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PubMed2002

Current issues in dendritic cell cancer immunotherapy.

Dendritic cells (DCs) initiate and direct the immune response. Their inability to detect danger signals from transformed cells and to generate an effective immunological response may allow cells with a malignant phenotype to evolve into cancers. This defect can be corrected for many cancer types and the immune response boosted to eliminate malignant cells by means of DC-based vaccines/therapies. Rapid advances in our understanding of basic DC physiology and improved methods for DC isolation have made clinical application of DC therapy practical, and encouraging phase I/II results are emerging.

Animals↗
PubMed2004

ISCOM based vaccines for cancer immunotherapy.

Immunostimulating complex (ISCOM) vaccines are particulate antigen delivery vehicles composed of saponin, cholesterol, phospholipid and immunogen. Here we illustrate that ISCOM-based vaccines represent an attractive modality for the development of anti-cancer vaccines. Using murine models and a model cancer antigen, ISCOM vaccines were shown to induce potent CD8 T cell responses, to mediate protection in three different tumor models, to promote Th1-biased immunity, and to induce CD8 T cell responses in the absence of CD4+ T cell help. The former three activities were also found to be substantially improved when the vaccine antigen was associated with the ISCOM structure. Furthermore, the presence in vivo of pre-existing antibodies against the vaccine antigen did not inhibit CD8 T cell induction by the ISCOM vaccine. Although vaccination was effective against challenge with vaccine-antigen expressing tumors, no activity against neighboring vaccine-antigen negative tumor cells was observed, indicating that determinant spreading or bystander activity does not lead to significant anti-cancer activity.

Animals↗
PubMedDate not supplied

Cancer immunotherapy with low-dose interleukin-2 subcutaneous administration: potential efficacy in most solid tumor histotypes by a concomitant treatment with the pineal hormone melatonin.

The antitumor efficacy of IL-2 is limited to renal cancer and melanoma. Several cytokines have been associated with IL-2 in an attempt to improve its activity, without, however, any clear benefit. Recent experimental and clinical studies have suggested the possibility to manipulate the host biological response by immunomodulating neurohormones, such as the pineal hormone melatonin (MLT). On the bases of these considerations, we have designed a neuroimmunotherapeutic protocol with low-dose IL-2 subcutaneous therapy (3 million IU/day for 6 days/week for 4 weeks) plus MLT (40 mg/day orally, starting 7 days before IL-2) in advanced solid neoplasms other than renal cancer and melanoma, which are generally resistant to IL-2 alone. The study included 82 patients, 72 of whom showed distant organ metastases. Tumor histotypes were, as follows: non-small cell lung cancer: 19; hepatocarcinoma: 16; colon cancer: 15; gastric cancer: 11; cancer of pancreas: 11; breast cancer: 6; miscellaneous: 4. Objective tumor regression were achieved in 17/82 (21%) patients, consisting of CR in 4 (liver: 2; pancreas: 1; stomach: 1) and PR in 13 (lung: 4; liver: 4; stomach: 2; pancreas: 1; breast: 1; colon: 1). The median duration of response was 8+ months. A stabilization of disease was obtained in 30 patients, while the other 35 patients progressed. The lack of progression was associated with a significantly higher increase in lymphocyte and eosinophil mean number and with a significantly lower increase in neopterin mean levels. The treatment was well tolerated in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Inhibition of prostaglandin E2 formation and histamine action in cancer immunotherapy.

The activity of cell-mediated defense systems is stimulated by consecutive formation of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2) and interferon gamma (IFN gamma). The system is inhibited by interleukin-4 (IL-4) and also by prostaglandin E2 (PGE2) and histamine, which are released when the immune system is activated. The inhibition is strong in cancer patients, because PGE2 is formed in many cancer cells and its formation is stimulated by IL-1 beta. The release of histamine is also stimulated by IL-1 beta. Thus PGE2 and histamine are feedback inhibitors of cell-mediated immunity. This inhibition can be abolished by inhibitors of the cyclo-oxygenase (e.g. indomethacin) and H-2 receptor antagonists (e.g. cimetidine). This may offer a new option to stimulate the immune system to kill cancer cells.

Dinoprostone↗
PubMed2004

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.

Antigens, Neoplasm↗
PubMed2005

Identification of noncanonical melanoma-associated T cell epitopes for cancer immunotherapy.

The identification of tumor-associated T cell epitopes has contributed significantly to the understanding of the interrelationship of tumor and immune system and is instrumental in the development of therapeutic vaccines for the treatment of cancer. Most of the known epitopes have been identified with prediction algorithms that compute the potential capacity of a peptide to bind to HLA class I molecules. However, naturally expressed T cell epitopes need not necessarily be strong HLA binders. To overcome this limitation of the available prediction algorithms we established a strategy for the identification of T cell epitopes that include suboptimal HLA binders. To this end, an artificial neural network was developed that predicts HLA-binding peptides in protein sequences by taking the entire sequence context into consideration rather than computing the sum of the contribution of the individual amino acids. Using this algorithm, we predicted seven HLA A*0201-restricted potential T cell epitopes from known melanoma-associated Ags that do not conform to the canonical anchor motif for this HLA molecule. All seven epitopes were validated as T cell epitopes and three as naturally processed by melanoma tumor cells. T cells for four of the new epitopes were found at elevated frequencies in the peripheral blood of melanoma patients. Modification of the peptides to the canonical sequence motifs led to improved HLA binding and to improved capacity to stimulate T cells.

Antigen-Presenting Cells↗
PubMed2005

[Cancer immunotherapy with CpG-ODN].

Bacterial DNA and synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN) are the ligands for the Toll-like receptor 9 (TLR9), which is expressed by B-lymphocytes and a subset of dendritic cells. CpG-ODN are strong activators of both innate and specific immunity, and drive the immune response towards the Th1 phenotype. Given the promising results obtained in several experimental models of allergies or infections, CpG-ODN are now entering clinical trials for these diseases. In cancer, promising approaches combined CpG-ODN with tumor antigens, monoclonal antibodies or dendritic cells. When no relevant tumor antigen is known, CpG-ODN can be used alone to activate locally the innate immunity and trigger a tumor-specific immune response, overcoming the need for the identification of a tumoral antigen. Preclinical models have shown impressive results and several clinical trials are on-going worldwide in melanoma, lymphoma, renal carcinoma, breast cancer and glioblastoma.

Animals↗
PubMed1994

Heat shock protein-peptide complexes in cancer immunotherapy.

Heat shock proteins (HSPs) are associated with a broad spectrum of peptides derived from the cells from which they are isolated. Vaccination with such HSP-peptide complexes elicits protective immunity against tumors or other cells used as the source of HSPs. These observations suggest that HSP-peptide complexes are suitable as vaccines against cancers and infectious diseases.

Animals↗
PubMed2006

Cancer immunotherapy and preclinical studies: why we are not wasting our time with animal experiments.

Experimental research on the immune response to transplanted tumors has led to pioneering discoveries that laid many of the foundations for the current field of immunology. Experimental research in oncology has proven that murine and human tumors have antigens that are truly cancer specific. This article discusses research investigating how can antigens on cancer cells be used to help eradicate cancer.

Animal Experimentation↗
PubMed2006

Optimal control in a model of dendritic cell transfection cancer immunotherapy.

We construct a population dynamics model of the competition among immune system cells and generic tumor cells. Then, we apply the theory of optimal control to find the optimal schedule of injection of autologous dendritic cells used as immunotherapeutic agent. The optimization method works for a general ODE system and can be applied to find the optimal schedule in a variety of medical treatments that have been described by a mathematical model.

Algorithms↗
PubMed2005

Genetic approaches for the induction of a CD4+ T cell response in cancer immunotherapy.

Recently, it has become more and more obvious that not only CD8+ cytotoxic T lymphocytes, but also CD4+ T helper cells are required for the induction of an optimal, long-lasting anti-tumor immune response. CD4+ T helper cells, and in particular IFN-gamma-secreting type 1 T helper cells, have been shown to fulfill a critical function in the mounting of a cancer-specific response. Consequently, targeting antigens into MHC class II molecules would greatly enhance the efficacy of an anti-cancer vaccine. The dissection of the MHC class II presentation pathway has paved the way for rational approaches to achieve this goal: novel systems have been developed to genetically manipulate the MHC class II presentation pathway. First, different genetic approaches have been used for the delivery of known epitopes into the MHC class II processing pathway or directly onto the peptide-binding groove of the MHC molecules. Second, several strategies exist for the targeting of whole tumor antigens, containing both MHC class I and class II restricted epitopes, to the MHC class II processing pathway. We review these data and describe how this knowledge is currently applied in vaccine development.

Animals↗
PubMed2002

Epitope identification and vaccine design for cancer immunotherapy.

The development of processes for engineering multi-epitope vaccines based on the identification and selection of epitope packages, along with vaccine design optimization using epitope placements and spacers to optimize processing efficacy, are reviewed. The Epimmune Inc epitope identification process has been applied to numerous cancer types, but also applies to infectious diseases. Epitope-analog efforts in novel vaccine design have also been explored and their uses in prophylactic and therapeutic applications are eagerly anticipated.

Animals↗
PubMed1989

Cancer immunotherapy: current status of treatment with interleukin 2 and lymphokine-activated killer cells.

In recent years, the medical community has witnessed a growing interest in the use of adoptive immunotherapy in patients with malignant lesions refractory to standard treatments. Systemic administration of interleukin 2, in combination with the adoptive transfer of a patient's own activated immune cells, has resulted in objective regression of several types of advanced cancers. Pronounced regression of tumor has also been observed with use of systemic interleukin 2 alone. This ability to augment the immune defense system of the host against cancer has stimulated intense clinical and laboratory investigations.

Animals↗
PubMed2000

Dendritic cell-based vaccines: from mouse models to clinical cancer immunotherapy.

B and T lymphocytes are the effectors of specific immunity. However, their function is critically dependent on dendritic cells (DC). DC are professional antigen presenting cells that both initiate and modulate the immune response. The recent breakthrough in the generation of DC from their progenitors has stimulated research on DC in both fundamental and clinical immunology. Objective immune response induction has now been reported in clinical studies using DC. In this review we discuss the development and potential of DC-based vaccines to induce antitumor immunity.

Animals↗
PubMed1983

[Immune RNA: its application in cancer immunotherapy].

RNA rich preparations from lymphoid tissues of appropriate immunized donors, namely immune RNA (I-RNA), can transfer specific immune reactivity to normal recipients or to their cells. Because of this ability, I-RNA was considered as a good candidate for the immunoprophylaxis and immunotherapy of different diseases. Its use in neoplasic processes is reviewed here. The regression of small tumors, as well as the effective prevention of metastasis appearance after primary tumor surgery has been obtained in animal models. The results from human cancer therapy with I-RNA are still very confuse; however the data suggest that I-RNA has altered the natural history of the studied tumor. An intensification of better planned immunotherapy in animals and humans tumor models will lead to a deeper knowledge of the usefulness of this therapy.

Animals↗
PubMed2001

New perspectives in dendritic cell-based cancer immunotherapy.

Dendritic cells are professional antigen-presenting cells with the unique capacity to initiate primary immune responses. Recently, several procedures to generate large numbers of dendritic cells from circulating precursors, including peripheral blood monocytes and CD34+ stem cells, have been developed. Stimulation with antigen-loaded dendritic cells was shown to break tolerance to tumour-associated antigens and to induce antitumour cytotoxic immune responses in vivo. Hence, numerous attempts to optimise delivery of tumour antigens to dendritic cells, as well as routes and schedules of administration to cancer patients, are currently under way. The first dendritic cell clinical studies have indicated this form of vaccination as feasible and safe; furthermore, in some cases, objective clinical responses were observed, even in patients heavily pretreated with standard chemo/radiotherapy approaches. These preliminary data, although encouraging, require further extensive investigations, which should address the technical and biological problems of manipulating human dendritic cells, as well as the clinical settings which could benefit from an immunotherapeutic approach.

Animals↗
PubMed2005

Investigation of the expression of melanoma antigen-encoding genes (MAGE-A1 to -A6) in oral squamous cell carcinomas to determine potential targets for gene-based cancer immunotherapy.

MAGE genes are silent in normal tissues except testis but are expressed in a variety of neoplastic lesions, and therefore represent ideal targets for immunotherapy. We analysed the expression of 6 MAGE-A genes (MAGE-A1 to -A6) to determine potential implications of these antigens as targets for immunotherapy in oral squamous cell carcinoma (OSCC). Oral tumor specimens (n=21) and non-neoplastic tissue samples (n=10) of oral mucosa from healthy patients were examined by a highly sensitive reverse transcription-nested polymerase chain reaction (MAGE-1- to -6 assay) which detect any cancer cells that express at least one of six MAGE subtype genes and allows also the identification of individual MAGE isotypes (M1 to M6). MAGE expression was restricted to neoplastic specimens. No expression of MAGE was observed in the non-neoplastic normal oral mucosal tissues. Fifteen of 21 (71%) oral carcinomas expressed at least one of MAGE-A1 to -6. The expression pattern of subtypes was heterogeneous: 62% of the tumor patients were positive for MAGE-3, 57% for MAGE-4, 48% for MAGE-6, 43% for MAGE-1, 38% for MAGE-2 and 24% for MAGE-5. Also coexpression of the genes could be determined: 13 (62%) coexpressed two, 10 (48%) coexpressed three, 8 (38%) coexpressed four, 6 (29%) coexpressed five and 5 coexpressed six of the 6 subtypes tested. The high incidence of MAGE expression in oral cancer indicates that monitoring of MAGE-A subtype expression in OSCC may be of potential interest to determine new immunotherapeutic targets and may be a possibility of specific immunotherapy with polyvalent anti-genes for this disease.

Antigens, Neoplasm↗