Malcolm K. Brenner, M.D., Ph.D.
Departments of Medicine and Pediatrics
Section of Hematology-Oncology
Baylor College of Medicine
- MB, B Chir, Cambridge University, London, England
- Ph.D., Cambridge University, England
- Fellow of the Royal College of Physicians (FRCP)
- Fellow of the Royal College of Pathologists (FRCPath)
Dr. Brenner's research in tumor immunology has shown that tumor cells genetically modified to express immunostimulatory genes will induce effective antitumor responses in a range of syngeneic animal models. He has compared the relative immunostimulatory and antitumor potencies of autologous and allogeneic tumor vaccines in children with advanced neuroblastoma, obtaining evidence of local immunity with both types of vaccines, with the autologous vaccine showing more potent systemic activity. In follow-up studies, efforts are being made to increase the immunogenicity of the tumor cells by transducing them with a combination of lymphotactin, a T- lymphocyte chemotaxin, and IL2, to amplify the response of tumor specific T cells attracted to the site of tumor inoculation. This strategy has proved to be extremely effective in several different murine models, and having shown promise in patients with relapsed tumor, it is now being extended to individuals with minimal residual disease. Similar studies are underway in patients with acute leukemia.
Dr Brenner's laboratory is also using molecular techniques to define the antigens on tumors recognized by stimulated immune system cells, with the aim of genetically modifying cells, so that they specifically recognize such antigens. Another area of research aims to improve immune reconstitution. Cancer patients who receive T-cell-depleted hematopoietic stem cell (HSC) transplants to prevent GVHD remain at risk for viral infections and relapse. An alternative strategy to reconstitute antigen-specific responses to multiple viruses and tumor cells would be to selectively deplete the graft of alloreactive cells that initiate GVHD, thus preserving tumor- and virus-specific cells. To test this hypothesis, Dr. Brenner and colleagues have developed techniques for depleting alloreactive T cells and transferring them to HSC recipients to provide antiviral and antitumor activity without the risk of GVHD. Trainees in this laboratory have the opportunity to undertake translational research in the field of tumor immunology and interact strongly with the vector and GMP cores and the Regulatory Affairs Office.
Selected Original Articles 2006-2007
- Russell HV, Strother D, Mei Z, Rill D, Popek E, Biagi E, Yvon E, Brenner M, Rousseau R. Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin. J Immunother. 2007 Feb-Mar;30(2):227-33.
- Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A, Yvon E, Weiss H, Cobbold M, Gaspar HB, Rooney C, Kuehnle I, Ghetie V, Schindler J, Krance R, Heslop HE, Veys P, Vitetta E, Brenner MK. Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood. 2006 Sep 15;108(6):1797-808.
- Lacuesta K, Buza E, Hauser H, Granville L, Pule M, Corboy G, Finegold M, Weiss H, Chen SY, Brenner MK, Heslop HE, Rooney CM, Bollard CM. Assessing the safety of cytotoxic T lymphocytes transduced with a dominant negative transforming growth factor-beta receptor. J Immunother. 2006 May-Jun;29(3):250-60.
- Leen AM, Myers GD, Sili U, Huls MH, Weiss H, Leung KS, Carrum G, Krance RA, Chang CC, Molldrem JJ, Gee AP, Brenner MK, Heslop HE, Rooney CM, Bollard CM. Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinically relevant effects in immunocompromised individuals. Nat Med. 2006 Oct;12(10):1160-6.
- Loskog A, Giandomenico V, Rossig C, Pule M, Dotti G, Brenner MK. Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia. 2006 Oct;20(10):1819-28.
- Rossig C, Bär A, Pscherer S, Altvater B, Pule M, Rooney CM, Brenner MK, Jürgens H, Vormoor J. Target antigen expression on a professional antigen-presenting cell induces superior proliferative antitumor T-cell responses via chimeric T-cell receptors. J Immunother. 2006 Jan-Feb;29(1):21-31.
- Rousseau RF, Biagi E, Dutour A, Yvon ES, Brown MP, Lin T, Mei Z, Grilley B, Popek E, Heslop HE, Gee AP, Krance RA, Popat U, Carrum G, Margolin JF, Brenner MK. Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood. 2006 Feb 15;107(4):1332-41.
- Savoldo B, Goss JA, Hammer MM, Zhang L, Lopez T, Gee AP, Lin YF, Quiros-Tejeira RE, Reinke P, Schubert S, Gottschalk S, Finegold MJ, Brenner MK, Rooney CM, Heslop HE. Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs). Blood. 2006 Nov 1;108(9):2942-9.
- Vera J, Savoldo B, Vigouroux S, Biagi E, Pule M, Rossig C, Wu J, Heslop HE, Rooney CM, Brenner MK, Dotti G. T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood. 2006 Dec 1;108(12):3890-7.
Pule M, Brenner MK. Gene transfer: methods and applications. In: Childhood Leukemia, 2nd ed. Ching-Hon Pui. Cambridge University Press, pp. 661-678, 2006.
Tey SK, Brenner MK. The continuing contribution of gene marking to cell and gene therapy. Mol Ther. 2007 Apr;15(4):666-76.