Combining gene and immunotherapy for prostate cancer

The nitroreductase (NR)/CB1954 enzyme prodrug system has given promising results in pre-clinical studies and is currently being assessed in phase I and II clinical trials in prostate cancer. Enhanced cell killing by apparent immune-mediated mechanisms has been shown in pancreatic and colorectal cancer models, by co-expressing murine granulocyte macrophage colony-stimulating factor (GM-CSF) with NR in a single replication deficient adenoviral vector. This consists of the CMV immediate early promotor driving expression of NR, with an internal ribosome entry site (IRES) and the gene for murine GM-CSF (mGM-CSF). To examine if similar enhancement of tumour cell killing could be produced in prostate cancer, the TRAMP model was chosen. Results illustrate that the combination of suicide gene therapy using NR and CB1954, with cytokine stimulation with mGM-CSF gives an improved response compared with either modality alone. The mechanism of this improved response is however likely to be non-immune based as it lacks a memory effect.     

Advances in specific immunotherapy for prostate cancer

OBJECTIVES: The absence of effective therapies for advanced prostate cancer has entailed an intensive search for novel treatments. This review presents an overview of specific immunotherapeutic strategies for prostate cancer. METHODS: Current literature was reviewed regarding the identification of tumor antigens and the design of T-cell- and antibody-based immunotherapy for prostate cancer. The PubMed database was searched using the key words antibodies, clinical trials, dendritic cells, immunotherapy, prostate cancer, and T cells. RESULTS: T cells and antibodies are powerful components of the specific antitumor immune response. CD8+ cytotoxic T lymphocytes (CTLs) efficiently destroy tumor cells. CD4+ T cells improve the antigen-presenting capacity of dendritic cells (DCs) and support the stimulation of tumor-reactive CTLs. Monoclonal antibodies exhibit their antitumor effects via antibody-dependent cellular cytotoxicity and complement activation. Consequently, much attention has been given to the identification of tumor antigens that represent attractive targets for specific immunotherapy. Several prostate cancer-related antigens were described and used in clinical trials. Such studies were based on the administration of peptides, proteins, or DNA. Furthermore, men with prostate cancer were vaccinated with peptide-, protein-, or RNA-loaded DCs, which display an extraordinary capacity to induce tumor-reactive T cells. Monoclonal antibodies directed against surface antigens were also used. Clinical trials revealed that immunotherapeutic strategies represent safe and feasible concepts for the induction of immunologic and clinical responses in men with prostate cancer. CONCLUSIONS: Specific immunotherapy represents a promising treatment modality for prostate cancer. Further improvement of the current approaches is required and may be achieved by combining T-cell- and antibody-based vaccination strategies with radio-, hormone-, chemo-, or antiangiogenic therapy.     

Clinical development of immunotherapy for prostate cancer

Prostate cancer is the most common cancer in men, and the second leading cause of cancer‐related death in Western countries. Prostate cancer‐related death occurs in patients with metastatic castration‐resistant prostate cancer. Although several new drugs for castration‐resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.     

The immunotherapy of prostate cancer

Advanced prostate cancer remains incurable with standard treatment options. Immunotherapy may be a realistic alternative given the growing evidence that the immune response can affect the growth of other solid tumours and the regulation of both specific and shared prostate cancer antigens. Early studies suggest that both non-specific and specific vaccines can effect relevant animal models and clinical trials based on these observations are now in progress. A number of other approaches including gene therapy with HSVtk are already undergoing clinical studies (Herman et al. Hum Gene Ther 1999; 10: 1239-1249). Prostate Cancer and Prostatic Diseases (2000) 3, 303-307     

Clinical trials of immunotherapy for advanced prostate cancer

There is a lack of effective therapeutic regimens for advanced hormone-refractory prostate cancer (HRPC). Recent combination regimens of chemotherapy have improved management of HRPC. Neither systemic chemotherapy nor radiation regimens have significantly improved survival. Conventional systemic cytokine therapy has had limited efficacy in the treatment of advanced prostate cancer patients and its toxicity is severe. Combinations of multiple biological response modifiers for treatment of this disease also have limited efficacy. Results from phase II trials have shown that the combination of interferon- and interleukin-2 therapy and the infusion of dendritic cells primed with peptides of prostate specific membrane antigen are promising. The former showed 31% response using the National Prostatic Cancer Project criteria, and the latter showed 27% of objective partial response with a reduction of >50% prostate specific antigen level. The toxicity of these two regimens was tolerated by patients. New approaches with tumor vaccines in conjunction with cytokine gene therapy have also been investigated. The clinical responses of these trials have been limited but promising. Immunotherapy may become an effective modality of prostate cancer treatment in the future.     

Rationale for chemotherapeutic approaches to prostate cancer

The problems of curing tumors with a low growth fraction with cytotoxic chemotherapeutic agents include 1) the fact that such agents attack biochemical pathways common and vital to all cells, 2) the existence in a tumor of cells with both temporary and permanent resistance to specific agents, and 3) the exponential nature of cell kill, which necessitates a much more intensive treatment to effect cure than to effect remission. The possible bases for selectivity of anticancer drugs include those factors that affect the concentration of the active form of the drug at the active site, those that affect the drug receptor interaction and those that determine whether this interaction will lead to cell death. Possible ways of overcoming resistance include combination chemotherapy, more intensive chemotherapy, adjuvant chemotherapy, and maneuvers leading to recruitment of cells into cycle. Because of tumor cell heterogeneity a different approach may be needed to effect cure from that required to induce complete remission.     

The immunotherapy of prostate and bladder cancer

The role of the immune system in controlling the growth of tumour cells is highly complex and has been extensively debated. It is well documented that the immune system controls virally induced cancers, and there is evidence for a role of specific immunity in other types of tumours. The greater understanding of the regulation and optimization of adoptive, specific immune responses, and the better characterization of tumour-associated antigens indicate the way for active specific vaccination and cell therapy in urological tumours. Currently, bacille Calmette Guerin immunotherapy is established for localized bladder cancer and many experimental immunotherapies are under evaluation. Here we review some timely aspects of tumour immunology, and describe the current status and development of immunotherapy in prostate and bladder cancer.     

Partially circumventing peripheral tolerance for oncogene-specific prostate cancer immunotherapy

BACKGROUND: Failure of cancer immunotherapy is essentially due to immunological tolerance to tumor-associated antigens (TAAs), as these antigens are also expressed in healthy tissues. METHODS: Here, we used transgenic adenocarcinoma of mouse prostate (TRAMP) mice, which develop lethal prostate cancer due to prostate-specific expression of SV40 T antigen (Tag), to evaluate effects of prostatic transformation on oncogene TAA-specific tolerance and to test the possibility of breaking such tolerance using a modified recombinant vaccinia virus. RESULTS: We showed that Tag expression in TRAMP mice is uniquely extra-thymic, and levels of prostatic Tag expression positively correlate with malignant transformation of the prostate. Yet, young tumor-free TRAMP mice were tolerant to Tag antigen. We therefore attempted overcoming such peripheral oncogene-specific T cell tolerance through immunization with a vaccinia construct encoding Tag immunogenic epitopes. This vaccination modality showed that oncogene-specific tolerance was successfully overcome by effective in vivo priming of Tag-specific cytotoxic T cells (CTLs). However, this was restricted to young TRAMP mice. Tag-specific CTL from "tumor na?ve" young TRAMP mice showed significant anti-tumor efficacy in vivo by eliminating established heterotopic prostate tumors and prolonging survival in SCID mice harboring Tag-expressing tumors. In contrast, older TRAMP mice with established prostate tumors exhibited oncogene-specific tolerance as evidenced by failure to generate Tag-specific CTL following Tag-specific immunization. CONCLUSIONS: Peripheral tolerance can be overcome for effective anti-tumor therapy following oncogene-specific immunization. However, this ability to elicit oncogene-specific CTL is impeded in the tumor-bearing host, in the context of increased oncogene expression associated with tumor progression.     

Effective antigen cross-presentation by prostate cancer patients' dendritic cells: implications for prostate cancer immunotherapy

Despite the potency with which dendritic cells (DCs) are able to utilize the exogenous MHC I antigen cross-presentation pathway to cross-present antigen for the activation of killer T cells in model systems, concern about defects in immune function in cancer patients has led to uncertainty regarding whether immune cells derived from patients can effectively be used to generate tumor vaccines. We have undertaken a careful analysis of the potency of using DCs obtained from prostate cancer patients to cross-present antigen derived from human prostate tumor cells for the activation of antigen-specific T cells. Such DCs can be matured ex vivo into functionally active cells and are capable of cross-presenting influenza antigen derived from internalized apoptotic prostate tumor cells. Importantly, we demonstrate effective stimulation of both CD4+ and CD8+ T cells, as evident by production of IFN-gamma, and the ability of CD8+ T cells to differentiate into effector CTLs. These results, defining conditions in which prostate cancer patient DCs can efficiently utilize the cross-presentation pathway and in which apoptotic tumor can serve as a source of antigen for DCs to activate T cells, demonstrate that this system warrants clinical study as a potential immunotherapy.     

Immunology and immunotherapy in neurosurgical disease

OBJECTIVE: For many years, the central nervous system (CNS) has been described as "immunologically privileged" and devoid of conventional immune reactivity. However, our more current understanding of neuroimmunology supports a different view. Although immune mechanisms within the CNS may behave differently from those located at peripheral anatomic sites, it is now widely accepted that biologically relevant immune responses can and do occur within the brain and that these responses can play important roles in CNS disease. The objective of this present review is to explore key aspects of recent insights into the cellular interactions involved in neuroimmunology, which may suggest more rational approaches to the immunotherapy of neurosurgical disorders. CONCLUSION: Modern advances in molecular medicine and basic immunology have yielded a plethora of new data about CNS immunobiology. The design of effective immunotherapeutic strategies for CNS diseases requires a contemporary understanding of the basic tenets of how the immune system works. The current renaissance in this field may give neurosurgeons hope that, in the future, immunotherapy-based paradigms may be able to successfully treat neurosurgical diseases that are currently refractory to traditional therapies.     

消融联合免疫疗法治疗前列腺癌研究进展

前列腺癌是男性最常见恶性肿瘤之一。以冷冻消融为代表的消融疗法治疗前列腺癌效果较好,但如何提高远期疗效、降低局部复发是目前面临的主要难题。消融治疗可激活机体的抗肿瘤免疫反应,进一步消除消融后残留、复发及远处转移病灶。本文对消融联合免疫疗法治疗前列腺癌的研究进展进行综述。     

Innovative approaches in prostate cancer ultrasound

Today, systematic random biopsies have virtually replaced ultrasound as an imaging tool in the early diagnosis and staging of prostate cancer. Transrectal ultrasonography (TRUS) is now utilized almost only to guide the biopsy needle into the correct anatomical or topographical region of the prostate. Nevertheless, a large number of clinically significant carcinomas are not discovered despite of multiple systematic biopsies. This has led to a dramatic increase in the number of biopsy samples taken, with 6, 10, 12 to 143 being taken during one session depending on the site. Newer modalities and innovative techniques are being investigated in order to accurately identify patients with prostate cancer at different stages of the disease. Innovative ultrasonography techniques may improve the diagnosis and staging of current imaging techniques.     

Novel approaches for the molecular classification of prostate cancer

Among the urologic cancers, prostate cancer is by far the most common, and it appears to have the potential to affect almost all men throughout the world as they age. A number of studies have shown that many men with prostate cancer will not die from their disease, but rather with the disease but from other causes. These men have a form of prostate cancer that is described as ＂very low risk＂ and has often been called indolent.     

Novel targets and approaches in advanced prostate cancer

PURPOSE OF REVIEW: The development of therapeutic resistance is the underlying cause for most cancer deaths. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy in prostate cancer, the rational design of targeted therapeutics is possible. We review new treatment options for men with advanced prostate cancer. RECENT FINDINGS: Although the taxanes currently represent the most active chemotherapeutic agents and standard of care for first-line treatment of metastatic hormone-refractory prostate cancer, most patients eventually progress because of intrinsic or acquired drug resistance. In recent years, increased knowledge of cancer progression and therapeutic resistance has identified many gene targets that regulate apoptosis, proliferation, and cell signalling. To date, numerous novel compounds have entered clinical trials as either single agents or in combination with cytotoxic chemotherapy. SUMMARY: Even though hormone-refractory prostate cancer is still incurable, it is not untreatable. As cancer cells are proficient at adapting to therapeutic stressors, a combination regimen with drugs that target crucial cellular networks like the apoptotic rheostat may be more promising than treatment with highly selective single-target agents. Recent findings are very hopeful, but challenges remain to demonstrate effective antitumour activity in phase III trials with survival as the principal endpoint.     

New treatment approaches for prostate cancer based on peptide analogues

OBJECTIVES: New therapy modalities for the treatment of advanced prostate cancer based on peptide analogues are reviewed. RESULTS: Agonists and antagonists of luteinising hormone-releasing hormone (LHRH) lead to androgen deprivation, but direct effects on tumours may also play a role. Radiolabeled somatostatin analogues can be targeted to tumours expressing receptors for somatostatin and have been successfully applied for the localization of these tumours. Tumoural LHRH, growth hormone-releasing hormone (GHRH), and bombesin/gastrin-releasing peptide (BN/GRP) and their receptors appear to be involved in the proliferation of prostate cancer. On the basis of the recent advances in the understanding of the role of neuropeptides in tumour growth and progression, new therapeutic modalities are being developed that are based on antagonists of GHRH and of BN/GRP, which inhibit growth factors or their receptors. Another promising approach for the therapy of prostate cancer consists of the use of cytotoxic analogues of LHRH, bombesin, and somatostatin, which can be targeted to receptors for these peptides in prostate cancers and their metastases. CONCLUSIONS: New promising forms of hormone therapy and targeted chemotherapy may improve therapy of advanced stage prostate cancer.     

Hormonal approaches in prostate cancer: application in the contemporary prostate cancer patient

Early studies beginning in the 1940s confirmed the importance of the androgen receptor and benefits of androgen depletion in metastatic prostate cancer. These studies helped to establish management strategies with an excellent response rate. Despite this, there remains some controversy as to the optimal approach for patients. Fueling this controversy is the fact that routine PSA testing did not come into practice until the early 1990s, while the majority of the large trials evaluating the use of hormonal therapy were conducted in the pre-PSA era and in patients who had metastatic disease identifiable with radiographic imaging. With the onset of routine PSA testing and the subsequent stage migration that has occurred in men presenting with prostate cancer, the question of when to initiate hormonal therapy has become ever more controversial.     

Granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy: the GVAX vaccine for prostate cancer

New approaches to therapeutics of advanced prostate cancer are urgently needed. GVAX (granulocyte-macrophage colony-stimulating factor [GM-CSF] gene transduced irradiated prostate cancer vaccine cells) offers the possibility that "host versus prostate cancer" immune responses can be generated in prostate cancer patients. Critical components involve the dendritic cell loading of candidate prostate cancer lymph node metastasis and candidate bone metastasis antigens derived from irradiated prostate cancer whole cells. GM-CSF acts at the vaccination site to enhance activation dendritic cells and antigen presentation to both the B-cell and T-cell arms of the immune system. GVAX preclinically-in both rat and transgenic prostate cancer models-has antitumor activity which has informed early clinical trial designs. Clinical investigations reviewed in this report suggest that vaccination is safe and immune tolerance can be broken against prostate cancer. Multi-institutional phase III investigation is currently underway to evaluate the impact of allogeneic prostate GVAX cellular immunotherapy on time to progression and overall survival in hormone refractory prostate cancer.     

Minimally invasive surgical approaches and management of prostate cancer

For clinically localized prostate cancer, radical prostatectomy remains the "gold standard" treatment. New forms of minimally invasive therapies are sought out by patients, however, because of the potential morbidity associated with open surgery. With quality-of-life aspects influencing patient decision making, minimally invasive therapeutic modalities have generated great interest among patients. Laparoscopic radical prostatectomy, robotic-assisted laparoscopic prostatectomy, brachytherapy, cryotherapy, and high-intensity focused ultrasound are all considered to be minimally invasive treatment options for the management of clinically localized prostate cancer.