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At least 217 records · Page 12Linked to original sources
PubMed1997

[Newly-developing therapies of pancreatic cancer--immunotherapy, gene therapy, differentiation therapy, endocrine therapy and others].

Pancreatic cancer is extremely resistant to various cancer therapies, however, variety of new therapies for pancreatic cancer have been investigated: (1) immunotherapy including cytokines like TNF, adoptive immunotherapy with lymphokine-activated killer cells or cytotoxic T-lymphocytes, and tumor vaccines using mutated Ki-ras oncoprotein or irradiated tumor cells which were transfected by cytokine genes; (2) gene therapy including transfer of cytokine genes or antisense Ki-ras oncogene, and a combination of gene transfer of herpes simplex virus thymidine kinase and subsequent administration of ganciclovir; (3) differentiation therapy including a quinolinone derivative, vesnarinone; (4) endocrine therapy including cholecystokinin-receptor antagonist, CR1505 or L364,718; (5) heavy water, and etc. All of these therapies will be applied for the treatment of pancreatic cancer in the near future.

Animals↗
PubMed1997

HLA and cancer: implications for cancer immunotherapy and vaccination.

Both animal models and studies in humans indicate that the immune response has enormous potential for the treatment of cancer, and that HLA plays a central role in this. This role is likely to become increasingly important in years to come, as effective strategies for immunotherapy of cancer are developed. In the last few years, much of the focus of tumour immunology has been on the identification and characterization of tumour-associated antigens that represent HLA-restricted tumour-specific targets. In the next few years the emphasis is likely to change, such that the HLA type and antigen profile of an individual's tumour may define the most appropriate form of therapy for the patient. The ability of tumour cells to down-regulate or lose expression of some or all HLA molecules may prove to be a major barrier to the effectiveness of such treatments. The next few years should show whether the potential of the advances in tumour immunology made over the last decade can be realized, or whether the application of these advances as therapeutic strategies falls short of their promise.

Antigens, Neoplasm↗
PubMed2000

Cancer immunotherapy in clinical oncology.

The identification of tumor-associated antigens recognized by cellular or humoral effectors of the immune system has opened new perspectives for cancer therapy. Different groups of cancer-associated antigens have been described as targets for cytotoxic T lymphocytes (CTLs) in vitro and in vivo: 1) cancer-testis (CT) antigens, which are expressed in different tumors and normal testis; 2) melanocyte differentiation antigens; 3) point mutations of normal genes; 4) antigens that are overexpressed in malignant tissues; and 5) viral antigens. Clinical studies with peptides derived from these antigens have been initiated to induce specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined, i.e., delayed-type hypersensitivity (DTH), CTL, autoimmmune, and tumor regression responses. Preliminary results demonstrate that tumor-associated peptides alone elicit specific DTH and CTL responses leading to tumor regression after intradermal injection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was proven effective in enhancing peptide-specific immune reactions by amplification of dermal peptide-presenting dendritic cells. Long-lasting complete tumor regressions have been observed after induction of peptide-specific CTLs. However, in single cases with disease progression after an initial tumor response, either a loss of the respective tumor antigen targeted by CTLs or of the presenting major histocompatibility complex (MHC) class I allele was detected as a mechanism of immune escape under immunization. Based on these observations, cytokines to enhance antigen and MHC class I expression in vivo are being evaluated to prevent immunoselection. Recently, a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1, which is regarded as one of the most immunogenic antigens known today inducing spontaneous immune responses in 50% of patients with NY-ESO-1-expressing cancers. Clinical studies involving antigenic constructs that induce both antibody and CTL responses will show whether these are more effective for immunotherapy of cancer.

Animals↗
PubMed2006

Glycoprotein A34, a novel target for antibody-based cancer immunotherapy.

To identify novel, tissue-restricted cell surface proteins in cancer which can serve as targets for antibody-based diagnostics and therapeutics, a translated version of the expressed sequence tag database (tblastn) was mined for transcripts with similarity to the glycoprotein A33 (GPA33) colon cancer antigen. A novel human transcript, termed A34, was identified which encoded a putative cell surface protein, GPA34, which is approximately 30% identical to GPA33 and other members of the junctional adhesion molecule (JAM) family. Conventional end-point and quantitative real-time RT-PCR showed that A34 mRNA expression is highly tissue-restricted, as it is expressed predominantly in stomach and testis. A34 mRNA was also detected in 6/19 (31%) gastric cancers, 8/16 (50%) esophageal carcinomas, and 4/17 (23%) ovarian cancers, but not in lung, breast or colon carcinomas. A murine monoclonal antibody (mAb A34) was generated to the extracellular domain of the A34 protein and used to biochemically and immunohistochemically characterize the A34 antigenic system. The mAb A34 specifically recognized glycoproteins ranging in apparent size from 55-70 kDa, present in normal gastric mucosa and in COS-7 cells transfected with A34 cDNA. Of 31 different normal tissues examined by immunohistochemistry, GPA34 protein expression was detected primarily in normal stomach mucosa and testicular germ cells, and in the tumor cells of 5/17 (29%) gastric cancers, 7/11 (63%) esophageal cancers, and 2/21 (9%) ovarian cancers, in agreement with gene expression results. The A34 antigen and monoclonal antibody may be of considerable value for immunotherapy of different types of cancer.

Amino Acid Sequence↗
PubMed2004

Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer.

Immunotherapy using adoptive cell transfer is a promising approach that can result in the regression of bulky, invasive cancer in some patients. However, currently available therapies remain less successful than desired. To study the mechanisms of action and possible improvements in cell-transfer therapies, we use a murine model system with analogous components to the treatment of patients. T cell receptor transgenic CD8+ T cells (pmel-1) specifically recognizing the melanocyte differentiation antigen gp100 are adoptively transferred into lympho-depleted mice bearing large, established, 14-day subcutaneous B16 melanoma (0.5-1 cm in diameter) on the day of treatment. Adoptive cell transfer in combination with interleukin interleukin-2 or interleukin-15 cytokine administration and vaccination using an altered form of the target antigen, gp100, can result in the complete and durable regression of large tumor burdens. Complete responders frequently develop autoimmunity with vitiligo at the former tumor site that often spreads to involve the whole coat. These findings have important implications for the design of immunotherapy trials in humans.

Adoptive Transfer↗
PubMed2006

Nonviral transfection of human umbilical cord blood dendritic cells is feasible, but the yield of dendritic cells with transgene expression limits the application of this method in cancer immunotherapy.

Dendritic cells (DC) generated from human umbilical cord blood might replace patients' DC in attempts to elicit tumor-specific immune response in cancer patients. We studied the efficiency of transfection of human cord blood DC with plasmid DNA carrying the enhanced version of green fluorescent protein (EGFP) as a reporter gene, to test if nonviral gene transfer would be a method to load DC with protein antigens for immunotherapy purposes. Cord blood mononuclear cells were cultured in serum-free medium in the presence of granulocyte-monocyte colony stimulating factor (GM-CSF), stem cell factor (SCF) and Flt-3 ligand (FL), to generate DC from their precursors, and thereafter transfected by electroporation. Maturation of DC was induced by stimulation with GM-CSF, SCF, FL and phorbol myristate acetate (PMA). Transfected DC strongly expressed EGFP, but transfection efficiency of DC, defined as HLA-DR(+) cells lacking lineage-specific markers, did not exceed 2.5%. Expression of the reporter gene was also demonstrated in the DC generated from transfected, purified CD34(+) cord blood cells, by stimulation with GM-CSF, SCF, FL, and tumor necrosis factor alpha (TNF-alpha). Transfection of CD34(+) cells was very efficient, but proliferation of the transfected cells was much reduced as compared to the untransfected cells. Therefore, the yield of transgene-expressing DC was relatively low. In conclusion, nonviral transfection of cord blood DC proved feasible, but considering the requirements for immunotherapy in cancer patients, transfection of differentiated DC or generation of DC from transfected hematopoietic stem cells provide only a limited number of DC expressing the transgene.

Antigens, CD34↗
PubMedDate not supplied

NY-ESO-1 may be a potential target for lung cancer immunotherapy.

PURPOSE: To evaluate the frequency of NY-ESO-1 expression in cultured lung cancer cells and to determine if this cancer-testis antigen can be presented for recognition by an HLA-restricted cytolytic T-cell clone specific for NY-ESO-1. METHODS AND RESULTS: Reverse transcriptase and polymerase chain reaction amplification techniques were utilized to screen a panel of lung and esophageal cancer cell lines for expression of NY-ESO-1 encoding a recently identified cancer-testis antigen. NY-ESO-1 expression was detected in 11 of 16 small cell lung cancer lines, three of seven non-small cell lung cancer lines, and zero of 12 esophageal cancer lines. 5-Aza-2' -deoxycytidine induced expression of NY-ESO-1 in lung cancer cells. Expression of HLA-A31 by plasmid transfection or retroviral transduction enabled recognition of lung cancer cells by an HLA-A31-restricted cytotoxic T lymphocyte clone specific for NY-ESO-1. CONCLUSIONS: NY-ESO-1 expression may be analogous to MAGE gene expression in lung cancer lines in terms of frequency and mechanism of transcriptional regulation. Furthermore, NY-ESO-1 can be presented on lung cancer cells for recognition by HLA-restricted cytotoxic T lymphocytes. Further investigation is warranted to determine if NY-ESO-1 can be exploited for the immunotherapy for lung cancer.

Antigens, Neoplasm↗
PubMed1999

Mimotopes of cytolytic T lymphocytes in cancer immunotherapy.

Rapid identification of the cytolytic T lymphocyte (CTL) epitopes that are presented by cancer cells will provide the basis for manipulation of tumor immunity but remains a major challenge in the field. By screening randomly synthesized peptide libraries, mimotopes for tumor-reactive CTLs can be readily constructed and they may be functionally equal to or potentially more potent than natural peptides in stimulating CTL responses; therefore, the peptide library approach provides great promise for design of cancer vaccines and adoptive tumor immunotherapy.

Animals↗
PubMed1996

Breast cancer immunotherapy: current status and future prospects.

The development of an immunotherapeutic approach to cancer is the concern for many immunologists, but despite the impressive progress over the past decade, such as the identification of tumour antigens and antigenic peptides as potential targets, there are still many obstacles in eliciting an effective immune response to eradicate cancer. Mucins have attracted interest as potential targets for immunotherapy in the development of vaccines for cancers expressing Mucin1 (MUC1; e.g. breast, pancreas, ovary etc.). All of the identified targets for cancer, including MUC1, are normal proteins; however MUC1 expressed on tumours can be considered as tumour specific due to their overexpression, altered glycosylation and its ubiquitous distribution on the cell surface rather than at the secretory pole in adenocarcinomas. These observations have led to the development of several different approaches to immunize against breast cancer using synthetic carbohydrates or peptides conjugated to carriers and given together with a variety of adjuvants to elicit the appropriate immune response. Mannan, a polymannose carbohydrate isolated from the cell wall of yeast, is an appropriate and effective protein carrier for eliciting a cellular (T1-type) or humoral (T2-type) immune response depending on the mode of conjugation (oxidized or reduced). In addition, mannan holds promise and opens many avenues as a carrier for vaccine development for other antigens. Several clinical trials are in progress to evaluate the immunogenicity of MUC1 and its suitability as to use for immunotherapy/vaccine for breast cancer.

Animals↗
PubMed1997

Common cancers--immunotherapy and multidisciplinary therapy: Parts III and IV.

The refractoriness of many solid tumors to cytotoxic chemotherapy has led to the exploration of new therapeutic modalities, including immunotherapy. Immunotherapy does not have a direct cytotoxic effect on the cancer cell but is an attempt to promote rejection of the tumor by the host, chiefly through the cellular arm of the immune system. The clinical success with immunotherapy (primarily adoptive immunotherapy) among patients with unresectable malignant melanoma and cancer of the kidney has not been marked by the large numbers of patients responding but by occasional dramatic effectiveness of therapy for these cancers, which usually are refractory to chemotherapy. Long-lasting responses and even complete disappearance of all known metastases are possible for a small percentage of patients with melanoma or renal cell carcinoma who undergo immunotherapy. A reasonable approach for patients with good performance status (no symptoms or ambulatory with symptoms but not bedridden) is entrance to clinical trials, especially trials examining adoptive or active immunotherapy for melanoma or adoptive immunotherapy for renal cancer. The overall treatment of patients with cancer has changed. Primary-care physicians detect almost all cancers. The days when "taking it out" is the best we could offer a patient are over. As we learn more about the use of adjuvant or neoadjuvant chemotherapy and radiation therapy, it is likely one or both of these modalities will be incorporated into the treatment of additional solid tumors previously managed solely with surgical resection. Increasingly, additional therapy is being given for earlier-stage disease as we define how to maximize the potential for cure with minimal toxicity. Many new therapies are on the horizon, including the use of noncytotoxic treatments as an adjunct to a surgical procedure. Such therapies include the use of angiogenesis inhibitors, tumor vaccines, and immunotherapy. Now and in the future, patients will be best served when treated in an environment that can integrate medical, surgical, and radiation oncology actively.

Breast Neoplasms↗
PubMed1987

Identification and expansion of human lymphokine-activated killer cells: implications for the immunotherapy of cancer.

Immunotherapy with lymphokine-activated killer (LAK) cells and interleukin 2 (IL-2) has been demonstrated to cause the regression of some human tumors. Expansion of peripheral blood lymphocytes (PBL) in recombinant or naturally produced IL-2, mitogens, and feeder cells results in a progressive expansion of cell number but a decline in lytic activity with time. Lytic activity for fresh tumor is best generated in IL-2 alone from specific purified subpopulations of lymphocytes. The precursor of the LAK cell has been isolated from a nonadherent, sheep erythrocyte receptor negative (E-) lymphocyte subpopulation by the selection of Leu 11+ and Leu 15+ cells by cell sorting. Separation resulted in a significant increase (P2 less than 0.05) in lytic activity against fresh tumor by the separated 11+15+ lymphocytes compared to the 11-/15- lymphocytes or PBL. Leu 11+/15+ lymphocytes could be expanded up to eightfold in IL-2 alone with maintenance of lytic activity. We identified two surface antigens on the LAK precursor cell, Leu 15 and Leu 11, and demonstrated a technique for obtaining purified populations of these cells. Purified and expanded LAK cells when administered to patients may have a role in increasing the potency and decreasing the toxicity associated with this therapy.

Cell Division↗
PubMed1998

p53-based immunotherapy of cancer.

Immunotherapy targeting p53 missense mutations, which occur in nearly half of all human tumors, is limited by several factors, including the constraints of antigen processing and presentation. Due to the accumulation of mutated p53 molecules in tumors expressing p53 mutations, an alternative approach would be to target wild-type sequence, CTL-defined p53 epitopes. Obviously, the possibility of an autoimmune response is a major potential drawback to this therapy. Immunization of BALB/c mice with bone marrow-derived dendritic cells (DC) generated in the presence of GM-CSF/IL-4 and prepulsed with the H-2Kd-binding wild-type p53(232-240) peptide has been shown to induce anti-peptide CTL. These effectors were cross-reactive against sarcomas expressing p53 missense mutations outside of the p53(232-240) epitope, but not within it. Mitogen-activated splenocytes, which express elevated levels of p53, were not sensitive to these CTL. The p53 peptide-pulsed DC-based vaccine was shown to be effective in inducing tumor rejection in immunization and therapy models in the absence of any observable deleterious effect on naive mice. The murine model has now been extended to include the use of genetically modified DC-based vaccines as well.

Animals↗
PubMed2000

Prostate cancer immunotherapy at the dawn of the new millennium.

Standard treatments for adenocarcinoma of the prostate, such as surgery, hormones, radiation and chemotherapy, often achieve a clinical response, but this is usually short-lived. Prostate cancer frequently recurs and second-line therapies have a poor response rate. Many clinicians seem comfortable in limiting their philosophy of treating advanced recurrent disease merely to new regimens of failed therapies, such as combination chemotherapy. However, other medical researchers have chosen to pursue novel approaches, including immunotherapy, several of which are summarised in this review. Although ranging widely in antigen specificity, all attempt to exploit the body's natural antitumour immunity. Furthermore, all aim to stimulate immunity above a threshold level necessary for tumour regression or to induce stability in the face of progression. The goal of in vivo or ex vivo gene therapy is the modification of gene expression within an antigen-presented cell by the introduction of a vector, DNA, or RNA. Within that field, much progress has been made and is ongoing currently concerning gene delivery systems, target identification and characterisation. Comparatively, monoclonal antibodies are an established type of cancer immunotherapy. However, the more recent development of humanized or fully human antibodies, as well as novel moieties they can be coupled to, renews their prospects for clinical impact. Lastly, various cell-based therapies are the focus of several recent clinical studies demonstrating tumour regression or stabilisation. Immune cells, for example, T-lymphocytes and dendritic cells, have already demonstrated treatment benefit, as well as the ability to maintain an excellent quality of life for participants. Overall, there is a multitude of approaches being considered for the treatment of prostate cancer. The following review concentrates on those approaches that are currently in human or animal studies and have a specific emphasis on prostate cancer.

Adenocarcinoma↗
PubMed2001

[Cancer immunotherapy in head and neck region].

There is no one common immunotherapy for the treatment of head and neck cancer (H&N cancer). A streptococcal agent, OK-432, which is classified as a biological response modifier (BRM), is occasionally used by means of local administration for recurrent H&N cancer, and the response rate is approximately 18%. In regard to specific immunotherapy, a murine monoclonal antibody (named mAb 225) against the epidermal growth factor receptor (FGFR) that is frequently overexpressed in H&N cancer has been produced in the U.S.A. Furthermore, to obviate human anti-mouse antibody responses, a chimeric human-to-murine version of mAb 225 (C225) was developed by exchanging the constant regions of mAb 225 to counterparts in human immune globulin. Phase I clinical trials of C225 in the U.S.A. demonstrated that treatment with C225 was well tolerated and that C225 given in combination with cisplatin has biologic activity. On the other hand, many tumor antigens recognized by cytotoxic T lymphocytes (CTL) have been identified from a variety of malignant tumors and some of them, including the MAGE-3 antigen, are frequently expressed in H&N cancer. We identified an MAGE-3-derived epitope recognized by HLA-A24-restricted CTL from peripheral blood mononuclear cells (PBMC). In contrast we failed to generate CTL specific for MAGE-3+/HLA-A24+ tumors from PBMC in any of 5 HLA-A24+ cancer patients whose tumors expressed the MAGE-3 gene. Therefore, we did not apply MAGE-3-derived CTL epitope in clinical uses such as peptide vaccine and peptide pulsed dendritic cell infusion for H&N cancer.

Antibodies, Monoclonal↗
PubMed1997

p53 as a target for anti-cancer immunotherapy.

The key to specific and non-toxic cancer therapy is likely to be identification and targeting of processes that are absolutely unique to the tumor. One such approach is to target cells expressing mutations in the oncoproteins that led to the development of the cancer, such as p53. In animal model systems, highly mutant p53-specific cytotoxic T cells can be induced, but it remains to be seen whether this can be translated into clinical practice, and what proportion of tumors will respond. In this review, the potential and problems of immunological targeting of mutant p53 in solid tumors are discussed.

Animals↗
PubMed1984

[Cancer immunotherapy].

A revision of the most promising clinical assays suggest that immunotherapy is useful for a certain number of selected patients. Immunotherapy cannot be used alone for primary treatment of cancer, excepting perhaps as local immunotherapy for readily accessible tumors. The most important role of immunotherapy is to be found in combination with other kinds of therapy, considering that it may restrain effectively hidden micrometastases that are the cause of relapse and fatal outcome. However, it is necessary to recognize that immunotherapy has shown until now a limited therapeutic efficacy.

Adjuvants, Immunologic↗