Biomedical subjects

N Berinstein

Publications and source records attributed to N Berinstein.

11 recordsLinked to original sources

PubMed2001

Therapeutic vaccines against melanoma and colorectal cancer.

Our overall strategy is to develop multivalent recombinant vaccines capable of eliciting broad immune responses in patients with malignant melanoma or colorectal cancer. We report herein results from initial studies conducted in cancer patients to evaluate the effect of intratumoral administration of recombinant canarypox viruses carrying cytokine genes. Our current focus is on the induction of tumor-specific T-cell responses using a prime/boost immunization schedule with a unique vector system derived from the canary pox virus called ALVAC, in which we incorporate genes encoding Tumor Associated Antigens (TAAs) of interest. Clinical studies in colorectal cancer evaluating an ALVAC CEA candidate vaccine have shown that this approach is safe and can induce tumor-specific T cell responses. Additional clinical studies evaluating candidate vaccines against melanoma and colorectal cancer, targeting either the gp100, Mage 1, Mage 3 or p53 molecules are ongoing.

Antigens, Neoplasm↗

PubMed2000

Risk-adapted therapy for clinical stage I-II Hodgkin's disease: 7-years results of radiotherapy alone for low-risk disease, and ABVD and radiotherapy for high-risk disease.

Treatment outcomes were documented for 204 adult patients with clinical Stage I-II Hodgkin's disease who were treated with risk-adapted ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and radiotherapy (RT) at the Toronto-Sunnybrook Regional Cancer Centre between 1984 and 1994. Forty-nine patients with clinical Stage I disease (excluding bulky mediastinal presentations) and 50 patients with a combination of clinical Stage IIA disease, age 50 years or less, and favourable pathology (lymphocyte predominant or nodular sclerosing histology) were identified as low risk and treated with RT alone to 35 Gy. One hundred and five high-risk patients were treated with chemotherapy (86 with ABVD) followed by RT to 25 Gy. The 7-year cause-specific, overall and disease-free survivals were 95%, 90% and 75% respectively for the low-risk cohort, and 91%, 90% and 88% respectively for the high-risk cohort. In-field relapses accounted for 50% of the failures in both groups. Sixteen of 24 (67%) patients with RT failure and 6/14 (43%) with combined modality therapy (CMT) failure were salvaged. Twenty-eight per cent of the patients treated with RT and 21% of those treated with CMT developed hypothyroidism by 7 years. Fatal complications were recorded in 6% of the low-risk patients managed with RT and 8% of high-risk patients managed with CMT. Septic death and second malignancy accounted for the majority of treatment-related fatalities. Risk-adapted therapy emphasizing RT alone for selected patients with favourable prognostic factors and CMT based on ABVD provides excellent long-term disease control. Further treatment refinements, including the wider application of CMT with lower doses of chemotherapy and RT, will be required to reduce the rate of fatal complications to more acceptable levels.

Adult↗

PubMed2000

Primary Hodgkin's disease of the CNS in an immunocompetent patient: a case study and review of the literature.

Primary Hodgkin's disease limited to the CNS is exceedingly rare. Little is known regarding etiologic risk factors, optimal management, and prognosis. A case of Hodgkin's disease confined to the CNS, with cerebrospinal fluid negative for cytology, is described in an immunocompetent patient previously treated for hyperthyroidism with 131I. The patient underwent craniotomy, with resection of two lesions in close proximity within the parenchyma of the temporoparietal lobe. Histopathology revealed classic nodular sclerosing Hodgkin's disease, without evidence of Epstein-Barr viral infection. Treatment included radiation to the whole brain with a boost to the tumor bed. The patient made a full neurologic recovery and remains free of disease recurrence 21 months after treatment. A literature review has identified only 9 additional cases. Seven of 8 evaluable patients remain alive and free of recurrence with a median follow-up of 13 months. The risk factors for this presentation remain undefined. Although follow-up is short, radiotherapy alone appears to provide excellent disease-free survival. Chemotherapy may be reserved for patients with positive cerebrospinal fluid, extracranial disease, or subsequent relapse.

Brain Neoplasms↗

PubMed1992

Gene replacement with one-sided homologous recombination.

Homologous recombination is now routinely used in mammalian cells to replace endogenous chromosomal sequences with transferred DNA. Vectors for this purpose are traditionally constructed so that the replacement segment is flanked on both sides by DNA sequences which are identical to sequences in the chromosomal target gene. To test the importance of bilateral regions of homology, we measured recombination between transferred and chromosomal immunoglobulin genes when the transferred segment was homologous to the chromosomal gene only on the 3' side. In each of the four recombinants analyzed, the 5' junction was unique, suggesting that it was formed by nonhomologous, i.e., random or illegitimate, recombination. In two of the recombinants, the 3' junction was apparently formed by homologous recombination, while in the other two recombinants, the 3' junction as well as the 5' junction might have involved a nonhomologous crossover. As reported previously, we found that the frequency of gene targeting increases monotonically with the length of the region of homology. Our results also indicate that targeting with fragments bearing one-sided homology can be as efficient as with fragments with bilateral homology, provided that the overall length of homology is comparable. The frequency of these events suggests that the immunoglobulin locus is particularly susceptible to nonhomologous recombination. Vectors designed for one-sided homologous recombination might be advantageous for some applications in genetic engineering.

Blotting, Southern↗

PubMed1992

Lymphadenopathy, oligoclonal T cell receptor rearrangement and systemic lupus erythematosus.

To investigate the cause of generalized lymphadenopathy in case of systemic lupus erythematosus (SLE), we performed a molecular genetic analysis of lymph node, peripheral blood mononuclear cell and bone marrow specimens with T cell receptor and immunoglobulin gene probes. Oligoclonal T cell receptor rearrangements were detected in the lymph node cells. The oligoclonal T cell expansion observed is the first such example reported in SLE, and may be indicative of an immune response to specific antigenic challenge. Alternatively, these changes may represent the earliest phases of a malignant process. Molecular genetic investigations in autoimmune disease such as SLE can provide opportunities to enhance our understanding of the underlying condition, or reveal unexpected abnormalities requiring further assessment.

Blotting, Southern↗

PubMed1990

Idiotypic variation in a human B lymphoma cell line.

The Ig Id of a B cell lymphoma serves as a distinct marker of the malignant clone and thus as a tumor-specific target for antibody therapy. Somatic variation of the Ig genes expressed by B cell tumors can lead to loss of reactivity with anti-Id antibodies and escape of tumors from the therapeutic effects of such antibodies. In our study, we have used anti-Id antibodies to screen for variants within a cell line derived from a patient with a large cell lymphoma of the B cell type. Cells were simultaneously stained on their surface for idiotypic and for isotypic Ig determinants using reagents labeled with different fluorochromes. Tumor cells expressing intact Ig molecules with alteration of their idiotypic determinants were isolated with the fluorescence activated cell sorter. Idiotypic variation was an ongoing process in vitro with Id- variants being generated at a rate of 2.7 x 10(-4)/cell per generation and Ig- cells being produced at a rate of 1.31 x 10(-5)/cell per generation. Subcloned variants expressed subtle differences in reactivity with a panel of three non-cross-blocking anti-Id antibodies. Analysis of Ig gene rearrangements by the Southern blotting technique using a JH probe established that the variants and the original tumor cells were all clonally related. Immunoprecipitation of surface labeled Ig molecules from the variant subclones disclosed major alterations of the lambda-L chains with no gross alterations of the mu-H chains. Related studies have established that the tumor cells undergo rearrangement and expression of new lambda-L chain genes.

Antibodies, Anti-Idiotypic↗

PubMed1990

Oncogene involvement in lymphoid malignancy.

Several nonrandom chromosomal translocations that occur in T and B cell malignancy have been shown to involve the juxtaposition of a putative proto-oncogene and one of the antigen receptor genes. Cloning studies of several of these breakpoints have helped to elucidate the structural basis of some of these chromosomal translocations as well as the molecular characteristics of some of the proto-oncogenes. One of the most studied proto-oncogenes is BCL2, frequently involved in a translocation in B cell lymphomas. Several biological studies of the expression of this proto-oncogene in cell lines and/or transgenic mice have shown that it is one of the factors which can induce lymphoid proliferation and may thus be an important etiologic factor in the generation of B cell lymphoma. Cloning studies of these chromosomal breakpoints have led to the application of molecular genetic techniques for the diagnosis and detection of expression of these proto-oncogenes. Further study of these oncogenes is required to establish their role in tumorigenesis and their usefulness in clinical practice.

Animals↗

PubMed1989

Activation of an excluded immunoglobulin allele in a human B lymphoma cell line.

Mature B cells that express surface immunoglobulin (Ig) are usually committed to their original Ig product. It was shown that such a cell can replace its light chain by rearranging and expressing a new light chain from the other allele. Anti-idiotype antibodies were used to isolate idiotypic variants from a surface IgM+lambda+ human B cell tumor line. The variants expressed a new lambda light chain. Both the original and the new lambda transcripts were present in the variant cells, but only the new one was expressed as a protein on the cell surface. Therefore, although the cell exhibited allelic exclusion and had only one Ig receptor at a time, the commitment to a particular light chain gene was reversible.

Alleles↗

PubMed1988

Specific enhancement of the therapeutic effect of anti-idiotype antibodies on a murine B cell lymphoma by IL-2.

We have previously reported on the augmentation of monoclonal anti-Id antibodies by IL-2 in the therapy of a murine B cell lymphoma. The mechanism of this augmentation was through the expansion by IL-2 of effector cells mediating antibody-dependent cellular cytotoxicity. In this paper we explore the power of IL-2 to enhance anti-Id therapy on larger tumor burdens and at sites distant from the site of injection. The combination treatment was able to induce regression of established 1-cm s.c. tumors associated with microscopic metastatic tumor in lungs, liver, and spleen. Further studies into the mechanism of activity showed that IL-2 was unable to augment in vivo or in vitro tumor lysis by F(ab')2 fragments, thus emphasizing the importance of Fc interactions with antibody-dependent cellular cytotoxicity effector cells. FcR-bearing NK cells were increased in the peritoneum of IL-2-treated mice. The augmented therapeutic effect by the combination treatment was specific for tumor cells expressing the target Id, and non-specific cytotoxicity on Id-negative variants was not seen.

Animals↗

PubMed1987

Antibody-directed targeting of liposomes to human cell lines: role of binding and internalization on growth inhibition.

Small unilamellar liposomes containing methotrexate or methotrexate-gamma-aspartate were conjugated to Staphylococcus aureus protein A and were thus able to bind cell-specific immunoglobulins for targeting to malignant human B- and T-cell lines. We were able to demonstrate enhanced protein A liposome uptake and growth inhibition by targeting with an anti-major histocompatibility complex class II antibody recognizing two different B-cell lines. The enhanced growth inhibition was specific for the targeting antibody and amounted to a 2- to 3-fold lowering of the concentration of drug required to inhibit cell growth by 50% as compared to nontargeted liposomes or liposomes targeted with an antibody not recognizing a cell surface antigen. A strong association between enhanced growth inhibition and liposome internalization as assessed by fluorescent-activated cell sorter analysis of carboxyfluorescein containing protein A liposomes was seen. By contrast, specific enhancement of growth inhibition was not seen with several anti-idiotype antibodies or antibodies to T-cell differentiation antigens. Liposome internalization did not occur with these antibodies. Failure of growth inhibition and PA liposome internalization could not be explained by differences in cell binding of the antibody PA liposomes or the degree of protein A binding of the targeting antibody. Although the ability of the targeting antibody to bind to the cell and to protein A are important, these factors alone are not sufficient to guarantee internalization and growth inhibition. Variations in rates of internalization of various cell surface antigen-antibody complexes may account for different protein A liposome mediated cytotoxicities.

Animals↗

PubMed1987

Treatment of a murine B cell lymphoma with monoclonal antibodies and IL 2.

A transplantable murine B cell lymphoma was used to study combination therapy with anti-idiotype antibody and interleukin 2 (IL 2). Class-switched IgG2a and IgG2b antibodies were compared. A marked additive and sometimes synergistic effect was seen when IL 2 was combined with either IgG2a or IgG2b anti-idiotype antibodies. A synergistic effect was also seen when similar experiments were performed in nude mice. In vitro antibody-dependent cellular cytotoxicity (ADCC) assays showed that IL 2 enhanced antibody-mediated lysis by peritoneal cells exposed to IL 2 in vitro in a dose-related manner. Peritoneal cells harvested from mice treated in vivo with IL 2 contained an increased number of T cells and asialo GM+ natural killer cells, and also mediated enhanced ADCC. Depletion of natural killer cells with anti-asialo GM and complement resulted in a marked decrease in the antibody-dependent cytotoxicity mediated by these peritoneal cells. The mechanism of synergy between monoclonal antibody and IL 2 may be due to the direct or indirect activation of natural killer cells mediating ADCC.

Animals↗