Biomedical subjects

Angus G Dalgleish

Publications and source records attributed to Angus G Dalgleish.

24 records · Page 2Linked to original sources

PubMed2002

Adjuvants and the promotion of Th1-type cytokines in tumour immunotherapy.

Immunotherapy includes both active and passive mechanisms that have the potential to treat many tumour types. Whereas monoclonal antibodies may kill cells by merely binding to them, 'cancer vaccines' involve the induction of an active immune response. The activation of tumour antigen-specific T-helper and cytotoxic T lymphocytes or non-specific macrophages and natural killer (NK) cells using immunotherapeutic approaches may lead to the subsequent destruction of tumour tissue. Administration of a tumour antigen alone is often not sufficient to stimulate an appropriate immune response. However, incorporating an immunological adjuvant into a vaccine regime often improves anti-tumour immunity. There are various types of adjuvants used in immunotherapy, ranging from microbial, chemical, and cellular components to proteins and cytokines. Previous reports have demonstrated that the induction of Th1-promoting cytokines, using specific adjuvants, can enhance anti-tumour immunity and can reduce or even prevent tumour growth. There is also increasing evidence that many adjuvants induce Th1-type cytokines, which correlates with the induction anti-tumour immunity. Th1-type responses which comprise cell-mediated immunity are characterised by the secretion of interferon-gamma by T cells, which is induced by antigen-presenting cell (APC)-derived IL-12. This review describes immunoadjuvants that are currently undergoing preclinical investigation, and emerging clinical data revealing that adjuvants which induce Th1-type responses can improve the efficacy of cancer vaccines. Therefore, the use of Th1-inducing adjuvants may provide an essential strategy for the future success of immunotherapy.

Adjuvants, Immunologic↗

PubMed2002

Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity.

Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. Our results are the first to demonstrate that a costimulatory thalidomide analog can prime protective, long-lasting, tumor-specific, Th1-type responses in vivo and further support their ongoing clinical development as novel anti-cancer agents.

Adjuvants, Immunologic↗

PubMed2002

Chronic immune activation and inflammation in the pathogenesis of AIDS and cancer.

Infection with the human immunodeficiency virus (HIV) invariably leads to the development of acquired immunodeficiency syndrome (AIDS) in most infected humans, yet does so rarely, if at all, in HIV-infected chimpanzees. The differences between the two species are not due to differences in cellular receptors or an inability of the chimpanzee to be infected, but rather to the lack of pan-immune activation in the infected primate. This results in reduced apoptotic death in CD4+ T-helper lymphocytes and a lower viral load. In humans the degree of chronic immune activation correlates with virus load and clinical outcome with high immune activation leading to high viral loads and the more rapid progression to AIDS and death. The type of immune perturbation seen in HIV-associated AIDS is similar to that of chronic graft-versus-host disease (GVHD) where reduced cell-mediated immune (CMI) responses occur early in the course of the disease and where humoral responses (HI) predominate. A reduced CMI response occurs in a number of chronic infectious diseases, including tuberculosis and leishmaniasis. More recently, it has become increasingly apparent that the CMI response is suppressed in virtually all malignant diseases, including melanoma and colorectal and prostate cancer. This raises the possibility that, as the malignant process develops, the cancer cells evolve to subvert the CMI response. Moreover, the reduced CMI response seen in colorectal cancer (CRC) patients is completely reversed following curative surgery strongly supporting the hypothesis that CRC can suppress the systemic immune response. Wound healing, ovulation, embryo implantation, and fetal growth are all associated with suppressed CMI and neovascularization (the formation of new blood vessels) or angiogenesis (the formation of new blood vessels from an existing vasculature). If unresolved, wound healing results in chronic inflammation, which can give rise to the phenomenon of "scar cancers." Indeed all the chronic inflammatory conditions known to be associated with the subsequent development of malignant disease, including chronic obstructive airway disease (COPD), ulcerative colitis (UC), and asbestosis, give rise to similar proangiogenic, suppressed CMI, and HI-predominant environments. In keeping with this CMI-associated cytokines such as interleukin (IL)-2 and interferon (IFN)-gamma tend to be antiangiogenic, whereas HI cytokines such as IL-6 tend to be proangiogenic. Furthermore, chronic immune activation leads to the synthesis and release of factors such as macrophage inflammatory protein (MIP)-1 that inhibit apoptosis through suppression of p53 activity. The "Golden Triangle" of suppressed CMI, angiogenesis, and reduced apoptosis would provide the ideal environment for the serial mutations to occur that are required for the development of malignant disease. If the observed association is relevant to carcinogenesis, then treatments aimed at reducing the components of these inflammatory conditions may be useful both in the setting of chemoprevention and the therapeutic management of established disease.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Recent developments in antiangiogenic therapy.

The use of antiangiogenic therapy is gaining momentum as a novel treatment for a number of conditions, ranging from cancer to psoriasis. This has stemmed from research in the early 1970s showing that the formation of new blood vessels by pre-existing endothelial cells is essential in tumour growth and progression. However, although antiangiogenic therapy was hailed as a new avenue of treatment for cancer, initial clinical data have been disappointing. This has led to the reassessment of antiangiogenic therapy for cancer, and new strategies have been proposed to increase the efficacy of these agents in this setting. Angiogenesis has also been implicated in other conditions that are notoriously difficult to treat, such as arteriosclerosis, arthritis, psoriasis and diabetic retinopathy. Increased understanding of the angiogenic process, the diversity of its inducers and mediators, appropriate drug schedules and the use of these agents with other modalities may lead to radically new treatment regimens for many of these conditions. The role of angiogenesis in different pathological settings, and emerging antiangiogenic agents currently in preclinical and clinical studies are discussed in this review. However, while potential benefits are profound, limitations of antiangiogenic therapy have also been identified, suggesting that there is also a need for caution in applying these compounds to the clinical setting.

Angiogenesis Inhibitors↗

PubMed2002

Immunological effects of thalidomide and its chemical and functional analogs.

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.

Adjuvants, Immunologic↗

PubMedDate not supplied

Angiogenesis and the immune response as targets for the prevention and treatment of colorectal cancer (review).

The carcinogenic process in previously normal human colonic mucosa involves hyperproliferation and adenoma formation, but it is not known why only a tiny proportion of adenomas undergo malignant transformation. There is accumulating evidence in favour of the hypothesis that inflammatory processes are a prerequisite for the development of malignancy. The data include upregulation of mediators of the inflammatory response such as cyclooxygenase-2, the generation of inflammatory cytokines which result in induction of cell proliferation and inhibition of apoptosis, and chronic inflammation which may lead to the production of reactive species that damage DNA. Angiogenesis, the formation of new blood vessels from an existing vasculature, is generally regarded as essential to the late stages of carcinogenesis, allowing tumours to grow beyond 1-2 mm in diameter, invade and metastasise. In this communication, it is argued that angiogenesis is not only present before neoplastic transformation occurs, but that it is of relevance to inflammatory diseases that increase risk of developing colorectal cancer. It is proposed that intervention to prevent or treat colorectal cancer should be targeted at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses.

Colorectal Neoplasms↗