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Biomedical subjects

M K Brenner

Publications and source records attributed to M K Brenner.

At least 73 records · Page 4Linked to original sources
PubMed1998

EBV specific CTL: a model for immune therapy.

We have been generating Epstein-Barr virus specific cytotoxic T cells for patients at high risk of developing EBV driven lymphoma. To discover the fate of the cells in vivo, we first marked them genetically, using a retroviral vector. Our results in 51 patients show that the approach is safe, that the CTL persist for several years and that they are able to mediate anti-viral and anti-tumor effects. We are now studying other virally-linked malignancies to discover whether a similar approach will be of therapeutic value.

Bone Marrow Transplantation↗
PubMed1998

Applications of gene transfer in hematologic malignancy.

Although gene transfer was originally conceived as a means to replace or correct defective genes in patients with inherited disorders, the process has shown broad potential for intervention in hematologic malignancy and for study of hematopoietic stem cell biology. Gene transfer strategies now under investigation for these applications include 1) repair of one or more genetic defects associated with the malignant process, 2) delivery of a prodrug-metabolizing enzyme that causes tumor cells to become sensitive to the corresponding anticancer drug, 3) modification of immune responses to the cancer, and 4) introduction of drug resistance genes to increase the therapeutic index of cytotoxic agents. Finally, by marking normal or malignant cells with readily detectable genes, one can monitor the efficacy of therapy or study the dynamics of stem cell behavior in vivo. At present these applications are limited by the quality of vectors, but as transduction efficiencies and gene regulatory mechanisms improve, gene transfer can be expected to evolve into a major therapeutic modality in its own right.

Drug Resistance, Neoplasm↗
PubMed1997

Antitumor responses induced by transgenic expression of CD40 ligand.

Because CD40 ligand (CD40L) is a co-stimulator molecule for multiple components of the immune response, we wanted to determine whether transgenic expression of the molecule would increase immune responses against a weakly immunogenic murine tumor, neuro-2a. Tumor cells were transduced with a retroviral construct containing the CD40L gene and co-injected with variable numbers of non-CD40L transduced cells into syngeneic mice. Mice injected with cells that expressed CD40L had a significant reduction in average tumor size as compared to controls (p < 0.0001). In addition, survival of the neuro-2a/CD40L mice was 48 days versus 34 days for the neuro-2a/neo controls (p < 0.02). Expression of CD40L by less than 1.5% of neuro-2a cells was sufficient for significant antitumor effects (p < 0.001). These antitumor effects protected mice from subsequent challenge with parental neuro-2a cells. The protective effects of CD40L were associated with systemic immunomodulation. In vivo depletion of CD8+ cells abrogated the CD40L-mediated antitumor effects. Analysis of spleens from CD40L-protected animals showed increased numbers of CD4+ and CD8+ cells, the majority of which co-expressed the activation marker CD25. In addition, an increased number of antigen-presenting cells (APCs) expressed the co-stimulatory molecule CD86. These experiments illustrate that transducing even a small percentage of tumor cells with CD40 ligand can create a long-lasting systemic immune response capable of impeding growth of unmodified neuroblastoma cells.

Animals↗
PubMed1997

Outcomes of transplantation with matched-sibling and unrelated-donor bone marrow in children with leukaemia.

BACKGROUND: For most conditions amenable to bone-marrow transplantation, grafts from HLA-matched but unrelated donors have yielded poorer results than those obtained from matched-sibling donors. We assessed this pattern in the light of improvements in donor selection and post-transplant supportive care. METHODS: We reviewed transplant outcome in 103 consecutive patients with childhood leukaemia who underwent allogeneic bone-marrow transplantation with HLA-matched sibling marrow (n = 52) or matched unrelated donor marrow (n = 51) between May, 1990, and March, 1996, at St Jude Children's Research Hospital. FINDINGS: Analysis of engraftment, frequency of procedure-related complications, and disease-free survival revealed no advantage from use of matched-sibling marrow. The 2-year disease-free survival estimate for standard-risk recipients of matched-sibling marrow was 81 [8.1]% compared with 73 [12.1]% in the unrelated donor marrow group (p = 0.77). In the high-risk category, patients with a matched-sibling donor had a 2-year disease-free survival of 31 [11.6]%, compared with 32 [15.1]% among recipients of matched unrelated donor marrow (p = 0.87). INTERPRETATION: We believe this improved result with unrelated donor marrow is a consequence of recent innovations in histocompatibility matching, prevention of graft-versus-host disease (GvHD), and antiviral prophylaxis. We suggest that such grafts can now be used in patients at both standard and high risk without compromising treatment outcome.

Bone Marrow Transplantation↗
PubMed1997

Hematological malignancies.

The present cure rate for leukemia and lymphoma represents one of the success stories of modern cancer therapy. However, treatments remain toxic, expensive, and ineffective for many patients. There is therefore considerable interest in exploring gene therapies for these disorders. To date, four major strategies have been adopted: 1) modifying the tumor cell itself either by "repairing" one or more genetic defect associated with the malignant process, introducing a gene that will trigger an anti-tumor immune response, or delivering a pro-drug metabolizing enzyme that will render the tumor sensitive to the corresponding cytotoxic agent; 2) modifying the immune response to the tumor by altering the specificity or effector function of immune system cells; 3) decreasing the sensitivity of normal host tissue by delivering cytotoxic drug resistance genes to marrow precursor cells and thereby increasing the therapeutic index of cytotoxic agents; and 4) marking normal and malignant hemopoietic cells in order to more closely monitor the efficacy of conventional therapies. Given the current "state of the art," all these approaches have significant limitations, but each has had its successes, offering encouragement for future applications in clinical practice.

Animals↗
PubMed1996

Mobilization of CD34+ progenitor cells by granulocyte colony-stimulating factor in human immunodeficiency virus type 1-infected adults.

We conducted a clinical trial to determine the feasibility of growth factor mobilization of CD34+ progenitor cells in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Eight asymptomatic, HIV-1-infected adults (median CD4+ T-cell count, 415 cells/microL), received 480 micrograms/d of granulocyte colony-stimulating factor (G-CSF) for 6 days without evidence of viral activation. Despite concerns that HIV-1 might inhibit hematopoiesis, CD34+ cells were successfully mobilized to the periphery of all donors, independent of the baseline CD4+ T-cell count, and the status of antiretroviral therapy. Leukapheresis was performed on day 6, and yielded a median of 194 x 10(6) CD34+ cells per leukapheresis (n = 7). CD34-enriched cells from the leukapheresis were predominantly myeloid-committed, but between 0.2% and 1.7% were primitive CD34+/CD38- progenitors. A median of 21.7% of the mobilized CD34+ cells were dimly positive for CD4. Consequently, CD34(+)-enriched cells were purified on the cell sorter (mean purity, 97.7% +/- 2.4%; n = 7), and examined for HIV-1 DNA. Purified CD34+ cells from two of seven donors were polymerase chain reaction (PCR)-positive for HIV-1, but only from one of three samples from each donor. We conclude that G-CSF can safely mobilize CD34+ progenitor cells in HIV-1-infected subjects, and that these cells are suitable for consideration in gene-transfer strategies.

Adult↗
PubMed1996

Gene therapy: socioeconomic and ethical issues. A roundtable discussion.

Gene therapy research has the potential to revolutionize the way in which many human diseases are treated. Despite its enormous potential, roundtable panelists concluded that the field needs time to mature scientifically without pressure to develop a marketable therapeutic product. In addition, health care decision makers, physicians, and the lay public need to be educated on the future medical, economic, and ethical ramifications of gene therapy.

Clinical Trials as Topic↗
PubMed1996

Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes.

Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) offers safe and effective therapy for certain viral infections and could prove useful in the eradication of tumor cells. Whether or not the infused T cells persist for extended periods, retaining their ability to expand in response to antigenic stimulation, is not known. We now report long-term detection of gene-marked Epstein-Barr virus (EBV)-specific CTLs in immunocompromised patients at risk for the development of EBV lymphoproliferative disease. Infusions of CTLs not only restored cellular immune responses against EBV, but also established populations of CTL precursors that could respond to in vivo or ex vivo challenge with the virus for as long as 18 months. Our findings support wider use of antigen-specific CTLs in adoptive immunotherapy.

Bone Marrow Transplantation↗
PubMed1996

Gene marking and gene therapy for transplantation medicine.

The classic application for gene therapy is in the correction of single gene defects, although this has been complicated by the low efficiency of gene transfer into hematopoietic cells. Gene therapy, however, has potential for the modulation of tumor cell growth, drug sensitivity, and antitumor immune responses. In addition, gene marking can be used, in spite of this limited transfer efficiency, to provide information on hematopoiesis, sources of cancer relapse after stem cell transplant, and the relative efficacy of graft manipulation techniques. This article reviews the applications of gene therapy and gene marking in transplantation medicine.

Biomarkers↗
PubMed1996

Gene transfer and therapeutic drug monitoring.

During the next decade, gene therapy will evolve from a medical curiosity into an essential component of medical practice. One of the elements necessary for this transition will be the development of simple and accurate ways of monitoring both the vectors used to transfer the genes of interest and the function of the genes themselves. This article reviews the difficulties in achieving these aims and describes ways in which the technology of gene transfer offers a novel means of monitoring current therapies.

Drug Monitoring↗
PubMed1996

Gene transfer in haematological malignancy.

Although gene transfer was first suggested to treat inherited monogenic disorders, at present most clinical protocols are intended to treat patients with malignant disease. Although current vector technologies profoundly limit the potential therapeutic applications of gene transfer, the technique is already being successfully used to complement longer established therapies. This article reviews current and forthcoming applications of gene transfer to treat haematological malignancies.

Clinical Trials as Topic↗
PubMed1996

Adoptive immunotherapy for Epstein-Barr virus-related lymphoma.

Epstein-Barr virus (EBV) causes opportunistic B cell lymphomas in patients whose cellular immunity is compromised. We have been investigating whether infusions of donor-derived, EBV-specific cytotoxic T cells can prevent and/or treat EBV-related lymphoproliferative disease in children receiving T cell-depleted bone marrow from HLA-matched, unrelated or HLA-mismatched, related donors. In this review, we discuss the rationale for this therapeutic approach, describe our experiences with the regimen thus far, and consider some future directions in immunotherapy.

Child↗