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Name:	H. Trent T. Spencer
Position:	Assistant Professor of Pediatrics
Degree:	Ph.D., Creighton University School of Medicine, 1991
Programs:	MSP, Full Member
Phone:	404 721-8554
Address:	Pediatrics, 2040 Ridgewood Dr, NE, 2172/003/1AA
Email:	Trent_Spencer@oz.ped.emory.edu
Research Descriptions:
Short:	Drug resistance gene therapy strategies for treatment of childhood cancers and inherited diseases.
Long:	Although gene therapy approaches for the treatment of cancer and several inherited diseases are now conceivable, a major limitation to the successful application of gene therapy to humans is low gene transfer efficiency, especially when using human bone marrow cells. Low transduction efficiencies can be overcome by 1) developing improved methods of gene transfer, ie better recombinant viruses and transduction protocols or 2) selective expansion of gene modified cells and inhibition of expansion of non modified cells. Tremendous efforts have been directed on both fronts. With respect to production of better retroviral vectors and transduction protocols, gene transfer efficiencies into human stem cells have increased from 0.01% to nearly 10%, with 5% being routinely achievable. Although encouraging, transduction efficiencies still limit many gene therapy applications. We are investigating the use of retroviral gene transfer of nucleic acid sequences in gene transfer strategies designed to protect hematopoietic cells against toxicities associated with chemotherapy. Protection of hematopoietic cells from chemotherapy induced toxicities can allow for: 1) The development of more aggressive chemotherapy regimens. 2) In vivo selection of genetically-modified cells. 3) Co-administration of immunotherapy and chemotherapy by protection of immunocompetent cells. We have successfully facilitated the development of several strategies for conferring drug resistance using gene therapy techniques. One of the current directions of the laboratory is to develop methods to increase the degree of resistance conferred to target cells as well as develop novel methods for conferring resistance to clinically relevant cancer chemotherapy agents. We have achieved remarkably high levels of resistance by retroviral expression of cDNAs that encode drug resistant variants of dihydrofolate reductase (which confers resistance to trimetrexate and methotrexate), thymidylate synthase (TS) variants (which confers resistance to Raltritrexed and U89), coexpression of enzymes metabolically related to TS (dUTPase and thymidine kinase, which increases resistance to TS-targeted inhibitors), cytosolic nucleotidase 1 (which confers resistance to 2-CdA), and expression of tyrosine-DNA-phosphodiesterase (which confers resistance to camptothecin and camptothecin analogues. We are also pioneering the use of drug resistance immunotherapy (DRI) for the treatment of cancer. In general, our approach is to genetically engineer cancer cells to express nucleic acid sequences that encode immuno-stimulatory proteins. The engineered cells are then used to induce an immune response against the tumor. The activated immune cells are then harvested and genetically modified with recombinant retroviruses that encode our drug resistance genes. The development of drug resistant immuno-competent cells allows for the co-administration of immunotherapy and chemotherapy. These studies are crucial because chemotherapy is not only toxic to tumor cells but is also toxic to potentially beneficial immune cells. It is hoped that by combining DRI and chemotherapy the effectiveness of cancer treatment can be increased.