Current Cancer Therapy Reviews - Volume 8, Issue 4, 2012

The approval of sipuleucel-T for the treatment of patients with metastatic asymptomatic and minimally symptomatic castration-resistant prostate cancer (CRPC) has validated immunotherapy, in general, as a valid approach for this disease. Multiple novel immune based approaches including adenoviral-based vector delivering targeted antigen, DNAbased vaccination, listeria-based vaccination, pox-viral based approach, immune checkpoint blockade and radioimmunoconjugates appear promising. In concert with the development of new immunotherapeutics, the development of optimal intermediate endpoints for clinical efficacy, measures of an optimal immune response and biomarkers predictive for benefit are warranted. We briefly review emerging immunotherapeutic approaches to treat patients with CRPC.

Delivery of plasmid DNA encoding an antigen of interest has been demonstrated to be an effective means of immunization, capable of eliciting antigen-specific T cells. Plasmid DNA vaccines offer advantages over other anti-tumor vaccine approaches in terms of simplicity, manufacturing, and possibly safety. The primary disadvantage is their poor transfection efficiency and subsequent lower immunogenicity relative to other genetic vaccine approaches. However, multiple preclinical models demonstrate anti-tumor efficacy, and many efforts are underway to improve the immunogenicity and anti-tumor effect of these vaccines. Clinical trials using DNA vaccines as treatments for prostate cancer have begun, and to date have demonstrated safety and immunological effect. This review will focus on DNA vaccines as a specific means of antigen delivery, advantages and disadvantages of this type of immunization, previous experience in preclinical models and human trials specifically conducted for the treatment of prostate cancer, and future directions for the application of DNA vaccines to prostate cancer immunotherapy.

There is an unmet need for new approaches to treat prostate cancer beyond hormonal deprivation and chemotherapy. Using immunotherapy to focus immune responses on prostate cancer antigens appears to be a valid therapeutic approach. Several immunotherapeutic agents are being developed employing a variety of approaches. In recent years, Listeria monocytogenes (Lm)-LLO immunotherapy has been well tolerated in early clinical studies and is currently being evaluated in the clinic for HPV-associated dysplasia and malignancies such as recurrent/refractory cervical cancer, cervical intraepithelial neoplasia (CIN) 2/3, and head and neck cancer. Lm is a strong stimulator of both innate and cellular immune responses due to its unique life-cycle. Attenuated Listeria-based Lm-LLO immunotherapy secreting human prostate specific antigen (PSA) (ADXS31-142) has been shown to cause the therapeutic regression of PSA-expressing tumors in mouse models. The therapeutic effect of ADXSD31-142 on tumor regression is associated with the generation of PSAspecific T cells and subsequently, their infiltration in the tumor microenvironment, accompanied by the reduction of regulatory T cells (CD4+CD25+Foxp3+) within the tumors. Further development is underway to advance ADXS31-142 Lm- LLO immunotherapy into the clinic for the treatment of castration resistant prostate cancer.

Prostate cancer is a significant health problem for men in the United States. While useful treatment modalities are available, their therapeutic efficacies are limited and severe side effects remain a concern. Alternatively, immunotherapy represents one of the most valuable treatments by inducing immune response targeting tumor cells. Sipuleucel-T is the only FDA approved immunotherapeutic agent for the treatment of patients with metastatic castration-resistant prostate cancer. Overall survival benefit with sipuleucel-T is modest, and the research field of cancer immunotherapy is continuously expanding. Numerous methods designed to induce tumor-specific immunity are at various developmental stages in clinical and preclinical studies. Among such modalities, the use of adenovirus vector (Ad) as an immunotherapy agent to deliver tumor-associated antigens is an attractive and versatile vector system. In this review, we describe the potential use of Ad-vector for prostate cancer immunotherapy.

The use of PSA (prostate-specific antigen) for its diagnostic utility in prostate cancer is a subject of discussion; however, due to its specificity to the prostate tissue, PSA remains a potential immunotherapy target. We developed a PSA-recombinant viral vector, adenovirus5-PSA (Ad5-PSA) that generated vigorous PSA-specific immune and antitumor responses in a prostate cancer mouse model. Using Ad5-PSA vaccine we successfully completed a Phase I clinical study and are conducting a Phase II trial. In this review, we summarize the clinical development of this Ad5-PSA vaccine as an immunotherapeutic agent and its potential utility for the treatment of prostate cancer.

In United States, prostate cancer is the most common cancer diagnosis (excluding dermatological malignancies) and the second leading cause of cancer related mortality in men [1]. Early stage prostate cancer has an indolent course; however local tumor progression and aggressive metastatic disease may develop in the long term [2]. Androgen deprivation therapy provides disease control for a substantial period of time; however the vast majority eventually progress [3, 4]. In hormone refractory cases, chemotherapy with docetaxel and prednisone led to a superior survival and quality of life [5]. This combination remained as the predominant first line of chemotherapeutic option for a significant period of time. Only recently have new advances in chemotherapeutic, anti-androgen and other novel therapeutic options made it into the clinic. Sipuleucel-T in patients with castration-resistant metastatic prostate cancer demonstrated a reduction in the risk of death [6]. The sipuleucel-T trial results have helped demonstrate a proof of concept of the potential of immunotherapy in prostate cancer but widespread acceptance of its use has been tempered by the time limited survival advantage of only four months. Therefore, we continue to need novel agents and combination strategies which build on this initial success. Several other inter-related patho-physiological mechanisms like inflammation and genetic/epigenetic modulation are under investigation in prostate cancer which could have further implications in the development of these new immunotherapeutic preventive and treatment strategies [7, 8]. In this article we will give an overview about the role and link of inflammation, epigenetic modulation and immune modulation in the development and treatment of prostate cancer. It is imperative that new approaches that further define immune responsiveness and identify which patients are most likely to benefit. With the increasing availability of novel agents, future advances will also lie in innovative combination strategies.

Cell migration is an essential characteristic of life. However, the indispensable, physiological migration of embryonic and adult stem cells, leukocytes, and fibroblasts is opposed to the pathological migration of tumor cells during metastasis formation. Leukemic cells take a special position, since they combine characteristics of leukocyte and tumor cell migration. Although migration occurs in many variants with regard to dynamics and molecular mechanisms, myosin is generally needed to generate locomotory forces in all of the aformentioned cells. Our work aims to the understanding on the involvement of different myosin isotypes in the migration of leukocytes and leukemic cells at various stages of differentiation. By means of our three-dimensional, collagen-based migration assay, we investigated the involvement of nonmuscle myosin II and myosin VI in the migration of adult CD133+ hematopoietic stem/progenitor cells (HSPCs) as well as of four leukemic cell lines (Jurkat, Molt-4, NB-4, Dohh-2) and cells from leukemia patients. We show that the spontaneous, matrix-induced migration of CD133+ HSPCs solely depends on the activity of myosin VI, whereas the stromal cellderived factor (SDF)-1-induced migration requires both myosin isotypes. In contrast, leukemic cells engage both myosin isotypes for the spontaneous and the SDF-1-induced migration with varying proportions. Our previous studies have shown that the migration of differentiated leukocytes is exclusively based on non-muscle myosin II. We conclude that the proportionate involvement of non-muscle myosin II and myosin VI varies due to the differentiation state of the cells. The involvement of myosin VI decreases with the grade of differentiation, whereas the role of non-muscle myosin II increases.

Surgery is the single most effective therapy for patients with solid tumors. However, up to half of the patients who receive surgical resection will relapse from their cancer. Despite the significant benefit from surgery, there is a growing body of evidence that suggests that surgery may also contribute to tumor recurrence. The evidence supporting this claim can be divided into immunologic and non-immunologic mechanisms. The non-immunologic mechanisms associated with surgery include direct seeding through tissue manipulation, pressure activation of malignant cells, the release of angiogenic factors, and an increase in circulating growth factors. Surgery also has dramatic implications for the immune system; these include the suppression of cell-mediated immunity, the activation of the neuroendocrine response, and anesthesia related immunosuppression. The factors associated with post-surgical tumor recurrence are complex; nevertheless, a better understanding of these mechanisms provides an opportunity to develop therapeutic interventions that can lower the recurrence rate in patients with solid tumors.

Introduction: The alterations in the expression of five different dopamine receptor genes (DRD1- DRD5) associated with certain diseases of the immune and nervous systems have previously been reported, and play multiple roles in various disorders such as cancer. This study focused on the relationship between changes in dopamine receptor gene expression and non - small - cell lung cancer. Methods: Peripheral blood were obtained from 30 non-small cell lung cancer (NSCLC) patients and normal individuals. Total cellular RNA was extracted from peripheral blood mononuclear cells (PBMC) and cDNA was synthesized. Real - Time PCR was carried out using primer pairs specific for the five dopamine gene receptors mRNA and β-actin ( as internal control). Finally the specificities of the obtained PCR products for the respective dopamine receptors fragments were confirmed by sequencing. Results: Statistical analysis using SPSS software showed significant difference (P-value<0.05) in DRD2, DRD3 and DRD4 expression in NSCLC patients with comparison to normal individuals. The expression of these genes in the patient group was lower than those in the healthy controls, however, DRD1 and DRD5 genes did not show any significant changes. Conclusions: It can be concluded that there is a quantitative significant difference of D2-like dopamine receptor genes expression in non- small -cell lung cancer that is not the same in all kind of receptor genes. On the other hand such significant differences and profiles could contribute to diagnosis, treatment, survey and monitoring of non- small- cell lung cancer. In addition, it could be of potential use in the design of future therapeutic strategies.