Cellular immunotherapies for prostate cancer.

Prostate cancer is currently the most commonly diagnosed malignancy, and the second leading cause of cancer-related death, in men in the United States. Most deaths from prostate cancer are due to metastatic disease that no longer responds to androgen deprivation. There have been several advances within the last decade leading to the approval of new agents for treating patients with castration-resistant prostate cancer. However, these agents can have significant side effects, and the average survival benefit from chemotherapy has been modest. Results from several clinical trials have suggested that immune-based therapies may have clinical benefits in patients with prostate cancer with significantly fewer adverse events. These new therapies, however, pose new potential benefits and risks. We review here two cellular immunotherapies furthest in clinical development for prostate cancer, and discuss the potential challenges to the treating oncologist with the possible advent of these new therapies.     

Technology evaluation: DCVax,Northwest Biotherapeutics

DCVax, a dendritic cell-based immunotherapy, is an active immunization platform being developed by Northwest Biotherapeutics for the potential treatment of multiple malignancies, including hormone-refractory metastatic prostate cancer, non-small-cell lung cancer, renal cancer and glioblastoma multiforme. The DCVax platform is tailored to a specific cancer type with either purified tumor-specific antigen or tumor cell extracts derived from patients at the time of resection. Phase I/II clinical trials of DCVax-Prostate have been completed, and phase III clinical trials have recently been initiated. DCVax-Brain is currently undergoing phase II clinical trials, and DCVax-Lung recently received approval from the US FDA for phase I clinical trials.     

Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design

Although docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer in 2004, additional therapies are still required. Prostate cancer is often slow-growing and expresses many tumor-associated antigens, making it a feasible target for immunotherapy. Several therapeutic cancer vaccines have been developed for prostate cancer, including antigen-presenting-cell-based, vector-based, and whole tumor cell vaccines. Initial trials demonstrated that vaccine approaches have limited toxicity. Clinical trials of targeted biologic therapies have demonstrated that patient selection is vital, and there is preliminary evidence that clinical parameters can be used to encompass metastatic prostate cancer patients who will more probably respond to vaccine treatment. In addition to appropriate patient selection, a successful clinical trial must have an appropriate primary endpoint as well. Three randomized, ‘placebo’-controlled studies in metastatic castration-resistant prostate cancer have suggested a clinically significant survival advantage in spite of a lack of improvement in time to progression, implying that overall survival is the ideal endpoint for such trials. Careful examination of data from completed immunotherapy clinical trials in prostate cancer has identified appropriate patient populations and endpoints. Those principles need to be applied to future trial design to properly evaluate prostate cancer vaccines.     

Prostate cancer gene therapy clinical trials.

Despite recent advances in early detection and treatment, prostate cancer is still the second leading cause of cancer death in men in the United States, and approximately 27,000 men will die from it this year. Better treatments are needed for aggressive forms of localized disease and hormone-refractory metastatic disease. Recently, several gene therapy strategies have generated provocative results in early-stage clinical trials, raising the possibility that gene therapy may have the potential to affect both localized and metastatic disease. Much work lies ahead. Nevertheless, for the time being, these studies provide hope that gene therapy may someday earn a place in the management of prostate cancer.     

Gene therapy for cancer treatment: past, present and future

The broad field of gene therapy promises a number of innovative treatments that are likely to become important in preventing deaths from cancer. In this review, we discuss the history, highlights and future of three different gene therapy treatment approaches: immunotherapy, oncolytic virotherapy and gene transfer. Immunotherapy uses genetically modified cells and viral particles to stimulate the immune system to destroy cancer cells. Recent clinical trials of second and third generation vaccines have shown encouraging results with a wide range of cancers, including lung cancer, pancreatic cancer, prostate cancer and malignant melanoma. Oncolytic virotherapy, which uses viral particles that replicate within the cancer cell to cause cell death, is an emerging treatment modality that shows great promise, particularly with metastatic cancers. Initial phase I trials for several vectors have generated excitement over the potential power of this technique. Gene transfer is a new treatment modality that introduces new genes into a cancerous cell or the surrounding tissue to cause cell death or slow the growth of the cancer. This treatment technique is very flexible, and a wide range of genes and vectors are being used in clinical trials with successful outcomes. As these therapies mature, they may be used alone or in combination with current treatments to help make cancer a manageable disease.     

In situ gene therapy for prostate cancer: immunomodulatory approaches

The development of effective treatments for prostate cancer is thwarted by the natural history of the disease. The biological and clinical potential of most individual cancers is uncertain. In many cases the disease will not progress to clinical significance but experimental and clinical studies indicate that prostate cancer can and may metastasise early in the course of the disease from relatively small foci (i.e., not necessarily the largest or index cancer). Localised prostate cancer is potentially curable with localised therapies (radical prostatectomy or irradiation therapy). However, there are no curative therapies for metastatic prostate cancer. Gene therapy, especially those approaches with an immunomodulatory component, may provide additional therapeutic options with the potential to affect both localised and systemic disease. We have pioneered the development and application of in situ gene therapy protocols using adenoviral vectors to transduce specific genes that generate cytotoxic activity and/or a systemic antitumour immune response. In addition we have completed initial studies that demonstrate the therapeutic potential of adenoviral vector-mediated gene modified cell-based vaccines. Our review discusses preclinical studies focused on the development of immunostimulatory in situ gene therapy approaches that hopefully will provide novel and effective treatments for localised and metastatic prostate cancer.     

Dimethyl sulfoxide-sodium bicarbonate infusion for palliative care and pain relief in patients with metastatic prostate cancer

Prostate cancer (adenocarcinoma of the prostate) is the most widespread cancer in men. It causes significant suffering and mortality due to metastatic disease. The main therapy for metastatic prostate cancer (MPC) includes androgen manipulation, chemotherapy, and radiotherapy and/or radioisotopes. However, these therapeutic approaches are considered palliative at this stage, and their significant side effects can cause further decline in patients' quality of life and increase non-cancer-related morbidity/mortality. In this study, the authors have used the infusion of dimethyl sulfoxide-sodium bicarbonate (DMSO-SB) to treat 18 patients with MPC. The 90-day follow-up of the patients having undergone the proposed therapeutic regimen showed significant improvement in clinical symptoms, blood and biochemistry tests, and quality of life. There were no major side effects from the treatment. In searching for new and better methods for palliative treatment and pain relief, this study strongly suggested therapy with DMSO-SB infusions could provide a rational alternative to conventional treatment for patients with MPC.     

Dimethyl Sulfoxide–Sodium Bicarbonate Infusion for Palliative Care and Pain Relief in Patients With Metastatic Prostate Cancer

ABSTRACT

Prostate cancer (adenocarcinoma of the prostate) is the most widespread cancer in men. It causes significant suffering and mortality due to metastatic disease. The main therapy for metastatic prostate cancer (MPC) includes androgen manipulation, chemotherapy, and radiotherapy and/or radioisotopes. However, these therapeutic approaches are considered palliative at this stage, and their significant side effects can cause further decline in patients’ quality of life and increase non–cancer-related morbidity/mortality. In this study, the authors have used the infusion of dimethyl sulfoxide–sodium bicarbonate (DMSO-SB) to treat 18 patients with MPC. The 90-day follow-up of the patients having undergone the proposed therapeutic regimen showed significant improvement in clinical symptoms, blood and biochemistry tests, and quality of life. There were no major side effects from the treatment. In searching for new and better methods for palliative treatment and pain relief, this study strongly suggested therapy with DMSO-SB infusions could provide a rational alternative to conventional treatment for patients with MPC.     

Chemotherapie beim Prostatakarzinom

For many years the benefit of chemotherapy in patients with prostate cancer was thought to be limited to palliation of late-stage disease, and thus this treatment option only became involved in patient care towards the end of the disease process, if at all. However, two landmark phase-III trials with docetaxel-based therapy (TAX 327 and Southwest Oncology Group, SWOG, 9916) have shown a survival benefit for patients with hormone refractory prostate cancer (HRPC) thus prompting a change in patterns of care. With raising interest for chemotherapeutic options and clinical trials for new drugs and new indications (neoadjuvant therapy, adjuvant therapy, increasing PSA levels after local treatment, and hormone sensitive cancer) under way our goal was to review within the context of a multidisciplinary team the available evidence and explore the standard for the medical treatment of prostate cancer outside of clinical trials. We are carefully evaluating the current treatment recommendations based on the available evidence and highlight potential future treatment options but also discuss important clinical topics (treatment until progression versus the advantage of chemo holidays, definition of particular patient subgroups and potential second line options) for which there are no clear cut answers to date. The role and importance of radiotherapy, biphosphonate treatment and the medical management of pain and side effects is also discussed. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists.     

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

Both the expression and biology of the tumor-associated antigen (TAA) 5T4 suggest that it is an effective target for cancer immunotherapy. This paper reviews the development of a novel immunotherapeutic vaccine comprising the highly attenuated modified vaccinia ankara virus encoding 5T4 (MVA-5T4, aka TroVax). Preclinical studies have demonstrated that MVA-5T4 is safe and highly effective in both the prophylactic and active treatment of syngeneic murine tumor models. More importantly, > 700 doses of MVA-5T4 have been administered to > 200 patients to date. Reported results from clinical trials in metastatic colorectal, metastatic renal and hormone-refractory prostate cancer patients demonstrate that MVA-5T4 is safe and highly immunogenic, both as a monotherapy and in combination with standard-of-care therapies including irinotecan, oxaliplatin, IFN-alpha and IL-2. These studies demonstrate that MVA-5T4 induces potent and sustained immune responses in approximately 95% of tested patients. In addition, post-hoc analyses of these studies have noted a correlation between anti-5T4 immune responses and indicators of clinical benefit. With its minimal side effects and demonstrated ability to produce strong immune responses in patient populations, MVA-5T4 is a promising addition to the cancer therapy arsenal.     

Quality of life in patients with prostate cancer

OBJECTIVES: Quality of life (QOL) issues are important for patients with prostate cancer because side effects from treatment are substantial, while the disease itself may be indolent. This article reviews prostate cancer QOL studies. DATA SOURCES: Selected studies published on QOL in prostate cancer using validated patient-assessed tools from the last 5 years. CONCLUSIONS: Prostate cancer treatments are associated with side effects: prostatectomy has more urinary and sexual side effects, while external radiation therapy has more bowel symptoms. Side effects are not highly correlated with overall QOL. IMPLICATIONS FOR NURSING PRACTICE: Patients must be made aware of potential gains in life expectancy as well as side effects of treatments to make informed decisions about treatment.     

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

Both the expression and biology of the tumor-associated antigen (TAA) 5T4 suggest that it is an effective target for cancer immunotherapy. This paper reviews the development of a novel immunotherapeutic vaccine comprising the highly attenuated modified vaccinia ankara virus encoding 5T4 (MVA-5T4, aka TroVax^®). Preclinical studies have demonstrated that MVA-5T4 is safe and highly effective in both the prophylactic and active treatment of syngeneic murine tumor models. More importantly, > 700 doses of MVA-5T4 have been administered to > 200 patients to date. Reported results from clinical trials in metastatic colorectal, metastatic renal and hormone-refractory prostate cancer patients demonstrate that MVA-5T4 is safe and highly immunogenic, both as a monotherapy and in combination with standard-of-care therapies including irinotecan, oxaliplatin, IFN-α and IL-2. These studies demonstrate that MVA-5T4 induces potent and sustained immune responses in ～ 95% of tested patients. In addition, post-hoc analyses of these studies have noted a correlation between anti-5T4 immune responses and indicators of clinical benefit. With its minimal side effects and demonstrated ability to produce strong immune responses in patient populations, MVA-5T4 is a promising addition to the cancer therapy arsenal.     

Clinical pathways for managing patients receiving interleukin 2

As biologic therapies enter the mainstream for cancer and HIV treatments, clinicians need the knowledge and expertise to safely and competently care for their patients who are undergoing these therapies. This article provides an overview of the immune system, emphasizing the elements that are affected by the biologic agent interleukin 2 (lL-2), lL-2 has been approved for use in the treatment of metastatic renal cell carcinoma and metastatic melanoma. Clinical trials currently are being conducted to determine its use in treating other cancers. The severity of side effects of lL-2 varies with the dose, route, and schedule of administration. The most common effects with all methods of administration are flu-like symptoms. Because the side effects of lL-2 are relatively predictable, clinical pathways offer practical tools for anticipating and managing the toxicities associated with lL-2 administration.     

Chemotherapy for prostate cancer: finally an advance!

Patients with metastatic prostate cancer can be treated with androgen deprivation strategies; however, most patients will eventually develop androgen-independent prostate cancer (AIPC). Until recently, chemotherapy has been shown to palliate symptoms of disease but not improve survival. Now 2 large phase 3 trials have demonstrated an overall survival advantage for docetaxel-based regimens compared with the best standard of care. This firmly cements docetaxel-based therapies as the standard of care for patients with metastatic androgen-independent disease. In addition, this foundation provides a platform for the translation of novel agents into new combination cancer therapies. In this paper, we not only review standard treatment options available for AIPC including the recently completed docetaxel trials, but also present some of the promising new drug combinations of currently available drugs.     

Biological therapy: chronicling 15 years of progress

ABSTRACT

Introduction: Intralesional immunotherapy supplements systemic treatments and often achieves higher remission rates as compared to systemic therapy. Its indication is metastatic melanoma with limited tumor burden, particularly in loco-regional metastasis and distant soft tissue metastasis.

Areas covered: This review describes intralesional immunotherapy with talimogene laherparepvec (T-VEC), with velimogene aliplasmid (Allovectin-7) and with intralesional interleukin-2. These therapies function exclusively by activating the immune system. Furthermore, Rose Bengal and electrochemotherapy have been included, as bystander effects have been observed with these treatments.

Expert opinion: Objective remissions are achieved in a higher percentage with intralesional immunotherapies, such as intralesional interleukin-2 with up to 69% of complete remissions, as compared to systemic treatment. Therefore, intralesional immunotherapy may act as supplement in the armament against metastatic melanoma. In particular, for patients with multiple cutaneous and subcutaneous metastases (20—≥ 100) and in patients with subcutaneous bulky disease intralesional immunotherapy can improve the disease outcome. The exact role of intralesional immunotherapy in the age of immune checkpoint blockade has still to be determined. A number of clinical trials are on the way in order to better understand synergistic actions of intralesional and systemic immunotherapy.     

Promising immunotherapy for prostate cancer

Introduction: Sipuleucel-T is the only currently approved immunotherapy for the management of prostate cancer. However, other immunotherapy agents have recently shown activity in prostate cancer and are being developed alone or in combination with other agents.

Areas covered: This article provides a review of positive or encouraging clinical trials of agents under development including vaccines, monoclonal antibodies, immune modulators, gene-mediated cytotoxic immunotherapy and chimeric antigen receptor-modified ‘designer’ T cells in patients with prostate cancer.

Expert opinion: Personalized peptide vaccines have been associated with improvements in overall survival in early phase clinical trials of patients with prostate cancer, which may lead to their future adoption into management. While single agent, monoclonal antibody-based immunotherapy trials and PSA-TRICOM’s phase III trial have not demonstrated statistically significant improvements in overall survival, combinations of these agents with complementary agents have demonstrated encouraging activity. To improve the development and targeting of these therapies, agent and patient selection/modification needs to occur in the context of a rational model of the immune system’s interaction with prostate cancer. In addition, some traditional surrogates of efficacy may need to be reconsidered as multiple trials of immunotherapy in prostate cancer have had conflicting results between progression-free survival and overall survival.     

Bisphosphonates for malignancy-related bone disease: current status, future developments

This review relates to the efficacy and safety of bisphosphonates in metastatic bone disease. It discusses practical recommendations and possible future indications for bisphosphonate therapy. The current aims of bisphosphonates for metastatic bone disease are to prevent skeletal-related events (SREs), reduce bone pain and improve quality of life. Phase III clinical trials of clodronate and pamidronate have established their efficacy against bone complications in patients with breast cancer and multiple myeloma, while randomized trials have shown SRE reductions with zoledronic acid in patients with breast cancer and multiple myeloma, prostate cancer, and lung and other solid tumors. These bisphosphonates also have some effect on metastatic bone pain. Ibandronate is a new aminobisphosphonate, available in more than 40 countries outside of the US as intravenous and oral formulations for the prevention of skeletal events in patients with breast cancer and bone metastases. Phase III studies have shown that both intravenously and orally administered ibandronate have efficacy for the prevention of skeletal events and for the reduction of metastatic bone pain. In addition to efficacy, the long-term tolerability of bisphosphonates in metastatic bone disease influences drug selection. Besides their use in patients with established bone metastases, recent and ongoing research suggests that bisphosphonates also have clinical benefit in the adjuvant setting, and for the treatment of cancer-treatment-induced bone loss. Such interesting new developments may underpin a new era of bisphosphonate use sometime in the near future.Professor Body has received honoraria and grant support from Hoffmann-La Roche, and grant support from Novartis.     

Einsatz offener Radionuklide in der Schmerztherapie

Chronic pain is one of the most frequent and distressing symptoms in patients suffering from bone metastases due to malignant disease. Besides pharmacological therapy using analgesics according to the WHO scheme and local surgical or radiotherapeutic treatment options, systemic radionuclide therapy is available, particularly for patients with multilocular metastatic disease. This palliative pain treatment is almost free of severe side effects and is thus indicated as a complementary therapy as part of an interdisciplinary approach in pain treatment. Moreover, preliminary data indicate a favorable cost:utility ratio. Positive clinical effects with marked reduction of pain are described in 70–80% of patients with breast or prostate cancer. However, complete analgesia is uncommon and, thus, most patients require analgesic treatment during the further course of their disease.     

Pain palliation using unsealed radionuclides

Chronic pain is one of the most frequent and distressing symptoms in patients suffering from bone metastases due to malignant disease. Besides pharmacological therapy using analgesics according to the WHO scheme and local surgical or radiotherapeutic treatment options, systemic radionuclide therapy is available, particularly for patients with multilocular metastatic disease. This palliative pain treatment is almost free of severe side effects and is thus indicated as a complementary therapy as part of an interdisciplinary approach in pain treatment. Moreover, preliminary data indicate a favorable cost:utility ratio. Positive clinical effects with marked reduction of pain are described in 70-80% of patients with breast or prostate cancer. However, complete analgesia is uncommon and, thus, most patients require analgesic treatment during the further course of their disease.     

Peptide-based vaccination for colorectal cancer

Recently, the number of patients with colorectal cancer has been increasing. Although most patients with early colorectal cancer have a good prognosis, in the case of recurrent or metastatic disease, the prognosis is poor and most patients will ultimately die of cancer. Furthermore, the conventional treatment, such as chemotherapy or radiation therapy, occasionally can not be continued due to reasons of toxicity and/or poor response. Therefore, novel therapeutic optional approaches based on immunotherapy are being explored at present. This review describes and sums up the principles and the longstanding problems of peptide vaccine therapy, and demonstrates the results of clinical trials with colorectal cancer peptide vaccine therapy, including the authors' personal appraisal. In conclusion, the future prospects of peptide vaccine therapy are described.