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M L Disis

Publications and source records attributed to M L Disis.

45 records · Page 3Linked to original sources
PubMed1995

Antibody to ras proteins in patients with colon cancer.

The current study examined sera from 160 colon cancer patients and 60 normal individuals to determine whether antibody to mutated p21 ras protein was present. Studies focused on the aspartic acid substitution at amino acid position 12 (denoted D12), one of the most common mutations in colon adenocarcinoma. IgA antibodies directed against mutated p21 ras-D12 protein were detected in 51 (32%) of 160 colon cancer patients, but only in 1 (2.5%) of 40 normal individuals. The greater incidence of antibody in cancer patients provides presumptive evidence that immunization to the ras proteins occurred as a result of the malignancy. Examination of sera for antibody reactivity to wild-type p21 ras protein (denoted p21 ras-G12) as well as p21 ras proteins bearing the D12, V12, S12, or L61 mutations showed that antibody detected was largely to normal segments of the p21 ras protein. Epitope mapping, using peptide neutralization assays with mutated or normal ras peptides as competitors, demonstrated that in 10 (67%) of 15 sera examined the antibody reactivity to p21 ras-G12 protein was neutralized by peptides near the carboxyl terminus of p21 ras protein, but not by peptides spanning the specific point mutation region. Antibody reactivities correlated with peripheral blood lymphocyte count, but did not correlate with patient age, sex, histology, stage, tumor locus, lymph node metastasis, or serum carcinoembryonic antigen.

Antibodies, Neoplasm↗
PubMed1994

In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein.

The development of T-cell therapy for the treatment of human malignancy has been hindered, in large part, by a lack of identifiable tumor antigens. Studies to identify potential T-cell targets in humans have been difficult because of practical problems limiting the use of in vivo immunization and a lack of reproducible in vitro priming methods. Oncogenic proteins are involved in malignant transformation and maintenance of the transformed phenotype and theoretically are potential targets to T-cell therapy. HER-2/neu protein is a protooncogene product overexpressed in a variety of human malignancies and is associated with malignant transformation and aggressive disease in human breast cancer. Previous studies have shown that some patients with breast cancer have existent helper/inducer T-cell immunity to p185HER-2/neu protein and peptides. The current study represents initial attempts to identify candidate cytotoxic T-lymphocyte (CTL) epitopes. Synthetic peptides were constructed identical to HER-2/neu protein segments with amino acid motifs similar to the published motif for HLA-2.1-binding peptides. Four peptides were synthesized and two were shown to be avid binders to HLA-A2.1. Two of the four peptides could be shown to elicit peptide-specific CTL by primary in vitro immunization in a culture system using peripheral blood lymphocytes from a normal individual homozygous for HLA-A2. p185HER-2/neu protooncogene protein contains immunogenic epitopes capable of generating human CD8+ CTL. The identification of candidate CTL epitopes will allow studies to determine whether some cancer patients have existent CTL immunity to HER-2/neu protein. The demonstrated ability to generate human peptide-specific CTL in vitro allows screening of other oncogenic proteins to identify candidate T-cell epitopes potentially useful for future immunotherapy studies.

Amino Acid Sequence↗
PubMed1994

Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer.

The HER-2/neu protooncogene is amplified and overexpressed in 20-40% of invasive breast cancers. HER-2/neu protein overexpression is associated with aggressive disease and is an independent predictor of poor prognosis in several subsets of patients. The protein may also be related to cancer formation, with overexpression being detectable in 50-60% of ductal carcinomas in situ. It has been suggested that it might be possible to develop specific T-cell therapy directed against proteins involved in malignant transformation. One question is whether normal proteins that are overexpressed are appropriate targets for therapeutic immune attack. This report demonstrates that some patients with HER-2/neu-positive breast cancers have both existent CD4+ helper/inducer T-cell immunity and antibody-mediated immunity to HER-2/neu protein. Initial studies performed on 20 premenopausal breast cancer patients identified antibodies to HER-2/neu in 11 individuals. Similar antibody responses have been found in some normal individuals. The patient with the greatest antibody response was studied in detail. In addition to a humoral immune response this patient had evidence of a significant proliferative T-cell response to the HER-2/neu protein and peptides. Similar T-cell responses have been detected in additional patients. It has been assumed that patients would be immunologically tolerant to HER-2/neu as a self-protein and that immunity might be difficult to generate. If immunity could be generated, the result might be destructive autoimmunity. The current data support the notion that HER-2/neu-specific immunity might be used in therapy without destroying normal tissue but also raises questions as to the role of existent immunity in immune surveillance and cancer progression.

3T3 Cells↗
PubMed1994

Immunity to the HER-2/neu oncogenic protein.

The study of oncogenic viruses led to the discovery that transforming retroviruses contain oncogenes homologous with and/or derived from cellular proto-oncogenes. In humans malignant transformation is often the result of the activation of proto-oncogenes. Normal proto-oncogenes can be activated to transforming proto-oncogenes by a variety of mechanisms including point mutation, translocation and amplification. Development of successful strategies for the immunotherapy of human cancers is an area of intense investigation. Part of the problem in developing cancer-specific immunotherapy has been the lack of well-defined tumour antigens. Our laboratory has focused on the question of whether oncogenic proteins expressed by transforming proto-oncogenes can serve as targets for immune attack. Some patients with HER-2/Neu-positive breast cancer have an existent immune response to the HER-2/neu protein with no clinical signs of autoimmunity, supporting the idea that overexpressed oncogenic proteins can be targeted in therapy without fear of destructive autoimmunity. The identification of candidate cytotoxic T lymphocyte epitopes might allow the generation of tumour-specific cytotoxic T lymphocytes for use in therapy and identify potential epitopes for peptide vaccines.

Amino Acid Sequence↗
PubMed1993

T-cell immunity to oncogenic proteins including mutated ras and chimeric bcr-abl.

The process of malignant transformation can be ascribed to a series of characteristics and definable mutations of genes which encode proteins that control cell growth and differentiation. During the course of malignant transformation the cancer-related genes are altered by a variety of mechanisms including translocations, deletions, and point mutations which commonly result in the expression of aberrant proteins. Our laboratory has focused on determining the extent to which cancer-specific proteins expressed by aberrant cancer-related genes can function as tumor-specific antigens. The current paper reviews our studies with two prototype cancer-specific proteins, mutated p21ras protein and chimeric p210bcr-abl protein. Ras protooncogenes are activated by point mutation in approximately 20% of human malignancies. The mutations occur primarily at codons 12 or 61 and result in the expression of p21ras proteins with single substituted amino acids. Only a limited number of amino acid substitutions occur. Murine studies demonstrate that immunization with synthetic peptides corresponding to the mutated segment can elicit both class II restricted CD4+ helper/inducer T-cell responses and class I restricted CD8+ cytotoxic T-cell responses specific for mutated p21ras protein. In addition, the existence in vivo of tumors expressing mutated ras proteins can be detected by assaying for T-cell immunity to the mutated segment of ras protein. Preliminary human studies show that some patients with colon cancer have existent antibody responses to p21ras protein, implying the possible existence of autochthonous T-cell immunity to mutated ras proteins in those patients. In chronic myelogenous leukemia the human c-abl protooncogene from chromosome 9 is translocated to the specific breakpoint cluster (bcr) region on chromosome 22. The translocation results in the formation of a bcr-abl fusion gene that encodes at 210-kD chimeric protein. The joining region segment of chimeric bcr-abl protein is composed of a unique combination of c-abl and bcr amino acids and is expressed only by malignant cells. Studies demonstrate that immunization of mice with synthetic peptides corresponding to the joining region segment can elicit class II restricted CD4+ T-cell responses to p210bcr-abl proteins. Preliminary studies show that bcr-abl peptides can bind in the groove of both murine and human class I MHC molecules and can elicit bcr-abl peptide-specific cytotoxic T lymphocytes (CTL). Whether bcr-abl peptide-specific CTL can lyse cells expressing bcr-abl protein is a yet unknown. In summary, the results of the studies reviewed confirm that cancer-specific oncogenic proteins can serve as tumor-specific antigens.

Animals↗
PubMed1993

Induction of T cells specific for the mutated segment of oncogenic P21ras protein by immunization in vivo with the oncogenic protein.

Many malignancies harbor mutated ras proto-oncogenes encoding 21 kDa proteins with single amino acid substitutions. Previous studies have shown that the aberrant p21ras proteins are potential tumor-specific antigens in that CD4+ class II major histocompatibility complex-restricted T cells specific for the mutated segment of various oncogenic p21ras proteins can be elicited by immunization in vivo with synthetic peptides corresponding to the mutated segment. T-cell recognition of an antigenic peptide within a protein may be influenced substantially, either positively or negatively, by flanking amino acid sequences as well as by more distal immunogenic or tolerogenic epitopes within the same protein. This study examined whether T cells specific for the mutated segment of an oncogenic p21ras protein can be elicited by immunization in vivo with the protein. The results showed that p21ras protein bearing the transforming single amino acid substitution of leucine for glutamine at residue 61 could elicit T cells specifically reactive to the mutated region of the protein in C3H/HeN mice. Thus, an abnormal p21ras protein specifically associated with malignant transformation can be immunogenic in vivo. These results predict that in some circumstances, mutated p21ras proteins expressed by malignancies might elicit detectable mutation-specific T-cell responses.

Amino Acid Sequence↗
PubMed1986

Circulating immune complexes in cystic fibrosis and their correlation to clinical parameters.

Circulating immune complexes (CIC) have been found to be elevated in individuals with cystic fibrosis (CF). Previous investigators, using a variety of assays, have reported high levels of CIC in as many as 86% of these patients. Our study followed the progress of 25 patients with CF over a period of 10 months to determine which, if any, clinical parameters correlated with the occurrence and/or concentration of CIC. Immune complex determinations were performed using a coprecipitation method with equine rheumatoid-complement complex. One hundred percent of the CF patients had CIC elevated above normal levels, however, levels of CIC did not correlate with the severity of an individual's acute exacerbation. Clinical parameters including pulmonary function tests, vital signs, total serum IgG levels, and other laboratory studies, were obtained on each individual and analyzed with respect to their relationship to CIC. Only four of 38 parameters examined had p less than 0.05. Factors that showed significant correlation to elevated CIC's in the highly elevated portion of our CIC population were poor NIH score, increased patient age, low peak expiratory flow rate, and elevated total serum IgG. These clinical values are associated more with the measurement of chronic disease. These data suggest that CICs cannot be used as an indication of short-term prognosis or as a monitor to follow the course of acute severe lung infections in the CF patient. Of interest was the observation that all patients who died during the course of the investigation had CIC levels greater than 80 micrograms/ml.

Adolescent↗
PubMedDate not supplied

Progress in ovarian cancer research: proceedings of the 5th Biennial Ovarian Cancer Research Symposium.

Ovarian cancer remains the most lethal gynecological malignancy. The 5th Biennial Symposium overviewed the progress of ovarian cancer research over the last few years. Molecularly based technologies have allowed the identification of multiple biomarkers to aid in ovarian cancer diagnosis and treatment. Furthermore, data analysis systems evaluating the behavior of these markers have been designed. Therapeutic use of ovarian cancer protein markers has been fueled by the development of animal models that more closely simulate the pathogenesis of ovarian cancer, and multiple new therapies are being developed that may have impact against the disease. Finally, the design of clinical trials both for ovarian cancer treatment and prevention are key in advancing the science of ovarian cancer into the clinic. The need for strategies that would optimize patient participation in clinical trials is paramount.

Biomarkers, Tumor↗