The anti-idiotype vaccines for immunotherapy

Certain anti-idiotypic antibodies that bind to the antigen-combining sites of antibodies can effectively mimic the three-dimensional structures and functions of the external antigens and can be used as surrogate antigens for active specific immunotherapy. Extensive studies in animal models have demonstrated the efficacy of these vaccines for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections as well as tumors. Several monoclonal anti-idiotype antibodies that mimic distinct human tumor-associated antigens have been developed and characterized. Encouraging results have been obtained in recent clinical trials using these anti-idiotype antibodies as vaccines. In this article, we will review the current literature and discuss the potential of this novel therapeutic approach for various human cancers.     

Vaccine therapies against digestive-system cancers

Cancer vaccine is a promising tool to achieve therapeutic responses in patients by inducing anti-tumor immunity. Several cancer vaccine trials have been performed in patients with digestive-system cancers. Two major candidates are peptide vaccine and dendritic cell (DC) vaccine. Since their clinical impacts are still limited, extensive studies are underway in order to identify more effective antigens or to potentiate DC functions. We developed a novel DC possessing potent stimulating activity for Th1, CTL, and NK cells, which are desirable for clinical DC vaccines. We performed the clinical trial using such DC for the treatment of colorectal cancer. In some of vaccinated patients, the capacity of NK cells and CTLs was successfully enhanced. Thus, cancer vaccines could be a therapeutic option for digestive-system cancers.     

Current status and prospects of cancer vaccine therapy

Cancer vaccine is proceeding to a promising therapy against cancer since 1990 when expression cloning method of tumor associated antigens was reported. Clinical trials showed immunological therapies contribute to prolonged survival in patients with cancers, such as prostate cancer and melanoma, so that FDA approved a dendritic cell vaccine in USA, and peptide vaccines are developing energetically in recent years in Japan. Peptide vaccines have advantages immunologically and economically as a cancer vaccine spreads all over the world, because CTL epitope peptides of tumor associate antigen has a highly antigen-specificity, and can be synthesized uniformly in large quantities for easy handing agents. However it has weak points, such as limited effectiveness in clinical responses due to cancer cells escaped from cancer immunity and possibility of unfavorable immune responses. For development of cancer peptide vaccines, biomarkers related with clinical effects and methods to measure favorable and unfavorable immune responses are necessary about vaccine alone and combination with multidisciplinary modalities in large scale phase III studies.     

Genetically modified dendritic cells in cancer immunotherapy: a better tomorrow?

Importance of the field: Dendritic cells (DC) are powerful antigen-presenting cells that induce and maintain primary cytotoxic T lymphocyte (CTL) responses directed against tumor antigens. Consequently, there has been much interest in their application as antitumor vaccines.

Areas covered in this review: A large number of DC-based vaccine trials targeting a variety of cancers have been conducted; however, the rate of reported clinically significant responses remains low. Modification of DC to express tumor antigens or immunostimulatory molecules through the transfer of genes or mRNA transfection offers a logical alternative with potential advantages over peptide- or protein antigen-loaded DC. In this article, we review the current results and future prospects for genetically modified DC vaccines for the treatment of cancer.

What the reader will gain: Genetically-modified dendritic cell-based vaccines represent a powerful tool for cancer therapy. Numerous preclinical and clinical studies have demonstrated the potential of dendritic cell vaccines alone or in combination with other therapeutic modalities.

Take home message: Genetically modified DC-based anti-cancer vaccination holds promise, perhaps being best employed in the adjuvant setting with minimal residual disease after primary therapy, or in combination with other antitumor or immune-enhancing therapies.     

Virus-based therapies for colon cancer

Viral vectors are under development for anticancer therapy. As they can infect tumours and activate the immune system, viral vectors may directly destroy cancers (oncolysis), deliver genes with antitumour activity directly to the cancer cells, or act as cancer vaccines. Better insights into the biology of the various vectors in use (e.g., poxvectors, adenovirus, adeno-associated virus, reovirus, Newcastle disease virus) are making it possible to engineer viruses that are more tumour-specific, efficient at tumour infection, and which have enhanced safety due to incorporation of safeguards should dissemination occur. As considerable research has focused on therapy of colon cancer with viral vectors, this review will illustrate the major concepts of viral therapy of cancers with examples from studies targeting colorectal carcinoma.     

Virus-based therapies for colon cancer

Viral vectors are under development for anticancer therapy. As they can infect tumours and activate the immune system, viral vectors may directly destroy cancers (oncolysis), deliver genes with antitumour activity directly to the cancer cells, or act as cancer vaccines. Better insights into the biology of the various vectors in use (e.g., poxvectors, adenovirus, adeno-associated virus, reovirus, Newcastle disease virus) are making it possible to engineer viruses that are more tumour-specific, efficient at tumour infection, and which have enhanced safety due to incorporation of safeguards should dissemination occur. As considerable research has focused on therapy of colon cancer with viral vectors, this review will illustrate the major concepts of viral therapy of cancers with examples from studies targeting colorectal carcinoma.     

Mannose receptor-targeted vaccines

Targeting antigens to endocytic receptors on professional antigen-presenting cells (APCs) represents an attractive strategy to enhance the efficacy of vaccines. Such APC-targeted vaccines have an exceptional ability to guide exogenous protein antigens into vesicles that efficiently process the antigen for major histocompatibility complex class I and class II presentation. Efficient targeting not only requires high specificity for the receptor that is abundantly expressed on the surface of APCs, but also the ability to be rapidly internalised and loaded into compartments that contain elements of the antigen-processing machinery. The mannose receptor (MR) and related C-type lectin receptors are particularly designed to sample antigens (self and non-self), much like pattern recognition receptors, to integrate the innate with adaptive immune responses. In fact, a variety of approaches involving delivery of antigens to the MR have demonstrated effective induction of potent cellular and humoral immune responses. Yet, although several lines of evidence in diverse experimental systems attest to the efficacy of targeted vaccine strategies, it is becoming increasingly clear that additional signals, such as those afforded by adjuvants, may be critical to elicit sustained immunity. Therefore, MR-targeted vaccines are likely to be most efficacious in vivo when combined with agents that elicit complementary activation signals. Certainly, a better understanding of the mechanism associated with the induction of immune responses as a result of targeting antigens to the MR, will be important in exploiting MR-targeted vaccines not only for mounting immune defenses against cancer and infectious disease, but also for specific induction of tolerance in the treatment of autoimmune disease.     

Mannose receptor-targeted vaccines

Targeting antigens to endocytic receptors on professional antigen-presenting cells (APCs) represents an attractive strategy to enhance the efficacy of vaccines. Such APC-targeted vaccines have an exceptional ability to guide exogenous protein antigens into vesicles that efficiently process the antigen for major histocompatibility complex class I and class II presentation. Efficient targeting not only requires high specificity for the receptor that is abundantly expressed on the surface of APCs, but also the ability to be rapidly internalised and loaded into compartments that contain elements of the antigen-processing machinery. The mannose receptor (MR) and related C-type lectin receptors are particularly designed to sample antigens (self and non-self), much like pattern recognition receptors, to integrate the innate with adaptive immune responses. In fact, a variety of approaches involving delivery of antigens to the MR have demonstrated effective induction of potent cellular and humoral immune responses. Yet, although several lines of evidence in diverse experimental systems attest to the efficacy of targeted vaccine strategies, it is becoming increasingly clear that additional signals, such as those afforded by adjuvants, may be critical to elicit sustained immunity. Therefore, MR-targeted vaccines are likely to be most efficacious in vivo when combined with agents that elicit complementary activation signals. Certainly, a better understanding of the mechanism associated with the induction of immune responses as a result of targeting antigens to the MR, will be important in exploiting MR-targeted vaccines not only for mounting immune defenses against cancer and infectious disease, but also for specific induction of tolerance in the treatment of autoimmune disease.     

Prostate-specific antigen vaccines for prostate cancer

Prostate cancer is the most common malignant tumour in men and there are few treatment options available once the tumour becomes refractory to hormonal manipulation. Prostate-specific antigen (PSA) is a secretory glycoprotein that is commonly expressed by prostatic epithelial cells and is found in elevated levels in the serum of men with prostate cancer. The identification of T cell specific epitopes within the coding sequence of PSA has led to the development of various vaccine strategies that target PSA in an attempt to treat established prostate cancer. These strategies have included human leukocyte antigen-restricted PSA peptides, dendritic cells pulsed with PSA, recombinant viruses expressing PSA and combinations of different vectors. In addition to PSA, several other antigens have been described that may be useful for targeting prostate tumours by vaccines. Animal studies have established the feasibility and safety for many of these agents and clinical trials are now in progress to evaluate the immunological and clinical responses of PSA vaccines. Further research in manipulating anti-PSA immunity with cytokines, costimulatory molecules and other immune modulating agents will likely improve the therapeutic effectiveness of PSA vaccines. Clinical trials designed to evaluate the effects of vaccination in different stages of disease and through different routes of administration need to be performed to define the optimal schedule for PSA vaccines in patients with prostate cancer, or for those at high risk of developing the disease.     

Prostate-specific antigen vaccines for prostate cancer

Prostate cancer is the most common malignant tumour in men and there are few treatment options available once the tumour becomes refractory to hormonal manipulation. Prostate-specific antigen (PSA) is a secretory glycoprotein that is commonly expressed by prostatic epithelial cells and is found in elevated levels in the serum of men with prostate cancer. The identification of T cell specific epitopes within the coding sequence of PSA has led to the development of various vaccine strategies that target PSA in an attempt to treat established prostate cancer. These strategies have included human leukocyte antigen-restricted PSA peptides, dendritic cells pulsed with PSA, recombinant viruses expressing PSA and combinations of different vectors. In addition to PSA, several other antigens have been described that may be useful for targeting prostate tumours by vaccines. Animal studies have established the feasibility and safety for many of these agents and clinical trials are now in progress to evaluate the immunological and clinical responses of PSA vaccines. Further research in manipulating anti-PSA immunity with cytokines, costimulatory molecules and other immune modulating agents will likely improve the therapeutic effectiveness of PSA vaccines. Clinical trials designed to evaluate the effects of vaccination in different stages of disease and through different routes of administration need to be performed to define the optimal schedule for PSA vaccines in patients with prostate cancer, or for those at high risk of developing the disease.     

Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice

Cancer immunotherapy faces a serious challenge because of low clinical efficacy. Recently, a number of clinical studies have reported the serendipitous finding of high rates of objective clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. However, the mechanism of this phenomenon remains unclear. Here, we tested in mice several cancer vaccines and an adoptive T cell transfer approach to cancer immunotherapy in combination with several widely used chemotherapeutic drugs. We found that chemotherapy made tumor cells more susceptible to the cytotoxic effect of CTLs through a dramatic perforin-independent increase in permeability to GrzB released by the CTLs. This effect was mediated via upregulation of mannose-6-phosphate receptors on the surface of tumor cells and was observed in mouse and human cells. When combined with chemotherapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens. These data suggest that small numbers of CTLs could mediate a potent antitumor effect when combined with chemotherapy. In addition, these results provide a strong rationale for combining these modalities for the treatment of patients with advanced cancers.     

Dendritic cell-based full-length survivin vaccine in treatment of experimental tumors

Survivin is a good candidate for cancer immunotherapy since it is overexpressed in most common human cancers, poorly expressed in most normal adult tissues and is essential for cancer cell survival. Previously, we and others have demonstrated that survivin-specific immune responses can be generated in mice and cancer patients. These responses resulted in a substantial antitumor effect. However, the fact that survivin is expressed in normal hematopoietic progenitor cells and endothelial cells may potentially limit the use of vaccination against survivin in the clinic due to possible toxicity. In this study, we have evaluated this risk by using dendritic cells (DC) transduced with an adenovirus encoding mutant human survivin (Ad-surv DCs). Immunization of mice with Ad-surv DCs resulted in generation of CD8 T cells recognizing multiple epitopes from mouse survivin. These responses provided significant antitumor effect against 3 different tumors EL-4 lymphoma, MC-38 carcinoma, and MethA sarcoma. Survivin-specific T-cells did not affect bone marrow hematopoietic progenitor cells and no autoimmune abnormalities were observed. However, as was the case with other tumor vaccines it provided only partial antitumor effect against established tumors. The existing paradigm suggests that generation of immune response against multiple tumor-associated antigens may provide a better antitumor effect. Here, we directly tested this hypothesis by combining vaccines targeting different tumor-associated proteins: survivin and p53. Despite the fact that combination of 2 vaccines generated potent antigen specific T-cell responses against both molecules they did not result in the improvement of antitumor effect in any of the tested experimental tumor models.     

DNA vaccines for non-infectious diseases: new treatments for tumour and allergy

The last decade of DNA vaccine research was characterised by a pioneer spirit and enormous enthusiasm, with a large number of publications demonstrating the usefulness of this approach. Unfortunately, DNA vaccines have not necessarily met the high clinical expectations and a number of complications need to be overcome. In the case of cancer and allergy, the requirements for achieving the objectives are very different. Vaccines against allergies need to suppress or alter an unwanted immune response, while a cancer DNA vaccine has to overcome tolerance and/or immune suppression and initiate a powerful immune response. This review addresses currently used general optimisation strategies for DNA vaccines such as modification of immunisation regimens, improving the delivery systems and using molecular adjuvants. In addition, cancer-specific approaches, such as the stimulation of innate and adaptive immunity with replicase-based DNA vaccines, and targeting non-tumour-associated antigens (TAAs) are discussed. Specifically for the optimisation of DNA vaccination against allergies, procedures such as allergen gene recoding, T helper (Th)1 modulation, and the creation of safe DNA vaccines by gene fragmentation, ubiquitination or using artificial hypoallergens are being analysed. These strategies, individually or in combination, hold the potential of making DNA vaccines useful for application in the clinic.     

DNA vaccines for non-infectious diseases: new treatments for tumour and allergy

The last decade of DNA vaccine research was characterised by a pioneer spirit and enormous enthusiasm, with a large number of publications demonstrating the usefulness of this approach. Unfortunately, DNA vaccines have not necessarily met the high clinical expectations and a number of complications need to be overcome. In the case of cancer and allergy, the requirements for achieving the objectives are very different. Vaccines against allergies need to suppress or alter an unwanted immune response, while a cancer DNA vaccine has to overcome tolerance and/or immune suppression and initiate a powerful immune response. This review addresses currently used general optimisation strategies for DNA vaccines such as modification of immunisation regimens, improving the delivery systems and using molecular adjuvants. In addition, cancer-specific approaches, such as the stimulation of innate and adaptive immunity with replicase-based DNA vaccines, and targeting non-tumour-associated antigens (TAAs) are discussed. Specifically for the optimisation of DNA vaccination against allergies, procedures such as allergen gene recoding, T helper (Th)1 modulation, and the creation of safe DNA vaccines by gene fragmentation, ubiquitination or using artificial hypoallergens are being analysed. These strategies, individually or in combination, hold the potential of making DNA vaccines useful for application in the clinic.     

Molecular targeting drugs--present status and future development

Development of molecular targeting drugs is a recent highlight in cancer therapeutic field. One can look for 'drugable' target(s) from many molecular targets specific in malignant characteristics of human cancers. Drugs targeting various malignancy-linked molecules such as EGF receptor and its family proteins. Bcr-abl, CD20, Ras and others are now approved or under clinical trials against cancer patients. These molecular targeting drugs will provide a novel and useful therapeutic strategy, but, at the same time, we have many problems to overcome. We should continue our further efforts to answer following problems: (1) How therapeutic efficacy of molecular targeting drugs could be determined in patients in evidence-based manner?; (2) What is promising molecular target for development of drug?; (3) How combination therapy of molecular targeting drug with other cytotoxic drugs should be designed?     

Broadly expressed tumour?associated proteins as targets for cytotoxic T lymphocyte-based cancer immunotherapy

T cell-based antigen-specific immunotherapy targeting self-proteins aberrantly expressed in many tumours offers the potential for widely applicable cancer immunotherapy, but carries the risk of autoimmunity. Immunological tolerance represents an inherent limitation of cancer vaccines targeting such broadly expressed tumour-associated proteins. Therefore, strategies to circumvent T cell tolerance have been developed and, when combined with T cell receptor (TCR) gene transfer technology, can generate highly avid tumour-reactive patient cytotoxic T lymphocytes (CTLs) specific for peptide epitopes of tumour-associated proteins. This review analyses the level of tolerance to broadly expressed tumour-associated proteins in the autologous T cell repertoire, assesses strategies that have been developed to circumvent T cell tolerance to such antigens, and evaluates the prospects for effective immunotherapy targeting broadly expressed tumour-associated proteins.     

Broadly expressed tumour-associated proteins as targets for cytotoxic T lymphocyte-based cancer immunotherapy

T cell-based antigen-specific immunotherapy targeting self-proteins aberrantly expressed in many tumours offers the potential for widely applicable cancer immunotherapy, but carries the risk of autoimmunity. Immunological tolerance represents an inherent limitation of cancer vaccines targeting such broadly expressed tumour-associated proteins. Therefore, strategies to circumvent T cell tolerance have been developed and, when combined with T cell receptor (TCR) gene transfer technology, can generate highly avid tumour-reactive patient cytotoxic T lymphocytes (CTLs) specific for peptide epitopes of tumour-associated proteins. This review analyses the level of tolerance to broadly expressed tumour-associated proteins in the autologous T cell repertoire, assesses strategies that have been developed to circumvent T cell tolerance to such antigens, and evaluates the prospects for effective immunotherapy targeting broadly expressed tumour-associated proteins.     

Vaccines: an innovative approach to treating cancer.

Recent scientific advances have expanded our understanding of the immune system and its response to malignant cells. Clinical trials are under way that attempt to translate this knowledge into effective cancer therapies. Vaccine therapy, an innovative approach to cancer treatment, attempts to activate the immune system to recognize cancer cells and eliminate them from the body. Preventive vaccines that already have been approved will have an impact on the incidence of certain cancers, and research is ongoing into treatment vaccines for various cancers.     

Challenges in the development of effective peptide vaccines for cancer

The ability of the immune system to recognize malignant cells has opened the door to development of tumor vaccines to treat or prevent various types of cancer. In the era of molecular biology, the tumor antigens recognized by the immune system have been identified, allowing the generation of subunit vaccines that may improve safety and efficacy compared with more crude vaccines such as irradiated tumor cells and tumor cell lysates. Synthetic peptides corresponding to defined antigenic epitopes for tumor-reactive lymphocytes represent one of the new types of vaccines currently being developed to treat or prevent various types of malignant disorders. The design of peptide-based vaccines to stimulate antitumor T-cell responses has many attractive features such as ease of manufacturing and characterization (ie, quality control), as well as an excellent safety profile in past clinical studies. However, ambiguous results from initial clinical trials indicate that these vaccines are far from optimal and that considerable efforts for their optimization lie ahead. We attempt to address the 8 most important challenges we currently face for developing peptide-based vaccines that would effectively induce immune responses leading to antitumor effects.     

Clinical applications of virosomes in cancer immunotherapy

Cancer immunotherapy is increasingly accepted as a treatment option for advanced stage disease. The identification of tumour-associated antigens in 1991 has prompted the development of antigen-specific immunotherapeutic strategies for a variety of cancers. Many of them result in some immunological responses in cancer patients; however, clinical results were not observed concomitantly with immunological responses; therefore, further improvements in the field of immunotherapy are urgently needed. Virosomes are lipidic envelopes devoid of genetic information, but which retain the antigenic profile and fusogenic properties from their viral origin. Virosomes are versatile antigen carriers and can be engineered to perform various tasks in cancer immunotherapy. Preclinical data have fostered the development of innovative clinical protocols. Hence, immunopotentiating reconstituted influenza virosomes will be assessed in breast and melanoma immunotherapy, and may contribute to the development of clinically effective cancer vaccines and ultimately improve patient outcomes. The objective of this review is to provide an overview of the potential clinical applications of virosomes as innovative and potentially effective reagents in active specific cancer immunotherapy.