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At least 19 recordsLinked to original sources
PubMed2006

Immunostimulatory colloidal delivery systems for cancer vaccines.

Cancer vaccine delivery is a multidisciplinary scientific field that is currently undergoing rapid development. An important component of cancer vaccines is the development of novel vaccine delivery strategies, such as colloidal immunostimulatory delivery systems. The importance of formulation strategies for cancer vaccines can be explained by the poor immunogenicity of tumour antigens. Colloidal vaccine delivery systems modify the kinetics, body distribution, uptake and release of the vaccine. This review explores recent research that is directed towards more targeted treatments of cancer through to colloidal vaccine delivery systems. Widely investigated carrier systems include polymeric micro- and nanoparticles, liposomes, archaeal lipid liposomes (archaeosomes), immune-stimulating complexes and virus-like particles. These systems are evaluated in terms of their formulation techniques, immunological mechanisms of action as well as the potential and limitations of such colloidal systems in the field of cancer vaccines.

Adjuvants, Immunologic↗
PubMed2004

Cancer vaccines.

Cancer vaccines - a dream or a reality? There is no doubt that a time will come when this new approach to cancer treatment will provide opportunities that will be both complementary and synergistic with existing treatments. Novelty is often linked to risk, and if there is a given medical field that desperately needs therapeutic improvement, cancer is it. Recent advances on the understanding of the functioning and manipulation of the immune system and on the host-tumour relationship, and on tumour escape, will soon pay off. However, the development of cancer vaccines is not an easy undertaking and the multitude of obstacles are presented and reviewed in this article. The cancer vaccine 'detractors' that are arguing negatively on the chances of success are, to this date, correct. Nevertheless, a parallel could be drawn from the monoclonal antibodies, which have suffered from a long and difficult history, to hold promise in man. Recent technological progress has once again demonstrated that one can eventually bypass the commonly accepted barriers, as there are now monoclonal-based products currently helping patients. The entire oncology community is eagerly awaiting the next chapter in the cancer vaccine story.

Adenoviridae↗
PubMed2001

Chemotherapy: friend or foe to cancer vaccines?

Cancer vaccines are on the threshold of taking their place alongside the more traditional cancer treatment modalities of surgery, radiation therapy and chemotherapy. The toxicology and immunopharmacology of therapeutic cancer vaccines, particularly those that secrete granulocyte macrophage colony stimulating factor (GM-CSF), are currently under active clinical investigation. Interestingly, drugs traditionally used for tumor cytoreduction can have both positive and negative effects on host immunity. Exploration of the potential pharmacodynamic interactions of antineoplastic drugs with GM-CSF-secreting vaccines has revealed that low doses of some chemotherapeutics can augment the antitumor immunity induced by GM-CSF-secreting vaccines. These interactions will require thorough preclinical evaluation to maximize the clinical impact of this type of therapeutic cancer vaccine.

Adjuvants, Immunologic↗
PubMed2001

Cancer vaccines.

Cancer vaccines have been extensively tested in animal models, and in humans. Initial studies focused on first generation vaccines based on whole cell preparations or tumor lysates derived from autologous or allogeneic tumors. Clinical studies conducted with such candidate vaccines contributed to establish the feasibility of immunizing cancer patients against their own tumors. Significant clinical benefits were observed, both in terms of long term survival and recurrence rate, in some of these trials. More recently, however, cancer vaccines targeting well-characterized tumor-associated antigens, i.e. molecules selectively or preferentially expressed by cancer cells but not by normal cells, have been designed and tested in humans. Results obtained as of today with these second-generation vaccines suggest that they are safe and that they can elicit humoral and cellular responses against tumor-specific antigens, without inducing unacceptable clinical signs of autoimmunity. Advances in tumor biology and tumor immunity have helped to better understand the mechanisms displayed by a number of tumors to escape host immunity. This bulk of new knowledge will be used to design future cancer vaccines, which will likely target multiple TAAs, presented by different antigen presentation platforms, in association with synthetic adjuvants and/or immunostimulatory cytokines. Lastly, specific tools allowing to assess in a qualitative and quantitative manner immune responses are critically needed in order to establish correlates between clinical and immune responses in patients receiving experimental vaccines.

Animals↗
PubMed2005

Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity.

Optimizing standard treatment modalities for breast cancer has improved the outlook for women afflicted with it, but the fact that 40% still ultimately die from the disease highlights the need for new therapies. Remarkable advances in molecular immunology and biotechnology have created a unique opportunity for developing active vaccination strategies that engage the patient's own immune system in the fight against breast cancer. Early clinical trials have established the safety and bioactivity of some breast cancer vaccine approaches, with a hint of clinical response. They have also highlighted the importance of elucidating the pharmacodynamic interactions between established therapies for breast cancer, such as tamoxifen, aromatase inhibitors, chemotherapy, the HER-2/neu-specific monoclonal antibody trastuzumab (Herceptin), and breast cancer vaccines. Preclinical studies have simultaneously defined the importance of developing targeted approaches for circumventing established immune tolerance to breast cancer during the vaccination process. The first strategies targeting the negative influence of CD4(+)CD25(+)T regulatory cells and the CTLA-4 signaling pathway are just entering clinical testing in combination with tumor vaccines. Developing the most potent approach for activating antitumor immunity while maintaining the efficacy of standard approaches to breast cancer management will ensure that active immunotherapy is successfully integrated into the standard of care.

Antineoplastic Agents↗
PubMed2004

[Development for a novel cancer vaccine].

Clinical trial using epitope peptides have been intensively performed in the world. From the results, it has been clarified that tumor specific CTLs were induced in the vaccinated cancer patients. In this manuscript, we demonstrated the problems to be clarified from clinical trial and recent advances for cancer vaccine using epitope peptides.

Antigens, Neoplasm↗
PubMed2005

Cancer vaccines: the challenge of developing an ideal tumor killing system.

Despite the evidence that the immune system plays a significant role in controlling tumor growth in natural conditions and in response to therapeutic vaccination, cancer cells can survive their attack as the disease progresses and no vaccination regimen should be currently proposed to patients outside experimental clinical trials. Clinical results show that the immune system can be actively polarized against malignant cells by means of a variety of vaccination strategies, and that in some cases this is associated with tumor regression. This implies that under some unique circumstances, the naturally "dormant" immune effectors can actually be put at work and used as endogenous weapons against malignant cells. Consequently, the main challenge of tumor immunologists appears to lie on the ability of reproducing those conditions in a larger set of patients. The complexity of the immune network and the still enigmatic host-tumor interactions make these tasks at the same time challenging and fascinating. Recent tumor immunology findings are giving new impetus to the development of more effective vaccination strategies and might revolutionize the way of designing the next generation of cancer vaccines. In the near future, the implementation of these insights in the clinical setting and the completion/conduction of comparative randomized phase III trials will allow oncologists to define the actual role of cancer vaccines in the fight against malignancy.

Antigens, Neoplasm↗
PubMed2002

Cancer vaccines.

Although cancer immunotherapy was initiated by William Coley more than a century ago, the field of cancer vaccines is in an early stage of development. Only recently, major advances in cellular and molecular immunology have allowed a comprehensive understanding of the complex and high rate of interactions between the immune system and tumor cells. We have learned that these tumor-immune system interactions may result either in strong immune antitumor response or tolerance to tumor-associated antigens. This article will discuss the profound interest in cancer vaccines derived from their potential to induce antitumor responses in vivo. Substantial data from several preclinical models and early human clinical trials have confirmed the ability of cancer vaccines to induce immune responses that are tumor-specific and, in some cases, associated with clinical responses. One future challenge will be to determine how to appropriately stimulate the pathways leading to effective interaction among antigen-presenting cells, T lymphocytes, and tumor cells. It also is critical to develop monitoring strategies that may allow the identification of patients who may benefit from cancer vaccines.

Cancer Vaccines↗
PubMed2005

Recent developments in therapeutic cancer vaccines.

Therapeutic cancer vaccines are being developed with the intention of treating existing tumors or preventing tumor recurrence. While the results of clinical trials, predominantly in the metastatic setting have been sobering, the central hypothesis of active immunotherapy i.e. that the human immune system can be activated to recognize and destroy tumor cells, remains a viable one. We believe that a fundamental shift in how clinical trials are performed, and what concepts they test is required to make meaningful strides towards future clinical use of cancer vaccines. First, we must reappraise whether the metastatic setting is the appropriate arena to test these agents. Second, we must arrive at a consensus on the most important biologic endpoints and rapidly test vaccines for their ability to achieve these endpoints. Third, we need to expend more effort on understanding how to manipulate the immune system beyond the initial stimulation provided by a vaccine. Fourth, in order to permit comparison of results across different studies, it would be helpful to narrow down the large number of vaccine platforms. We will discuss the current state of development of cancer vaccines and the relevance for future clinical use of these agents to treat and prevent cancers.

Antigens, Neoplasm↗
PubMed2005

Clinical trial designs for therapeutic cancer vaccines.

Therapeutic cancer vaccines have characteristics that require a new paradigm for phase I and phase II clinical development. Effective development plans may take advantage of some of the following observations: Dose ranging safety trials are not appropriate for many cancer vaccines. Dose ranging trials to establish an optimal biologic dose are often not practical. We have presented an efficient design of Korn et al. (4) to identify an immunogenic dose. Vaccine efficacy can be efficiently evaluated with tumor response as endpoint utilizing a two stage design with only 9 patients in the first stage. If no partial or complete responses are observed in the initial 9 patients, accrual to the trial is terminated. Optimization of vaccine delivery by comparing results of single arm phase II studies using immunological response as endpoint is problematic because of assay variation and potential non-comparability of patients in different studies. Randomized screening studies can be used to efficiently optimize vaccine immunogenicity. Efficiency in use of patients depends on having assay variation and inter-patient variability small relative to the difference in immunogenicity to be detected. Phase II studies using time to progression as endpoint are most interpretable if they employ randomized designs with a no-vaccine control group. Such designs may use an inflated type 1 error rate, and need not be prohibitively large if patients with rapidly progressive disease are studied. Interim monitoring plans may effectively limit the size of the trials by terminating accrual early when results are not consistent with the targeted improvement.

Cancer Vaccines↗
PubMed1995

Animal models of human-derived cancer vaccines.

Preclinical cancer vaccine studies must address vaccine safety, immunogenicity, and efficacy, as well as mechanism of vaccine action. Animal models of vaccines employing human tumor-associated antigen or epitopes (TAA, TAE) differ fundamentally from those employing tumor-specific antigens or epitopes (TSA, TSE). TSA and TSE vaccines will most likely demonstrate similar toxicity, immunogenicity, and efficacy in both tumor-bearing animals and patients. In contrast, TAA/TAE immunizations may have to overcome a host's immunological tolerance to TAA/TAE expressed not only on tumor, but also on normal tissues; immunity to TAA/TAE will potentially target normal tissues and thus may induce autoimmunity. Various experimental models for human-derived TAA/TAE vaccines have been developed. These models include transgenic mice, mice with severe combined immunodeficiency (SCID), and non-human primates. Recently, unique animal models of TAA/TAE cancer vaccines have been developed, taking advantage of the discovery of animal tissue antigens with significant sequence homologies to human TAA/TAE. These models mimic perhaps most closely the situation in cancer patients.

Animals↗
PubMed2006

Potency assays for therapeutic live whole cell cancer vaccines.

Therapeutic cancer vaccines are under development with the goal of enhancing the body's immune response to cancer cells sufficient to arrest cancer cell growth. Among the various approaches being used are those based on whole tumor cells. Developing a suitable measure of the potency of such vaccines presents a significant challenge because neither cellular associated markers nor in vivo biological responses that are correlated with efficacy have been identified; nevertheless, manufacturers and regulatory agencies will need to develop methods to evaluate these products. At this moment, the challenge for manufacturers who are developing whole cell vaccines is to demonstrate batch-to-batch consistency for the vaccine used in clinical studies and to show that comparable vaccine batches have the same capacity to achieve an acceptable level of biological activity that may be related to efficacy. This is particularly challenging in that animal models to test that activity do not exist and direct serological or immunological correlates of clinical protection are not available because protection has not yet been established in clinical trials. In the absence of well-defined biological markers and tests for manufacturing consistency, manufacturers and regulators will need to rely heavily on a highly reproducible manufacturing process--the consistency of the process therefore becomes critical. In developing regulatory approaches to whole cell cancer vaccines, the experience from the field of infectious disease vaccines should be examined for general guidance. A framework that draws heavily on the field of infectious disease vaccines is presented and suggests that at this point in the development of this new class of products, it is reasonable to develop data on quantitative antigen expression as a measure of potency with the expectation that when clinical efficacy has been established it will confirm the appropriateness of this approach. But because this will not be known until the end of a pivotal trial, a bioassay should be considered and run in parallel. Several examples of bioassays are presented along with their advantages and disadvantages. The final selection of a potency assay for use in lot release of a commercializable therapeutic whole cell vaccine ultimately will depend on the totality of the data available at the time of approval by regulatory agencies. Based on information currently available, it is likely that quantitative antigen expression or a bioassay could be used to measure potency. If both are determined to be acceptable, the use of quantitative antigen expression could be considered for routine lot release, while the bioassay could be reserved for use as one of the elements in establishing comparability when manufacturing changes are being considered after approval.

Animals↗
PubMed2001

Current concepts in cancer vaccine strategies.

Cancer vaccines are entering a new phase of popularity, in part because of the recognition of when a therapeutic vaccine is most effective and the identification of appropriate target antigens. New technologies, most notably gene transfection into dendritic cell and DNA vaccination approaches, have spurred further clinical evaluations. While many researchers consider humoral responses as not being viable for large tumors, these responses may play a role in regulating micrometastases (i.e., adjuvant setting). The recent approval of antibodies as therapeutics for cancer treatment has lent to the viability of this therapy concept. The success of carbohydrate-conjugate vaccines in bacterial systems has also renewed interest in developing such vaccines for cancer immunotherapy. Carbohydrates can be further converted into peptide/protein mimetics with several of these mimetics in clinical trials. These mimetic forms can be manipulated into DNA vaccine types that may be combined into DNA cassettes that contain CTL-associated epitopes to further define a novel strategy for future vaccine development.

Animals↗
PubMed2002

Synthetic peptides as cancer vaccines.

Effective cancer therapy or prevention has been the dream of physicians and scientists for many years. Although we are still very far from our ultimate goal of cancer prevention, significant milestones have been realized in terms of our knowledge base and understanding of the pathogenesis of cancerous cells and the involvement of the immune system against both self- and virus-associated tumor antigens. Immunotherapeutic strategies are now accepted to being superior in terms of the exquisite specificity that they offer in targeting only tumor cells as opposed to the existent chemotherapy or radiation therapy that is more general and invasive with many associated side effects. There are several immunotherapeutic strategies that are currently under investigation. This review primarily focuses on the significant advances made in the use of synthetic peptides in the development of subunit cancer vaccines. We have attempted to highlight some of the fundamental issues regarding antigen processing and presentation, Major Histocompatibility Complex (MHC) restriction, T-cell help, structural determinants in antibody recognition, and the use of these concepts in the rational design and delivery of peptide vaccines to elicit protective humoral and cell mediated immune responses. The recent use of costimulatory molecules and cytokines to augment immune responses also has been discussed along with the contributions of our laboratory to the field of synthetic peptide vaccine development.

Adjuvants, Immunologic↗