Malcolm Brenner, M.D., Ph.D.
Professor of Molecular and Human Genetics
Professor, Departments of Pediatrics and Medicine; Stem Cells and Regenerative Medicine (STaR) Center; Program in Translational Biology & Molecular Medicine
Director, Center for Cell and Gene Therapy
B.A., Cambridge University, 1972
M.B.B.Ch., University of Cambridge, 1975
Ph.D., University of Cambridge, 1981
Dr. Brenner's primary research interest is the use of gene transfer to augment the immune response to human tumors, using vaccines and adoptive transfer of genetically modified T cells.
In neuroblastoma, Dr. Brenner and co-investigators have shown that T cells expressing a chimeric antigen receptor (CAR) for a surface marker (GD2) on neuroblastoma cells can produce tumor responses in more than half the patients with refractory or relapsed disease leading to complete remission in 3/11 patients. His Center is also studying the benefits of T cells modified with CARs directed to other tumor antigens on hematological malignancies and solid tumors including Hodgkin Disease and Glioblastoma multiforme and initial clinical results are promising. Efforts are being made to further increase the effectiveness of these CAR-T cells by incorporating genes that enhance T cell growth and survival and that render the T cells resistant to the inhibitory effects of many human tumors.
To enhance the safety of genetically modified T cells, Dr. Brenner and colleagues have implemented an inducible caspase system that will rapidly cause apoptosis of T cells within minutes of administration of a small molecule dimerizing drug, allowing adverse effects from the T cells to be reversed. Initial clinical trials showed significant activity, and the approach is now being broadened to other novel T cell therapeutics.
Dr. Brenner’s group combines these adoptive transfer strategies with immunization against the tumors to produce synergistic benefits and clinical studies in chronic lymphocytic leukemia have recently begun.
Finally, in collaboration with the laboratories of Drs. Rooney, Heslop and Bollard, Dr. Brenner is continuing to study the use of gene modified cytotoxic T lymphocytes to prevent and treat the Epstein Barr virus associated malignancies, immunoblastic lymphoma, Hodgkin disease, and nasopharyngeal cancer (NPC). By transducing dendritic cells with EBV antigens, we are able to generate potent immune responses against the weak EBV latency antigens expressed in Hodgkin disease and NPC. Studies in 23 patients with relapsed or refractory EBV-positive Hodgkin and Non-Hodgkin lymphoma patients have produced complete responses in more than half. The potential to increase the effectiveness of the T-cells in vivo using monoclonal antibodies directed to immunological checkpoints is now being evaluated in clinical trials.
- Di Stasi A, Tey SK, Dotti GP,...,Rooney CM, Brenner MK (2011). Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy. N. Engl. J. Med. 365(18): 1673-83. PubMed PMID: 22078471
- Heslop HE, Slobod KS, Pule MA, Hale GA, Rousseau A, Smith CA, Bollard CM, Liu H, Wu MF, Rochester RJ, Amrolia PJ, Hurwitz JL, Brenner MK, Rooney CM (2010). Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115(5): 925-35. PubMed PMID: 19880495
- Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, Yvon E, Weiss HL, Liu H, Rooney CM, Heslop HE, Brenner MK (2008). Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14(11): 1264-70. PubMed PMID: 18978797
- 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 (2006). Monoculture-derived T lymphocytes specific for multiple viruses expand and produce clinical relevant effects in immunocompromised patients. Nat. Med. 12(10): 1160-6. PubMed PMID: 16998485
- 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 (2006). Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 108(6): 1797-808. PubMed PMID: 16741253
- Hirschmann-Jax C, Foster AE, Wulf GG, Nuchtern JG, Jax TW, Gobel U, Goodell MA, Brenner MK (2004). A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc. Natl. Acad. Sci. U S A 101(39): 14228-33. PubMed PMID: 15381773
- Amrolia PJ, Muccioli-Casadei G, Yvon E, Huls H, Sili U, Wieder ED, Bollard C, Michalek J, Ghetie V, Heslop HE, Molldrem JJ, Rooney CM, Schlinder J, Vitetta E, Brenner MK (2003). Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. Blood 102(6): 2292-9. PubMed PMID: 12763937
- Rousseau RF, Haight AE, Hirschmann-Jax C, Yvon ES, Rill DR, Mei Z, Smith SC, Inman S, Cooper K, Alcoser P, Grilley B, Gee A, Popek E, Davidoff A, Bowman LC, Brenner MK, Strother D (2003). Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood 101(5): 1718-26. PubMed PMID: 12406881
- Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK (1999). Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med. 5(3): 309-13. PubMed PMID: 10086387
Malcolm Brenner, M.D., Ph.D.
Center for Cell and Gene Therapy
One Baylor Plaza, MS BCM505
Houston, TX, 77030, U.S.A.