). While the lack of success of gene therapy in clinical trials has dampened enthusiasm, the search continues for a successful and translatable gene therapy strategy for CVD. Ultrasound-mediated gene delivery (UMGD) is a non-invasive technique for gene delivery that utilizes gene-bearing carrier microbubbles and high power ultrasound to facilitate transfection in vivo. Many pre-clinical studies have shown benefit in animal models of CVD, but this has yet to be translated to human applications.

Areas covered: In this review, the basic principles of UMGD will be examined along with an overview of pre-clinical studies to date in CVD, focusing on cardiac and vascular applications and key findings. In addition, the potential path to the clinical translation of UMGD is discussed.

Expert opinion: Ultrasound-mediated gene delivery holds promise as a non-invasive technique for gene delivery in CVD, with the ability to deliver multiple genes with repeated deliveries over time. If the substantial hurdles to clinical translation can be overcome, UMGD may prove to be a key aspect in the success of cardiovascular gene therapy in the future.     

Enhanced T cell receptor gene therapy for cancer

Importance of the field: Adoptive therapy with T cell receptor- (TCR-) redirected T cells has shown efficacy in mouse tumor models and first responses in cancer patients. One prerequisite to elicit effective anti-tumor reactivity is the transfer of high-avidity T cells. Their generation, however, faces several technical difficulties. Target antigens are often expressed at low levels and their recognition requires the use of high-affine receptors. Yet, mainly low-affine TCRs have been isolated from tumor-infiltrating lymphocytes. Furthermore, upon transfer into a T cell the introduced receptor has to compete with the endogenous TCR.

Areas covered in this review: This review discusses how the functional avidity of TCR-modified T cells can be enhanced by i) increasing the amount of introduced TCR heterodimers on the cell surface; and ii) generating receptors with high affinity. Risks of TCR gene therapy and possible safety mechanisms are discussed.

What the reader will gain: The reader will gain an overview of the technical developments in TCR and T cell engineering.

Take home message: Despite technical obstacles, many advances have been made in the generation of high-avidity T cells expressing enhanced TCRs. Mouse studies and clinical trials will evaluate the effect of these improvements.     

Bevacizumab for the treatment of high-grade glioma: an update after Phase III trials

Introduction: Gliomas are highly vascular and rich in VEGF, which promotes angiogenesis. Bevacizumab is a monoclonal antibody against VEGF, inhibiting angiogenesis by preventing receptor activation. Early Phase II clinical trials using bevacizumab in both newly diagnosed and recurrent high-grade gliomas (HGG) showed promising results, but these have not been confirmed in recent Phase III trials. This review is an update including recently reported Phase II and III study results.

Areas covered: This is a review of clinical trials investigating bevacizumab in newly diagnosed and recurrent HGG with a focus on outcome results. A future perspective about the expected future role of bevacizumab is given. Bevacizumab efficacy, safety and tolerability, the combination of radiation and bevacizumab, as well as the use of bevacizumab to treat pseudoprogression are discussed. Further criteria of response evaluation needed to be adjusted in the age of antiangiogenic therapy are also discussed.

Expert opinion: Bevacizumab has been shown to be safe and tolerable in HGG. In the recurrent disease setting, bevacizumab might offer clinical benefits and is currently approved as a single agent for this indication. Although clinical trials demonstrate a prolonged progression-free survival (PFS) in bevacizumab-treated HGG, a benefit on overall survival has not been demonstrated. Research so far shows that bevacizumab appears to prolong PFS in newly diagnosed glioblastoma. Available data do not demonstrate a survival benefit in newly diagnosed patients. In the recurrent setting, there is no adequately powered randomized clinical trial to address whether there is a PFS or survival benefit with bevacizumab. Bevacizumab has also been introduced into other settings in neuro-oncology, including concurrent administration with re-irradiation for recurrent HGG.     

Communicating in context: a priority for gene therapy researchers

Introduction: Diseases of the liver represent a major health problem. Often treatments are ineffective, prompting the need for new therapeutic strategies. From extensive preclinical studies, gene therapy in particular mediated by adeno-associated virus (AAV)-derived vectors, has now emerged as the prime candidate for clinical application. AAV-mediated gene therapy for inherited liver diseases has now become a clinical reality, in particular for the treatment of hemophilia B.

Areas covered: This review provides a summary of current literature on AAV-mediated gene therapies for both inherited and acquired liver diseases and outlines different strategies to overcome current clinical limitations. The unique properties of AAV over other viral vectors are highlighted as well as the current challenges which are faced for wide-ranging clinical application.

Expert opinion: Despite the extensive positive results from animal models, successful application in clinical settings is hampered by immunological barriers. However, immune suppression and other strategies can be employed to overcome these limitations. Given some of their unique advantages, AAV vectors are currently the most obvious candidate for hepatic gene therapy applications, however, serotype-related issues of immune reactivity still represent a formidable barrier for clinical success.     

Modification of mesenchymal stem cells for cardiac regeneration

Importance of the field: Mesenchymal stem cells (MSCs) have the greatest potential for use in cell-based therapy of human heart diseases, especially in myocardial infarcts. The therapeutic potential of MSCs in myocardial repair is based on the ability of MSCs to directly differentiate into cardiac tissue and on the paracrine actions of factors released from MSCs. However, the major obstacle in the clinical application of MSC-based therapy is the poor viability of the transplanted cells due to harsh microenvironments like ischemia, inflammation and/or anoikis in the infarcted myocardium. Recently, various approaches have been implemented in an effort to improve the survival of implanted MSCs through ex vivo manipulation of MSCs.

Areas covered in this review: Major obstacles in MSC-based therapy are discussed, along with recent advances for enhancing therapeutic potential of engrafted MSCs from the past decade.

What the reader will gain: This review focuses primarily on ex vivo manipulation of MSCs before transplantation, which includes pretreatment, preconditioning and genetic modification of MSCs, and future directions.

Take home message: Modification of MSCs before transplantation has developed into a promising option for enhancing the beneficial effects of MSC-based therapy for cardiac repair after myocardial infarction.     

Biological therapy for non-obstructive azoospermia

Introduction: Most male patients with non-obstructive azoospermia (NOA) have no therapeutic options outside of assisted reproductive techniques to conceive a biological child. If mature sperm cannot be obtained from the testes, these patients must rely on options of donor sperm or adoption. Several techniques are in the experimental stage to provide this patient population alternatives for conceiving.

Areas covered: This review discusses three of the experimental techniques for restoring fertility in men with NOA: spermatogonial stem cell transplantation, the use of adult and embryonic stem cells to develop mature gametes and gene therapy. After this discussion, the authors give their expert opinion and provide the reader with their perspectives for the future.

Expert opinion: Several limitations, both technical and ethical, exist for spermatogonial stem cell transplantation, the use of stem cells and gene therapy. Well-defined reproducible protocols are necessary. Furthermore, several technical barriers exist for all protocols. And while success has been achieved in animal models, future research is still required in human models.     

Recent advances in the biologic therapy of lupus: the 10 most important areas to look for common pitfalls in clinical trials

ABSTRACT

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease affecting different organs. The improved knowledge of the disease’s pathogenesis has contributed to the emergence of immune targets and new biologic drugs directed at them. Although rheumatologists continue to use off-label biologics in SLE resistant to other immunosuppressants, only belimumab has been approved as a biological therapy since 2011.

Areas covered: In this review, an overview is provided on: 1) the classification of the biologic drugs in clinical trials and of those under research; 2) the results of clinical trials of biologic therapy with an interpretation of pitfalls and syntheses of potential approaches to overcome these pitfalls and, 3) the commonly used disease activity metrics and composite indices for assessing response to drugs.

Expert opinion: Some drugs that have failed in previous drug trials have shown to be efficacious in the treatment of lupus in observational studies. Moreover, the post-hoc analyses of the data of negative drug trials have shown that results of the same trials could be altered with the modification of some pitfalls. For future clinical trials, the consideration of these pitfalls is crucial when designing clinical trials. This could potentially enhance the approval of novel drugs for SLE.     

HER2 as a target for breast cancer therapy

Importance of the field: Differential levels of HER2 expression in normal versus HER2-overexpressing breast carcinomas, together with the demonstration of a key role for HER2 in tumor progression, make HER2 an ideal target for specific therapeutic approaches.

Areas covered in this review: This review considers the clinical value of trastuzumab and lapatinib, the two HER2-targeted therapies approved for clinical practice. References were chosen by searching the PubMed and MEDLINE datasets using as search term: ‘HER2’, in association with ‘prognosis’, ‘response’, ‘trastuzumab’, ‘lapatinib’ and ‘resistance’.

What the reader will gain: This review deals with HER2 as a target for breast carcinoma treatment, focusing on anti-HER2 therapies used in clinical practice, their merits and shortcomings.

Take home message: The benefit of anti-HER2 therapies demonstrated in clinical trials indicates that HER2 is, to date, one of the most promising molecules for targeted therapy. Nevertheless, since tumor cells utilizing alternative growth signaling pathways through transmembrane receptors as well as intracellular signaling transduction molecules can bypass HER2 blockade, a future ambitious aim is the successful combination of anti-HER2 strategies with drugs directed to molecules that contribute to anti-HER2 resistance.     

Drug resistance-related microRNAs in esophageal cancer

Introduction: Drug resistance has been the main obstacle in cancer therapy. A number of drug resistance-related molecules are under investigation but no one agent has already been used in clinical practice. The research on drug resistance-related microRNAs (miRNAs) may eventually lead to improved clinical strategies and outcomes for patients with esophageal cancer (EC).

Areas covered: This review summarizes the recent advances in drug resistance-related miRNAs in EC, and also analyzes the clinical and therapeutic applications they provide. The authors envisage future developments in the molecular mechanisms of these miRNAs and their potential applications to cancer treatment.

Expert opinion: Drug resistance-related miRNAs can be used as a useful therapeutic tool for EC. More investigations should be performed to promote the success of therapeutic–clinical use of miRNAs in cancer.     

siRNA therapy for cancer and non-lethal diseases such as arthritis and osteoporosis

Importance of the field: Gene silencing mediated by siRNA has been widely investigated as a potential therapeutic approach. The success of these therapies depends on effective systems capable of selectively and efficiently conveying siRNA to targeted cells/organs with minimal toxicity.

Areas covered in this review: This review discusses current experimental approaches to siRNA delivery strategies available for arthritis treatment and the management of other musculoskeletal disorders. The review covers literature on the subject from 2000 to 2010.

What the reader will gain: In the last decade, extensive improvements have been made to optimize siRNA-based gene therapy and have been tested on several arthritis and orthopedic conditions. However, except for Phase I – II DNA-based gene therapy trials on arthritis, no clinical studies have reported siRNA application in these domains.

Take home message: Most musculoskeletal disorders, such as rheumatoid arthritis, osteoarthritis, fracture, aseptic loosening, cartilage and intervertebral disc degeneration are non-fatal and age-related chronic inflammatory conditions, but represent significant morbidity and a socio-economic burden. siRNA-based gene therapy offers treatment opportunities that are less invasive, more effective and less expensive than existing modalities. Future directions for siRNA therapy include the development of safe and more efficient delivery systems and the selection of optimal gene targets for disease control.     

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.     

Stem-cell therapy for erectile dysfunction

Introduction: Stem cells (SCs) have been investigated for the treatment of erectile dysfunction (ED).

Areas covered: This review covers key disease targets and all 33 preclinical studies, including their use of SC types, animal models, transplantation routes, and outcome assessment methods.

Expert opinion: In the past one and half years there have been more stem-cell-for-erectile-dysfunction studies than the prior 8 years combined. These new studies tend to use combinatory treatment approaches by modifying or supplementing SCs with angiogenic or neurotrophic genes or proteins. However, when considering all risks and benefits, these combinatory approaches do not seem more advantageous than single-SC approaches. Another trend is the choice of transplantation routes other than the standard intracavernous (IC) injection. However, with the exception of intravenous injection, these new transplantation approaches are more cumbersome than IC injection and yet offer no evidence of producing better outcomes. In contrast to these variations, a consensus among these studies is the suggestion that paracrine action, as opposed to cellular differentiation, is the principal therapeutic mechanism. In conclusion, IC injection of a single SC type should be the choice protocol for initial clinical trials, and this is clearly the case with two clinical trials that are currently recruiting patients.     

Recent advances in immunotherapy for the treatment of prostate cancer

Introduction: Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development.

Areas covered: An autologous antigen presenting cell vaccine loaded with prostate acid phosphatase conjugated with GM-CSF, sipuleucel-T confers a survival advantage in men with metastatic castration-resistant prostate cancer (CRPC) and is now FDA approved based on the IMPACT trial. A poxvirus-based vaccine, PROSTVAC-VF TRICOM targeting prostate-specific antigen (PSA), has demonstrated improved survival in a randomized Phase II trial of patients with metastatic CRPC. Novel T lymphocyte checkpoint inhibitors of cytotoxic T lymphocyte antigen 4 and programmed death-1 are also emerging. Recognition of improved survival without an earlier clinical signal of activity by conventional criteria has led to new guidelines to evaluate immunotherapeutic agents. The clinical benefit of combining vaccines with chemotherapy, radiotherapy and other immunotherapeutic and biologic agents is being evaluated in the context of disappointing results of combination GVAX vaccine and docetaxel chemotherapy.

Expert opinion: To build on the success of early phase trials, efforts must be made to optimize vaccine approaches and patient selection.     

Towards the mechanisms for efficient gene transfer into cells and tissues by means of cell electroporation

Introduction: Intracellular gene electrotransfer by means of electroporation has been on the increase during the past decade. Significant progress has been achieved both in characterizing mechanisms of gene electrotransfer and in optimizing the protocol in many preclinical trials. Recently this has led to initiation of clinical trials of gene electrotransfer to treat metastatic melanomas. Further progress with the method in various clinical trials requires better understanding of mechanisms of gene electrotransfer.

Areas covered: A summary of recent progress in understanding mechanisms of gene electrotransfer, imparting general knowledge of cell electroporation and intracellular molecule electrotransfer.

Expert opinion: Gene electrotransfer into cells and tissues is a complex process involving multiple steps that lead to plasmid DNA passage from the extracellular region to the cell nucleus crossing the barriers of the plasma membrane, cytoplasm and nucleus membrane. Electrical parameters of pulses used for gene electrotransfer affect the initial steps of DNA translocation through the plasma membrane and play a crucial role in determining the transfection efficiency. When considering gene electrotransfer into tissues it becomes clear that other nonelectrical conditions are also of primary importance.     

Non-BRAF-targeted therapy,immunotherapy, and combination therapy for melanoma

Introduction: Melanoma is an aggressive disease characterized by a complex etiology. The discovery of key driving mutations (primarily BRAF mutations) led to the development of specific molecular inhibitors providing clinical benefit.

Areas covered: Although BRAF-specific drugs have perhaps yielded the best results in melanoma-targeted therapy, there still remain several limitations, mostly due to the emergence of resistance and the lack of efficacy in patients without BRAF mutation. Novel drugs are currently being tested in clinical trials and showed encouraging results. Such drugs can specifically target molecular pathways aberrantly activated or repressed during melanoma development (targeted therapy) or act in a way to enhance the host immune system to fight cancer (immunotherapy). Here we provide a detailed overview of the current clinical strategies, which lay beyond BRAF-targeted therapy, spanning from molecular-targeted therapy to immunotherapy and to combination therapy.

Expert opinion: Major advances in our understanding of the mechanisms behind melanoma development have led to the implementation of novel therapeutic drugs. Unfortunately, tools allowing prediction of responsiveness to a given treatment are not available yet. The increasing availability of high-throughput technologies will allow the elucidation of molecular mechanisms underlying responsiveness to cancer therapy and unveil an increased number of potential therapeutic targets.