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Results for “Cancer immunotherapy”

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PubMed1981

The use of polymerised autologous tumor tissue particles for experimental cancer immunotherapy in rats bearing Shay chloroma.

The effects of the specific active cancer immunotherapy utilizing autologous tumor tissue particles polymerise with ethylchlorformiate, and used in combination with PPD tuberculin, were studied on the growth of chloroma in an inbred strain of Wistar rats. As control animals, rats not immunised, or immunised with autologous muscle tissue polymer + PPD, or PPD alone, were studied. A clear-cut enhancement of tumor growth was observed in the group of animals receiving the tumor polymer, as evidenced by the largest tumors, the lowest incidence of tumor rejection and the lack of histological signs of host response against the growing chloroma. Immunisation with the PPD tuberculin, on the other hand, favorably influenced the host's immune system thus contributing to the tumor rejection and the development of pronounced host response in a high percentage of cases. The results were discussed in the light of favorable experiences gained with this mode of cancer immunotherapy in a number of clinical trials, as well as in a previous experimental DBA/2 mouse mastocytoma model. This apparent controversy between the previously obtained and the present results was interpreted to be caused by the different antigenic properties of the tumors used in these studies. The importance of the selection of an appropriate model system was emphasized, when it was attempted to obtain data relevant to human tumors for experimental cancer immunotherapy systems.

Adjuvants, Immunologic↗

PubMed1992

Monoclonal antibodies in cancer immunotherapy.

The preceding article focused on some novel approaches for the adjuvant treatment of human melanoma and neuroblastoma with mAbs against antigens preferentially expressed on these tumors. It should be emphasized that the major goal of the immunotherapy modalities described here is to apply them in an adjuvant setting for the treatment of micrometastases. The major aim is to decrease the rate of development of metastases in a setting of very low tumor burden and ultimately achieve a prolongation in life span. The combination of powerful modern technologies achieving genetic engineering of mAbs, resulting in more human-like molecules, will lead to a reevaluation of these reagents alone or in combination with molecularly defined cytokines and growth factors for the immunotherapy of cancer. The initial, albeit anectodal, findings, of phase I clinical trials mentioned in this article lead to cautious optimism that immunotherapy may find a place and will eventually contribute to the adjuvant treatment of cancer.

Antibodies, Monoclonal↗

PubMed2005

Blood brothers: carbohydrates in xenotransplantation and cancer immunotherapy.

Carbohydrate antigens have a central role in the hyperacute rejection of animal-to-human organ grafts (xenotransplantation) and they are emerging in importance in the immunotherapy of cancer. This article traces the historical origins of the discovery of key carbohydrate antigens and explores the future impact of recent technological advances of the field of glycobiology as it relates to xenotransplantation and cancer.

Animals↗

PubMed1980

Polymerised autologous tumor tissue particles in experimental cancer immunotherapy with special reference to the effects on the immune system of the host.

The efficacy of the specific active cancer immunotherapy utilizing autologous tumor tissue particles polymerised with ethylchlorformiate, and used in combination with the PPD tuberculin adjuvant, was studied in the mastocytoma (P-815 X2)-DBA/2 mouse system. Special attention was focused on the effects of the therapy on the immune system of the host as evaluated on the basis of the spleen white pulp morphology. The signs of tumor rejection by the host (tumor-surrounding fibrous scar, lymphocyte and plasma cell infiltrations, and disappearance of the tumor tissue) were most marked in mice receiving the specific immunotherapy. The specific cancer immunotherapy instituted was capable of reverting to a considerable degree the profound depletion of the T- and B-lymphocyte populations found in the spleen white pulp of mice not receiving any therapy for their tumor. Conclusion was drawn that the favorable influence on the tumor rejection exerted by the specific immunotherapy tested, most probably is attributable to its stimulatory effects on the cells responsible for both the cell-mediated and humoral immune reactions, the appropriate co-operation of both of which is needed to ensure the most effective host response against the tumor cells.

Animals↗

PubMed2003

Determinant spreading and tumor responses after peptide-based cancer immunotherapy.

Modern immunological assays are very sensitive for detection of antigen-specific T cells. These assays are used to detect increased levels of T cells after peptide-based immunotherapy for cancer in an attempt to describe surrogate endpoints correlated with anti-tumor activity. Recent reports demonstrate that determinant spreading develops in a high frequency of subjects with tumor regression responses after this type of immunotherapy and could be valuable for trial monitoring and the design of more effective vaccines.

Cancer Vaccines↗

PubMed2004

Cancer immunotherapy: a treatment for the masses.

Cancer immunotherapy attempts to harness the exquisite power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is clearly capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for immunotherapy is to use advances in cellular and molecular immunology to develop strategies that effectively and safely augment antitumor responses.

Animals↗

PubMed1994

T-cell based cancer immunotherapy: direct or redirected tumor-cell recognition?

In development of strategies for immunotherapy of cancer a new emphasis is emerging, termed T-cell retargeting, which involves artificial redirection of cytotoxic T lymphocytes (CTL) against cancer cells, using bispecific reagents. In this article, Gideon Beun, Cornelis van de Velde and Gert Jan Fleuren evaluate this potential strategy for cellular immunotherapy, and propose how the gap between in vitro results and clinical application might be bridged.

Animals↗

PubMed2005

Yeasts encoding tumour antigens in cancer immunotherapy.

Immunotherapy for cancer represents an attractive therapeutic target because of its specificity and lack of toxicity, but products investigated so far have been limited by neutralisation, complexity of manufacturing and requirement for patient-specific products. Recombinant yeast cells are capable of stimulating the immune system to produce highly specific and potent cellular responses against target protein antigens with little toxicity. Data from animal models suggest that Tarmogens (yeast-based immunotherapeutics) can elicit protective immunity against xenografted and chemically induced tumours. This concept is now being tested in a Phase I trial in patients with colorectal, pancreatic and non-small cell lung cancers.

Animals↗

PubMed1980

Experimental cancer immunotherapy in DBA/2 mouse-mastocytoma model utilizing autologous tumor tissue polymerised with ethylchlorformiate.

The effects of the specific active cancer immunotherapy utilizing autologous tumor tissue particles polymerised with ethylchlorformiate, and used in combination with PPD tuberculin, were studied with respect to the growth of mastocytoma (P-815 X 2) in DBA/2 mice. As a control material, animals not immunised or immunised only with the nonspecific reticuloendothelial system stimulator, PPD tuberculin, were used. The frequency of the tumor metastases in the organs surveyed (lymph nodes, spleen, liver, kidney, lung and thymus) was lowest in mice having received the specific immunotherapy regimen. Similarly, the signs of tumor rejection by the host (tumor-associated fibrous scar, lymphocyte and plasma cell infiltration, and disappearance of the tumor tissue totally or subtotally) were found to be most pronounced in this series of mice. The findings were discussed against the background of the successful clinical trials made with this mode of specific cancer immunotherapy during the recent few years in patients whose neoplasia had escaped the reach of conventional cancer therapy. The findings were also discussed in the light of the mechanisms involved in cancer immunity in general, and a conclusion was drawn that this kind of specific active cancer immunotherapy seems to exert beneficial effects on the host's immune system, and thus seems to contribute to tumor rejection by the host.

Animals↗

PubMed2003

Large-scale immunomagnetic selection of CD14+ monocytes to generate dendritic cells for cancer immunotherapy: a phase I study.

Dendritic cells (DC) are professional antigen-presenting cells that are widely used in the experimental immunotherapy of cancer. For clinical use GMP-like protocols for the preparation of functionally active dendritic cells (DC) in large numbers and at high purity are needed. However, the currently available protocols have certain disadvantages. In this study we tested the generation and clinical applicability of DC from monocyte preparations produced by immunomagnetic CD14(+) selection using a semiautomated clinical scale immunomagnetic column. Peripheral blood mononuclear cells (PBMC) of 10 patients with metastatic solid tumors were used. With the immunomagnetic separation, we obtained a cell suspension of high CD14(+) purity (median 97.4%, range 94.9-99.0) with a high monocyte yield (median 82.3%, range 63.9-100.0). Differentiation of CD14(+) cells into mature monocyte-derived DC was induced by incubation with IL-4, GM-CSF, TNF-alpha, PGE(2), IL-1 beta, and IL-6. Mature DC showed a high expression of CD83, HLA-DR, and the co-stimulatory molecules CD80 and CD86. Overall CD83(+) yield was 12.1% (range 4.0-29.4). Allogeneic T stimulatory capacity could be demonstrated for all DC preparations in proliferation assays. No significant differences in marker expression or T cell stimulation was detected between fresh DC and those derived from cryopreserved immature DC. Clinical administration of autologous DC by three different parenteral routes was tolerated by all 10 patients without systemic signs of toxicity. Our results indicate that immunomagnetic isolation of CD14(+) monocytes using the CliniMACS device is a suitable method for clinical-scale generation of functional DC under GMP-grade conditions. The selection can be performed in a closed system. Therefore, immunomagnetic CD14(+) selection can be seen as an alternative way to generate DC for clinical tumor vaccination protocols.

Adult↗

PubMed1998

Novel methods to monitor antigen-specific cytotoxic T-cell responses in cancer immunotherapy.

Monitoring cytotoxic T lymphocyte (CTL) responses to tumor antigens that have been defined at the molecular level has become essential to assess novel approaches to the specific immunotherapy of cancer. Nevertheless, because of the low affinity of the interactions between T-cell receptors and their ligands, there are no straightforward, well-standardized methods to meet this need. In this review, we describe several novel methods to track antigen-specific CTL responses.

Antigens, Neoplasm↗

PubMed2005

Inhibiting complement regulators in cancer immunotherapy with bispecific mAbs.

Although monoclonal antibody (mAb)-mediated immunotherapy of cancer has been proven to be feasible for clinical use, success rates until now have been disappointing. One reason for this might be the overexpression of membrane-bound complement regulatory proteins (mCRPs) by tumour cells. As complement activation is an important effector mechanism induced by therapeutic mAbs, inhibition of complement activation by tumour cells might reduce therapeutic efficacy by decreasing direct complement-mediated lysis as well as complement-dependent cellular cytotoxicity. Modulation of the function of these mCRPs might be achieved with therapeutic bispecific (bi-)mAbs that target a tumour antigen and simultaneously block a major mCRP. Clinical results will probably increase with such bi-mAbs compared with monovalent antitumour mAbs. In this review the feasibility of this approach is discussed.

Animals↗

PubMed1990

Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy.

Cells of the macrophage lineage are considered to be of special importance in the defense of the host against tumor development and spread. Immunotherapeutic strategies to stimulate macrophage (MAC) tumor cytotoxicity make use of activating compounds such as gamma-interferon which are given systemically. However, there are several lines of evidence that in malignant disease the generation of cytotoxic effector MACs is impaired. Both defective cell maturation and loss of responsiveness to activation are described. Here, a first clinical phase I trial of adoptive immunotherapy in cancer patients using autologous MACs generated in vitro from blood monocytes (MOs) is reported. Mononuclear cells were isolated by cytapheresis and density centrifugation and cultured in hydrophobic Teflon bags for 7 days with 2% autologous serum and recombinant human gamma-interferon being present for the last 18 h. Cytotoxic MO-derived MACs were then purified by countercurrent elutriation and reinfused into the patient. A total of 72 therapies have been performed with patients being treated i.v. (n = 8) and i.p. (n = 7). In vitro generated MACs proved to be mature as judged by the expression of maturation-associated surface molecules (MAX antigens, CD16, CD51, CD71), were cytotoxic to U937 tumor cells, and were efficient secretory cells. Cell dose escalation was performed in the first patients beginning with 10(8) MACs to finally infuse the total number of cells recovered from one single cycle of isolation and culture. MAC yield varied from 1 to 17 x 10(8) representing 13-79% of MOs initially seeded. Adoptive MAc transfer was well tolerated. Side effects observed were low-grade fever (less than 38.5 degrees C), induction of the coagulation cascade, and abdominal discomfort after i.p. application. The procoagulant activity of MAC autografts was cell dose dependent and demonstrated by detection of circulating fibrin monomers and thrombin-antithrombin complexes. Biological responses observed included elevated serum neopterin levels and the appearance of interleukin-6 in sera and ascitic fluids. Indication of a possible therapeutic effect was only observed in i.p.-treated patients and consisted of disappearance of malignant ascites in 2 of 7 patients.

Adult↗

PubMed2004

Role of 4-1BB:4-1BB ligand in cancer immunotherapy.

The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation. The CD28:B7 molecules are one of the best-studied costimulatory pathways, thought to be the main mechanism through which primary T-cell stimulation occurs. However, a number of molecules have been identified which serve to amplify and diversify the T-cell response, following initial T-cell activation. These include the more recently described 4-1BB:4-1BB ligand (4-1BBL) molecules. 4-1BB:4-1BBL are a member of the TNFR:TNF ligand family, which are expressed on T cells and antigen-presenting cells (APCs), respectively. Therapies utilizing the 4-1BB:4-1BBL signaling pathway have been shown to have antitumor effects in a number of model systems. In this paper, we focus on the 4-1BB:4-1BBL costimulatory molecules. In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer.

4-1BB Ligand↗

PubMed1990

Evaluation of the cardiovascular toxicity related to cancer immunotherapy with interleukin-2 by monitoring atrial natriuretic peptide secretion: a case report.

Increased capillary permeability and severe hypotension represent the two major cardiovascular complications of IL-2 immunotherapy. The mechanisms responsible for IL-2 cardiovascular toxicity are still obscure. Since increased vascular permeability and vasodilatation may be also induced by the cardiac hormone atrial natriuretic peptide (ANP), we have evaluated ANP concentrations in relation to mean arterial pressure in one patient with metastatic renal carcinoma, treated with a 24-h intravenous infusion of IL-2 at a dose of 3 x 10(6) Cetus U/m2/day for 5 days. The results showed that episodes of important hypotension were associated with abnormally high plasma levels of ANP. Owing to its vasodilator activity, exaggerated ANP secretion, perhaps due to an inappropriate cardiac endocrine function in response to hemodynamic changes induced by IL-2, may play a role in hypotension, which occurs during IL-2 immunotherapy for cancer.

Atrial Natriuretic Factor↗

PubMed2002

A mutated superantigen SEA D227A fusion diabody specific to MUC1 and CD3 in targeted cancer immunotherapy for bile duct carcinoma.

In cancer immunotherapy research, many bispecific antibodies (BsAbs) have been developed for directing T cells toward tumor cells. Recent advances in genetic engineering have made it possible to prepare immunoglobulin fragments consisting of variable domains using bacterial expression systems. Therefore, recombinant BsAbs, termed diabodies, have attracted particular attention. We have previously produced an anti-MUC1 x anti-CD3 diabody (Mx3 diabody) in an Escherichia coli ( E. coli) expression system. In order to reinforce the antitumor effects of the Mx3 diabody, mutated superantigen staphylococcal enterotoxin A (SEA) D227A was genetically fused to the Mx3 diabody. The SEA D227A fusion Mx3 diabody (SEA D227A-Mx3 diabody) thus constructed showed remarkable MUC1-specific antitumor effects when used with effector cells (lymphokine-activated killer cells with T-cell phenotype [T-LAK] and peripheral blood mononuclear cells [PBMCs]). In the bile duct carcinoma (BDC)-xenografted severe combined immunodeficient (SCID) mouse model, it also demonstrated strong antitumor activity when administered i.v. together with T-LAK cells and interleukin-2 (IL-2). In this experiment, the complete disappearance of tumors was observed in 3 out of 6 mice, and the other 3 showed marked retardation of tumor growth. Therefore, the SEA D227A-Mx3 diabody is considered to be a promising reagent in specific targeted immunotherapy for BDC and other MUC1-positive carcinomas. This is the first report on a diabody that is effective in treating human solid cancers in the xenografted SCID mouse experimental model.

Animals↗

PubMedDate not supplied

Cancer immunotherapy: hopes and pitfalls: a review.

Cancer immunotherapy (IT) started approximately 100 years ago with attempts to use a prepared immune serum against osteosarcoma. Since then, IT was attempted by use of various immunopotentiating agents like whole bacterial cells, bacterial cell fractions, cytokines and thymic humoral factors. The therapeutic efficiency of IT alone was limited and erratic. Accordingly, combined IT with other procedures were used. This included use of "immunomodulating" anticancer drugs as cyclophosphamide (CY) and melphalan (L-PAM) and use of IT in combination with tumor-reducing procedures like surgery, radiation and chemotherapy. The use of immunomodulating drugs was based on findings showing that CY and L-PAM enhance the ability of the immune system to react against tumor cells, in addition to their antitumor activity. Combined treatments were employed with the aim to reduce tumor-burden and as such, render IT more effective. Other therapeutic procedures consisted on use of specific antitumor antibodies as a vehicle for carrying radioactive lethal amounts to tumor cells, use of macrophages activated against tumor cells, use of prostaglandin antagonists and use of specific antitumor vaccines. The general conclusion is that while IT might have some beneficial therapeutic effect especially in conjunction with other procedures, it might be not sufficient to insure cure but it might increase the survival time and improve the quality of life of cancer patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

From pathogen to medicine: HIV-1-derived lentiviral vectors as vehicles for dendritic cell based cancer immunotherapy.

Over the years, the unique capacity of dendritic cells (DC) for efficient activation of naive T cells has led to their extensive use in cancer immunotherapy protocols. In order to be able to fulfil their role as antigen-presenting cells, the antigen of interest needs to be efficiently introduced and subsequently correctly processed and presented by the DC. For this purpose, a variety of both viral and non-viral antigen-delivery systems have been evaluated. Amongst those, HIV-1-derived lentiviral vectors have been used successfully to transduce DC. This review considers the use of HIV-1-derived lentiviral vectors to transduce human and murine DC for cancer immunotherapy. Lentivirally transduced DC have been shown to present antigenic peptides, prime transgene-specific T cells in vitro and elicit a protective cytotoxic T-lymphocyte (CTL) response in animal models. Different parameters determining the efficacy of transduction are considered. The influence of lentiviral transduction on the DC phenotype and function is described and the induction of immune responses by lentivirally transduced DC in vitro and in vivo is discussed in detail. In addition, direct in vivo administration of lentiviral vectors aiming at the induction of antigen-specific immunity is reviewed. This strategy might overcome the need for ex vivo generation and antigen loading of DC. Finally, future perspectives towards the use of lentiviral vectors in cancer immunotherapy are presented.

Animals↗