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PubMed2000

Intratumoral injection of adenoviral vectors encoding tumor-targeted immunoconjugates for cancer immunotherapy.

The efficacy and safety of a new immunotherapy protocol for cancer were tested in a severe combined immunodeficient mouse model of human skin and metastatic lung melanoma. The protocol involves intratumoral injections of replication-incompetent adenoviral vectors encoding immunoconjugates composed of the Fc region of an IgG1 immunoglobulin conjugated to a tumor-targeting domain. One targeting domain is factor VII that binds to tissue factor expressed on endothelial cells lining the tumor neovasculature and on tumor cells; the active site of factor VII was mutated to inhibit the initiation of blood coagulation. Another targeting domain is a single-chain Fv antibody that binds to a cognate antigen expressed on human melanoma cells. The adenoviral vectors infect mainly the cells of the injected tumor, which synthesize and secrete the immunoconjugates. The bloodborne immunoconjugates induce a cytolytic immune response against the targeted neovasculature endothelial cells and tumor cells. The mouse model experiments showed that intratumoral delivery of the factor VII immunoconjugate, either alone or together with the single-chain Fv immunoconjugate, resulted in growth inhibition and regression of the injected tumor, and also of distant metastatic tumors, without evidence of damage to normal organs. There was extensive destruction of the tumor neovasculature, presumably mediated by the factor VII immunoconjugate bound to tissue factor on neovasculature endothelial cells. Because tissue factor is generally expressed on neovascular endothelial cells and tumor cells, a factor VII immunoconjugate could be used for immunotherapy against a broad range of human solid tumors.

Adenoviridae↗
PubMed2005

Identification of immunoglobulin superfamily 11 (IGSF11) as a novel target for cancer immunotherapy of gastrointestinal and hepatocellular carcinomas.

We previously performed gene expression profile analyses of 20 intestinal-type gastric cancers, and identified a set of genes whose expression levels were elevated in cancer tissues compared to their corresponding non-cancerous tissues. In the present study we focused on the immunoglobulin superfamily 11 gene (IGSF11). Its expression was also elevated in colorectal cancers and hepatocellular carcinomas as well as intestinal-type gastric cancers. Northern blot analysis showed that it was expressed abundantly in testis and ovary. These data suggest that IGSF11 is a good candidate of cancer-testis antigen. Furthermore, suppression of IGSF11 by siRNA retarded the growth of gastric cancer cells. To investigate the possibility of clinical application of peptide vaccine to IGSF11, we synthesized candidate epitope peptides for IGSF11 and tested whether the peptides elicit IGSF11-specific CTL. As a result, we successfully established oligo-clonal CTL by stimulation with IGSF11-9-207 (ALSSGLYQC). In addition, we also established additional CTL using IGSF11-9V (ALSSGLYQV), anchor-modified peptides of IGSF11-9-207. These peptides showed IGSF11-specific cytotoxic activity in an HLA-A*0201-restricted fashion, suggesting that these peptides may be applicable for cancer immunotherapy. These findings have provided a novel insight into carcinogenesis of the stomach, colon and liver, and will be helpful for the development of novel therapeutic strategies to a wide range of human cancers.

3T3 Cells↗
PubMed2000

Dendritic cells in cancer immunotherapy.

The potential to harness the potency and specificity of the immune system underlies the growing interest in cancer immunotherapy. One such approach uses bone marrow-derived dendritic cells, phenotypically distinct and extremely potent antigen-presenting cells, to present tumor-associated antigens and thereby generate tumor-specific immunity. Support for this strategy comes from animal studies that have demonstrated that dendritic cells, when loaded ex vivo with tumor antigens and administered to tumor-bearing hosts, can elicit T cell-mediated tumor destruction. These observations have led to clinical trials designed to investigate the immunologic and clinical effects of antigen-loaded dendritic cells administered as a therapeutic vaccine to patients with cancer. In the design and conduct of such trials, important considerations include antigen selection, methods for introducing the antigen into MHC class I and II processing pathways, methods for isolating and activating dendritic cells, and route of administration. Although current dendritic cell-based vaccination methods are cumbersome, promising results from clinical trials in patients with malignant lymphoma, melanoma, and prostate cancer suggest that immunotherapeutic strategies that take advantage of the antigen presenting properties of dendritic cells may ultimately prove both efficacious and widely applicable to human tumors.

Animals↗
PubMed2003

A highly effective and stable bispecific diabody for cancer immunotherapy: cure of xenografted tumors by bispecific diabody and T-LAK cells.

PURPOSE: In the field of cancer immunotherapy research, the targeting of effector cells with specific antibodies is a very promising approach. Recent advances in genetic engineering have made it possible to prepare immunoglobulin fragments consisting of variable domains using bacterial expression systems. METHODS: We have produced an anti-epidermal growth-factor receptor (EGFR) x anti-CD3 bispecific diabody (Ex3 diabody) in an Escherichia coli (E. coli) expression system with refolding method. The Ex3 diabody targets lymphokine-activated killer cells with a T-cell phenotype (T-LAK cells) to EGFR positive bile duct carcinoma cells with dramatic enhancement of cytotoxicity in vitro. This specific killing of EGFR-positive cells was completely inhibited by parental mAb IgGs directed to EGFR and the CD3 antigen. RESULTS: When T-LAK cells were cultured with EGFR-positive tumor cells in the presence of Ex3 diabody, they produced much higher levels of IFN-gamma, GM-CSF, and TNF-alpha than in its absence, this being a possible mechanism underlying specific antitumor activity. The Ex3 diabody showed good stability when tested at 37 degrees C for 48 h, and also markedly inhibited tumor growth of bile duct carcinoma xenografts in severe combined immunodeficient (SCID) mice. When Ex3 diabody (20 microg/mouse) was administrated intravenously, together with T-LAK cells and interleukin-2 (IL-2), complete cure of tumors were observed in three of six mice, and the other three showed marked retardation of tumor growth. CONCLUSION: The Ex3 diabody can be considered a highly promising reagent for study of specific targeting immunotherapy against bile duct and other EGFR-positive carcinomas.

Animals↗
PubMed2000

American Association for Cancer Research: potential target antigens for cancer immunotherapy. April 1-5, 2000, San Francisco, CA, USA.

The 91st annual meeting of the American Association for Cancer Research (AACR) convened this year in San Francisco, USA. Nearly 5600 abstracts were published within ten broad research categories ranging from basic molecular, cellular and pharmaceutical research to cancer epidemiology and prevention. The largest number of poster presentations belonged in the 'Pharmacological and Experimental Therapeutics' section, followed closely by 'Molecular Biology' and 'Cell and Tumour Biology'. Novel tumour antigens and their potential application in cancer immunotherapy were displayed primarily in a section categorised as 'Immunology/Preclinical and Clinical'. This article reports some of the significant tumour antigen-related studies presented at this meeting.

Antigens, Neoplasm↗
PubMed2001

Soft tissue sarcoma as a model disease to examine cancer immunotherapy.

Immunotherapy is in its infancy for many diseases, whether they are neoplastic or autoimmune. The major issues for cancer immunotherapy today involve the definition of molecular targets and the generation of effector mechanisms to attack the targets of interest. Soft tissue sarcomas provide a unique opportunity to examine the immune response against defined antigens. Many types of sarcomas contain tumor-specific chromosomal translocations encoding fusion proteins, which are attractive targets for immunotherapy. Our understanding of the immune system is also coming into clearer focus with the discovery of dendritic cells as powerful natural adjuvants and the teasing out of mechanisms leading to immunity versus tolerance as examples. It is hoped that the intersection of cellular immunology and sarcoma molecular biology will lead to new modalities of therapy for this group of patients with this heterogeneous group of diseases.

Antigens, Neoplasm↗
PubMed2003

CpG oligodeoxynucleotides for immune stimulation in cancer immunotherapy.

Synthetic oligodeoxynucleotides containing CG motifs (CpG ODNs) have potent immunostimulatory properties, and have potential as immunotherapeutic agents in cancer. Animal models suggest that CpG ODNs may be useful as both single agents and to enhance the efficacy of monoclonal antibody therapy. CpG ODNs can also enhance the efficacy of tumor immunization through use as an immune adjuvant, to activate antigen presenting cells, or as a component of DNA vaccines. Clinical trials are now beginning to assess whether the promise of these agents in the laboratory will translate into CpG ODNs becoming a valuable component of clinical cancer immunotherapy.

Adjuvants, Immunologic↗
PubMed1995

Paracrine cytokine adjuvants in cancer immunotherapy.

Advances in our understanding of the molecular events of antigen recognition by T cells and T cell activation are opening up new approaches to cancer immunotherapy. The identification and cloning of cytokines provide one important set of tools for manipulating immunologic responses. For cancer therapy, cytokines such as interleukin-2 have been administered systemically. However, systemic administration of cytokines ignores the paracrine nature of their action. Recently, an alternative approach has been explored that produces high concentrations of cytokines local to the tumor cells. This is achieved either by transduction of the tumor cells with the cytokine gene or by mixture of the tumor cells with cytokine containing biodegradable polymer microspheres. Under these circumstances, the locally released cytokine produces a strong local inflammatory response specific to the particular cytokine. In some cases, a potent tumor-specific T cell response results, capable of mediating regression of systemic tumor deposits. This paracrine delivery of cytokines can therefore be considered as a new type of adjuvant in the design of vaccines for cancer as well as microbial infections.

Adjuvants, Immunologic↗
PubMed2002

Histamine in cancer immunotherapy: a preclinical background.

Natural killer (NK) cells and T cells are the primary targets of interleukin-2 (IL-2) and other cytokines used in cancer immunotherapy. However, these tumoricidal lymphocytes are frequently dysfunctional or apoptotic when residing within melanomas and other solid cancers. This phenomenon--tumor-induced immunosuppression--is poorly understood and conceivably limits the efficiency of strategies aiming at activating lymphocyte-mediated antitumor immunity. Recent studies imply that reactive oxygen species (oxygen radicals), produced by tumor-infiltrating monocyte/macrophages, may contribute to the state of lymphocyte inhibition in neoplastic tissue. Histamine, acting via H2-type histamine receptors on monocyte/macrophages, suppresses the activity of a key enzyme in oxygen radical formation, the NADPH oxidase. By this mechanism, histamine protects NK cells and T cells against oxygen radical-induced dysfunction and apoptosis, and also maintains their activation by IL-2 and other lymphocyte activators. In this review, these properties of histamine are discussed in relation to the current use of histamine as an adjunct to IL-2 in metastatic melanoma and other malignant diseases.

Adjuvants, Immunologic↗
PubMed2003

Dendritic cells in cancer immunotherapy - a short review.

Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their recent application to therapeutic cancer vaccines. Isolated DCs loaded with tumour antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumour immunity. In the present report we describe the most common methods of culturing DCs and delivering tumour antigens and we summarise clinical trials of cancer immunotherapy using DCs-based vaccines.

Antigens, Neoplasm↗
PubMed2006

Viral vectors for cancer immunotherapy.

Over the last decade, immunotherapy approaches for the treatment of cancer have been investigated with renewed vigour, perhaps catalyzed by the clinical successes seen with monoclonal antibody and cytokine based therapies. The identification of tumor-associated antigens (TAAs) in multiple cancer types has enabled the development of targeted immunotherapies and allayed some of the safety concerns associated with the induction of deleterious autoimmune reactions. In addition to the TAA or therapeutic gene, the antigen delivery system is equally as important for the development of a successful cancer vaccine. One approach to induce a potent and targeted antitumor response is to use viruses to deliver the TAA to cells of the immune system. A diverse array of oncolytic viruses and recombinant viral vectors encoding numerous therapeutic genes or TAAs have been tested in pre-clinical studies and produced results which, in some cases, justify their clinical development as potential cancer immunotherapies. Within the last 5-10 years, many such recombinant vectors have made the transition from pre-clinical research to clinical development and it is these, which are given most weight in this review.

Animals↗
PubMed2006

Molecular imaging of cell-mediated cancer immunotherapy.

New strategies based on the activation of a patient's immune response are being sought to complement present conventional exogenous cancer therapies. Elucidating the trafficking pathways of immune cells in vivo, together with their migratory properties in relation to their differentiation and activation status, is useful for understanding how the immune system interacts with cancer. Methods based on tissue sampling to monitor immune responses are inadequate for repeatedly characterizing the responses of the immune system in different organs. A solution to this problem might come from molecular and cellular imaging - a branch of biomedical sciences that combines biotechnology and imaging methods to characterize, in vivo, the molecular and cellular processes involved in normal and pathologic states. The general concepts of noninvasive imaging of targeted cells as well as the technology and probes applied to cell-mediated cancer immunotherapy imaging are outlined in this review.

Animals↗
PubMed2005

Adoptive T cell therapy: Addressing challenges in cancer immunotherapy.

Adoptive T cell therapy involves the ex vivo selection and expansion of effector cells for the treatment of patients with cancer. In this review, the advantages and limitations of using antigen-specific T cells are discussed in counterpoint to vaccine strategies. Although vaccination strategies represent more readily available reagents, adoptive T cell therapy provides highly selected T cells of defined phenotype, specificity and function that may influence their biological behavior in vivo. Adoptive T cell therapy offers not only translational opportunities but also a means to address fundamental issues in the evolving field of cancer immunotherapy.

Journal Article↗
PubMedDate not supplied

Chemokines and anti-cancer immunotherapy: anti-tumor effect of EBI1-ligand chemokine (ELC) and secondary lymphoid tissue chemokine (SLC).

Various attempts at anti-cancer immunotherapy have used immunostimulatory cytokines, accessory molecules or tumor antigen-loaded dendritic cells. However, all these trials have exhibited only a limited anti-tumor response. A specific anti-tumor response should be enhanced by attracting to the site of antigen presentation large numbers of cells capable of eliciting an effector function on presentation and activation by tumor antigen. Chemokines play an important role in specific immune response. In this article, we have reviewed the anti-tumor effects of chemokines, such as inhibition of angiogenesis and attraction of immune effector cells to the tumor site. Although chemokines acting alone seem to have limited anti-tumor activity, chemokines produce more potent anti-tumor activity when used as adjuvants. The systemic anti-tumor immunity evoked by the chemokines, EBI1-ligand chemokine and secondary lymphoid tissue chemokine, is significantly potentiated when they are used in combination with interleukin-2 and granulocyte-macrophage colony-stimulating factor.

Animals↗
PubMed2003

Full-length dominant-negative survivin for cancer immunotherapy.

PURPOSE: The goal of this study is to investigate the possible utility of dendritic cells (DCs) transduced with the human full-length dominant-negative survivin for cancer immunotherapy. EXPERIMENTAL DESIGN: Mononuclear cells were collected from HLA-A2-positive healthy volunteers and patients with prostate cancer. DCs were transduced with an adenoviral vector containing a full-length, dominant-negative survivin gene. After three rounds of stimulation, the T-cell response against three different survivin-derived HLA-A2-matching peptides was tested in IFN-gamma enzyme-linked immunospot and CTL assays. RESULTS: Seven of eight healthy volunteers and cancer patients showed a significant response to at least two different survivin-derived epitopes in the enzyme-linked immunospot assay. One patient responded to only one peptide. All four healthy volunteers and two of three patients tested demonstrated a specific CTL response against T2 target cells loaded with one survivin-derived epitope. Two donors and two patients had a significant CTL response against two different epitopes. Significant cytotoxic activity was seen against HLA-A2-positive MCF-7 tumor cells that express survivin. That response was specific for survivin and was MHC class I restricted. Because survivin is expressed in CD34(+) hematopoietic progenitor cells (HPCs), we tested whether the antisurvivin CTLs can recognize normal HPCs. The incubation of survivin-specific CTLs with CD34(+) cells did not significantly decrease the colony-forming ability of HPCs. CONCLUSIONS: DCs transduced with dominant-negative survivin induce potent survivin-specific CTL responses able to recognize and kill tumor cells. This response does not significantly affect HPCs. Thus, this study may provide rationale for immunotherapeutic clinical trials using a DC vaccine transduced with the dominant-negative survivin.

Adenoviridae↗
PubMed1999

Why are dendritic cells central to cancer immunotherapy?

Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable alternative to radiation or chemotherapy in the treatment of cancer. The resurgence of interest in cancer immunotherapy reflects the promising results that have been obtained in both animal models and early clinical trials with the DC-based approach. Here I suggest that this optimism is justified because the efficient capture and presentation of antigens by DCs is central to the induction of an immune response. I argue that the mechanism by which DCs capture antigen suggests that the immune system might actually be 'blind' to tumours, thereby challenging the theory of immune surveillance.

Animals↗
PubMed2002

A recombinant E. coli vaccine to promote MHC class I-dependent antigen presentation: application to cancer immunotherapy.

We have examined the potential of recombinant Escherichia coli expressing listeriolysin O (LLO) to deliver tumour antigens to dendritic cells (DCs) for cancer immunotherapy. Using OVA as a model tumour antigen, we have shown in murine DCs that E. coli expressing cytoplasmic LLO and OVA proteins can deliver the OVA K(b)-restricted epitope SIINFEKL for MHC class I presentation. In contrast, when E. coli expressing OVA alone were used, MHC class II presentation of the OVA 323-339 I-A(b)-restricted peptide was predominant. When injected in vivo, DCs pulsed with E. coli expressing LLO and OVA induced production of cytotoxic T-lymphocytes capable of lysing an OVA-expressing melanoma cell line (B16-OVA) and resulted in suppression of tumour growth following challenge with B16-OVA. Immunisation of mice by direct injection of E. coli LLO/OVA provided a more potent anti-tumour response, resulting in complete protection in 75% of mice. Injection of live bacteria was not necessary as immunisation with paraformaldehyde-fixed E. coli LLO/OVA provided an even stronger anti-tumour response against B16-OVA. Altogether, our data highlight the potential of this system as a novel and efficient strategy for tumour immunotherapy.

Animals↗