Tumor vaccines

Vaccination against tumor, either as a prophylactic procedure or as a mode of treatment, has been a distant goal of immunologists for many years. Ideally, the less specific therapies such as chemotherapy would be replaced by an anti-tumor immune response in the host that would be present on a continuing basis. However, progress has been hampered by a lack of understanding of the role of viruses in human tumor development and the molecular nature of tumor-associated antigens. Recent developments using the techniques of molecular biology and monoclonal antibody reagents are beginning to remedy this deficiency so that vaccination has become a real possibility for certain human cancers. The natural fluctuations in growth rates of some human tumors, and the observation that tumors can occasionally remain dormant for years, has led to the idea that the host has an intrinsic ability to control tumor growth, and that this ability is a property of the immune system. Attempts to enhance this putative control are being made by treating the host with defined biological modifiers that stimulate cells involved in immunity in vivo, and by seeking and expanding such cells in vitro before reinfusing them into the host. These attempts to harness the immune system to attack tumor cells that have evaded the host's defenses might be considered optimistic, but they will at least tell us a great deal about tumor cell behavior and the ability of the host to influence it.     

Tumor idiotype vaccines

In this study, the contribution of idiotype-positive antitumor antibodies (anti-Id) in protective tumor immunity was investigated. We have previously shown that among various anti-Id generated and typed as the internal-image Ab2 of the tumor-associated antibody (TAA) gp52, only 2F10 antibody induces protective immunity. Increase of the 2F10 idiotope in sera of tumor-bearing mice correlated with long-term survival, while in mice with short survival the circulating 2F10 idiotype decreased. 2F10⁺ Ig were purified from sera of tumor-bearing mice with longterm survival and the amount of 2F10⁺ anti-TAA antibodies was determined. Only about 3% of 2F10⁺ antibodies are 2F10⁺ anti-TAA⁺. Hybridomas were generated from a 2F10 high mouse with spontaneous tumor regression. Only 2 out of 52 tumor-specific hybridomas were 2F10⁺. These results suggest that the protective effect induced by 2F10 vaccination may not be directly mediated by 2F10⁺ antibodies but indirectly through the stimulation of a 2F10-specific cellular immune response.Supported in part by a grant from N.I.H. no. CA51434     

Tuberculosis vaccines: beyond bacille Calmette-Guerin

Tuberculosis (TB) disease caused by Mycobacterium tuberculosis (M. tb) remains one of the leading infectious causes of death and disease throughout the world. The only licensed vaccine, Mycobacterium bovis bacille Calmette-Guérin (BCG) confers highly variable protection against pulmonary disease. An effective vaccination regimen would be the most efficient way to control the epidemic. However, BCG does confer consistent and reliable protection against disseminated disease in childhood, and most TB vaccine strategies being developed incorporate BCG to retain this protection. Cellular immunity is necessary for protection against TB and all the new vaccines in development are focused on inducing a strong and durable cellular immune response. There are two main strategies being pursued in TB vaccine development. The first is to replace BCG with an improved whole organism mycobacterial priming vaccine, which is either a recombinant BCG or an attenuated strain of M. tb. The second is to develop a subunit boosting vaccine, which is designed to be administered after BCG vaccination, and to enhance the protective efficacy of BCG. This article reviews the leading candidate vaccines in development and considers the current challenges in the field with regard to efficacy testing.     

Cancer immunotherapy: moving beyond current vaccines

Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.     

Tumor vaccines in 2010: Need for integration

Induction of tumor-specific immunity is an attractive approach to cancer therapy, however to date every major pivotal trial has resulted in failure. While the phenomena of tumor-mediated immune suppression has been known for decades, only recently have specific molecular pathways been elucidated, and for the first time, rationale means of intervening and observing results of intervention have been developed. In this review we describe major advances in our understanding of tumor escape from immunological pressure and provide some possible therapeutic scenarios for enhancement of efficacy in future cancer vaccine trials.     

The next 15 years: taking plant-made vaccines beyond proof of concept

Significant potential advantages are associated with the production of vaccines in transgenic plants; however, no commercial product has emerged. An analysis of the strengths, weaknesses, opportunities and threats for plant-made vaccine technology is provided. The use of this technology for human vaccines will require significant investment and developmental efforts that cannot be supported entirely by the academic sector and is not currently supported financially by industry. A focus on downstream aspects to define potential products, conduct of additional basic clinical testing, and the incorporation of multidisciplinary strategic planning would accelerate the potential for commercialization in this field. Estimates of production cost per dose and volume of production are highly variable for a model vaccine produced in transgenic tomato, and can be influenced by the optimization of many factors. Commercialization of plant-made vaccine technology is likely to be led by the agricultural biotechnology sector rather than the pharmaceutical sector due to the disruptive nature of the technology and the complex intellectual property landscape. The next major milestones will be conduct of a phase II human clinical trial and demonstration of protection in humans. The achievement of these milestones would be accelerated by further basic investigation into mucosal immunity, the codevelopment of oral adjuvants, and the integration of quality control standards and good manufacturing practices for the production of preclinical and clinical batch materials.     

Tumor immunotherapy using adenovirus vaccines in combination with intratumoral doses of CpG ODN

The combination of viral vaccination with intratumoral (IT) administration of CpG ODNs is yet to be investigated as an immunotherapeutic treatment for solid tumors. Here, we show that such a treatment regime can benefit survival of tumor-challenged mice. C57BL/6 mice bearing ovalbumin (OVA)-expressing EG.7 thymoma tumors were therapeutically vaccinated with adenovirus type 5 encoding OVA (Ad5-OVA), and the tumors subsequently injected with the immunostimulatory TLR9 agonist, CpG-B ODN 1826 (CpG), 4, 7, 10, and 13 days later. This therapeutic combination resulted in enhanced mean survival times that were more than 3.5× longer than naïve mice, and greater than 40% of mice were cured and capable of resisting subsequent tumor challenge. This suggests that an adaptive immune response was generated. Both Ad5-OVA and Ad5-OVA + CpG IT treatments led to significantly increased levels of H-2 K^b-OVA-specific CD8+ lymphocytes in the peripheral blood and intratumorally. Lymphocyte depletion studies performed in vivo implicated both NK cells and CD8+ lymphocytes as co-contributors to the therapeutic effect. Analysis of tumor infiltrating lymphocytes (TILs) on day 12 post-tumor challenge revealed that mice treated with Ad5-OVA + CpG IT possessed a significantly reduced percentage of regulatory T lymphocytes (Tregs) within the CD4+ lymphocyte population, compared with TILs isolated from mice treated with Ad5-OVA only. In addition, the proportion of CD8+ TILs that were OVA-specific was reproducibly higher in the mice treated with Ad5-OVA + CpG IT compared with other treatment groups. These findings highlight the therapeutic potential of combining intratumoral CpG and vaccination with virus encoding tumor antigen.     

Tumor profiling using protein biomarker panels in malignant melanoma: application of tissue microarrays and beyond

In the past decade, analysis of the urinary proteome (urinary proteomics) has intensified in response to the need for novel biomarkers that support early diagnosis of kidney diseases. In particular, this also applies to acute kidney injury, which is a heterogeneous complex syndrome with a still-increasing incidence at the intensive care unit. Unfortunately, this major need remains largely unmet to date. The current report aims to explain why attempts to implement urinary proteomic-discovered acute kidney injury diagnostic candidates in the intensive care unit setting have not yet led to success. Subsequently, some key notes are provided that should enhance the chance of translating selected urinary proteomic candidates to valuable tools for the nephrologist and intensivist in the near future.     

Tumor idiotype vaccines. VI. Synergistic anti-tumor effects with combined "internal image" anti-idiotypes and chemotherapy

Anti-Id antibodies that have biologic activity as stimulators of specific immunity have been used in experimental vaccines and tumor protection models. However, very little is known about the therapeutic potential of anti-Id antibodies in animals and men. In this study we explored the combination of anti-Id and chemotherapy in a murine tumor system for which we had previously generated protective anti-Id mAb. First, we investigated various protocols by using a protective anti-Id in active immunization. Mice preimmunized before tumor transfer and challenged again after tumor survived significantly longer. Next, we explored the use of soluble anti-Id as immunostimulator in tumor-bearing mice. Although this treatment did not induce long-term survival, it significantly increased survival time. Interestingly, this anti-Id effect was dose dependent, whereby large and small doses had no effect. Finally, stimulatory anti-Id therapy and cyclophosphamide (Cy) treatment was combined. Tumor bearing mice were given a single dose of Cy followed by different doses of soluble anti-Id. The optimal effect on tumor growth and survival was achieved with 80 mg/kg Cy and 10 micrograms/mouse of anti-Id, where 80% of mice survived longer than 100 days. These results provide guidelines for developing clinical protocols for cancer patients by using combination therapy of anti-Id and chemotherapy.     

Anammox and beyond

When looking back and wonder how we did it, I became even more aware of how my wanderings in microbiology are all linked, from the start of my PhD with Hans Veldkamp on sulphur-oxidizing bacteria in chemostats. My interests broadened from obligate chemolithoautotrophic bacteria to facultative organisms and the question about the ecological niches of these different metabolic types. The sulphide oxidizing bacteria also may be used to produce elemental sulphur, which can easily be removed from wastewater. This fitted in a long-standing collaboration with Dimitry Sorokin on the ecophysiology and application of alkaliphilic sulphur bacteria. Then came the denitrifying sulphur-oxidizing bacteria and their application to remove sulphide from wastewater, which lead to our interest in nitrate, nitrite and ammonium removal in general. The big surprise was the serendipitous discovery of the ‘anammox’-process, whereby ammonium is anaerobically oxidized to dinitrogen gas with nitrite as electron acceptor. The early days of our anammox research are the main focus of this article, which describes the struggle of growing and identifying the most peculiar bacteria we ever came across. A specialized organelle, the anammoxosome was shown to be responsible for the key ammonium oxidation, whereby a rocket fuel, hydrazine, turned out to be an intermediate. Soon after we became aware that anammox is everywhere and in the marine environment makes up a major portion of the nitrogen cycle. The intense scientific collaboration with Mike Jetten and Mark van Loosdrecht and colleagues led to our further understanding and application of this fascinating process, which is briefly summarized in this article. My broader interest in environmental microbiology and microbial ecology has been a regularly returning theme, taking me all over the world to great collaborations lasting to this very day.     

NSF-fusion and beyond

NSF (N-ethylmaleimide-sensitive fusion protein) was the first protein to be isolated as a crucial factor in intracellular membrane-fusion events, such as the fusion of synaptic vesicles with the presynaptic membrane during neurotransmission. Although the activation of membrane SNARE proteins for subsequent fusion is clearly a primary role of NSF, recent studies have provided surprising evidence that NSF also interacts with glutamate receptors at the postsynaptic membrane in a way that does not seem to involve SNAREs. These results suggest that NSF might act as a molecular chaperone not only on SNAREs but also on other proteins.     

Prostatic preneoplasia and beyond

Prostate cancer is a heterogeneous neoplasm both with regard to its development, molecular abnormalities and clinical course. For example, in the United States, 1 in 6 men is diagnosed with prostate cancer whilst only 1 in 34 dies of metastatic disease [A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, M.J. Thun, Cancer Statistics, 2007, CA Cancer J. Clin. 57 (2007) 43-66]. In this review, we summarise novel understandings of the early molecular events in prostatic carcinogenesis that may underlie both the molecular and clinical heterogeneity. Issues covered include those related to stem cells and embryonic signalling, oncogene/tumor suppressor abnormalities, androgen signalling, apoptosis and the nature of tumor-stromal interactions. Emphasis is placed on signalling pathway abnormalities, their causation, consequences and interactions. For example, genomic abnormalities involving the TMPRSS2-ETS and PTEN loci and the resulting signalling effects suggest the importance of genomic instability as a crucial factor in the emergence of this neoplasm. Together with new insights into signalling pathways consequent to abnormalities such as these, a greater understanding of the pathophysiology involved in prostatic carcinogenesis will lead to targeted approaches for both therapy and chemoprevention in the future.