The Cancer Center Program in Cell and Gene Therapy (CCGT) is a component of the overall Center for Cell and Gene Therapy. It was established at the beginning of l998, and employs over 40 clinical and research faculty and approximately 300 ancillary staff. The Center for Cell and Gene Therapy began and continues as a tri-institutional collaboration between Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, and all three institutions continue to provide exceptional support to the center as a whole and to its cancer-focused missions in particular.
The CCGT Program has 21 research members and six clinical members from several departments including Medicine, Pediatrics, Surgery, Immunology, Molecular and Cell Biology and Human Genetics. Of the research members, all 20 are funded by NIH or CPRIT for cancer related studies, and focus on biological questions in stem cell biology, transplantation and the active and adoptive immunotherapy of malignancy. The center also runs the adult and, in collaboration with the Pediatric Cancer Program, the pediatric hemopoietic stem cell transplant programs located at Houston Methodist Hospital and Texas Children’s Hospital, which perform approximately 280 transplants per year.
The purpose of the program is to rapidly but safely move between basic research and clinical translational studies, and to share our core scientific expertise in cell and gene therapies with other programs. We are facilitated in this aim by our own program project grant in cellular therapy for cancer, by our Lymphoma SPORE, by our Leukemia and Lymphoma SCOR, our Specialized Center of Cell Therapy award, and our three programmatic stem cell grants, all of which include both basic and translational researchers in individual projects.
The program is organized into three major themes each with a basic and clinical/translational leader.
- Normal and Malignant Stem Cell Biology
- Adoptive Cellular Immunotherapy of Cancer
- Improving the Outcome of Hemopoietic Stem Cell Transplantation
Normal and Malignant Stem Cell Biology
Basic Leader: Margaret Goodell, Ph.D.
Clinical/Translational Leader: Malcolm Brenner, M.D., Ph.D.
This research theme reaches from embryonic stem cell biology to the interactivity of multiple tissue-specific stem cells for the formation of complex organs such as bone or malignant tumors. The similarities between the mechanisms used for self perpetuation and differentiation in normal and malignant stem or progenitor cells are becoming increasingly evident, as is the contribution to tumor growth of the normal cellular elements that develop from normal progenitor cells in the tumor bed. Hence, all investigators described under this theme have made efforts to ensure that the cancer-oriented aspects of their work are appropriately acknowledged and explored. The Human Stem Cell Core Shared Resource, is important for this goal and provides cancer cell-derived iPSCs, which are increasingly recognized as valuable reagents for studying human cancers originating from tissues and cell types that have a limited lifespan in tissue culture or cannot be easily obtained from live patients. Cancer-derived iPSCs also allow the modeling of tumors in which the human cancer-associated genes have no clear mouse counterpart or have mutations that are too complex to engineer into the mouse genome. The core is led by Jean Kim.
Selected Recent Publications
Glasgow SM, Carlson JC, Zhu W, Chaboub LS, Kang P, Lee HK, Clovis YM, Lozzi BE, McEvilly RJ, Rosenfeld MG, Creighton CJ, Lee SK, Mohila CA, Deneen B. Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis. Nat Neurosci. 2017;20(11):1520-8.
John Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Zhang Y, Zhu W, Mohila CA, Ahmed N, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, Deneen B. Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci. 2017;20(3):396-405.
Zhang X, Su J, Jeong M, Ko M, Huang Y, Park HJ, Guzman A, Lei Y, Huang YH, Rao A, Li W, Goodell MA.DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat Genet. 2016;48(9):1014-23; PMCID: PMC4957136.
Bissig-Choisat B, Kettlun-Leyton C, Legras XD, Zorman B, Barzi M, Chen LL, Amin MD, Huang YH, Pautler RG, Hampton OA, Prakash MM, Yang D, Borowiak M, Muzny D, Doddapaneni HV, Hu J, Shi Y, Gaber MW, Hicks MJ, Thompson PA, Lu Y, Mills GB, Finegold M, Goss JA, Parsons DW, Vasudevan SA, Sumazin P, Lopez-Terrada D, Bissig KD. Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer. J Hepatol. 2016;65(2):325-33.
Ku AT, Shaver TM, Rao AS, Howard JM, Rodriguez CN, Miao Q, Garcia G, Le D, Yang D, Borowiak M,Cohen DN, Chitsazzadeh V, Diwan AH, Tsai KY, Nguyen H. TCF7L1 promotes skin tumorigenesis independently of beta-catenin through induction of LCN2. Elife. 2017;6; PMCID: PMC5438253.
Nakada D, Oguro H, Levi BP, Ryan N, Kitano A, Saitoh Y, Takeichi M, Wendt GR, Morrison SJ. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature. 2014;505:555-8. PMC4015622
Zohren F, Souroullas GP, Luo M, Gerdemann U, Imperato MR, Wilson NK, Gottgens B, Lukov GL, Goodell MA. The transcription factor Lyl-1 regulates lymphoid specification and the maintenance of early T lineage progenitors. Nat Immunol. 2012;13:761-9. PMC3411897
Adoptive Cellular Immunotherapy of Cancer
Basic Leader: Cliona Rooney, Ph.D.
Clinical/Translational Leader: Carlos Ramos M.D.
Basic and translational researchers are identifying new targets for immunotherapy, optimizing presentation of weak tumor antigens to the immune system and developing strategies to overcome tumor evasion mechanisms. Our translational investigators are moving cell and gene based therapies from the bench to the bedside in a series of small-scale iterative laboratory-clinical-laboratory protocols, and are also developing pivotal later phase clinical trials. Major accomplishments include the demonstration of activity of virus specific cytotoxic T lymphocytes in virus-associated cancers and studies showing the anti-tumor activity of genetically modified T cells in subjects with neuroblastoma and lymphoma.
Selected Recent Publications
Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, Bilgi M, Wu MF, Liu H, Grilley B, Bollard CM, Chang BH,Rooney CM, Brenner MK, Heslop HE, Dotti G, Savoldo B. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest. 2017;127(9):3462-71; PMCID: PMC5669573.
Heczey A, Louis CU, Savoldo B,Dakhova O, Durett A, Grilley B, Liu H, Wu MF,Mei Z, Gee A,Mehta B, Zhang H, Mahmood N, Tashiro H, Heslop HE, Dotti G, Rooney CM, Brenner MK.CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol Ther. 2017;25(9):2214-24; PMCID: PMC5589058.
Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, Rouce RH, Bao G, Brenner MK, Mamonkin M.CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood. 2017;130(3):285-96; PMCID: PMC5520470.
Bollard CM, Tripic T, Cruz CR, Dotti G, Gottschalk S, Torrano V, Dakhova O, Carrum G, Ramos CA, Liu H, Wu MF, Marcogliese AN, Barese C, Zu Y, Lee DY, O'Connor O, Gee AP, Brenner MK, Heslop HE, Rooney CM. Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma. J Clin Oncol. 2018:JCO2017743179.
Shum T, Omer B, Tashiro H, Kruse RL, Wagner DL, Parikh K, Yi Z, Sauer T, Liu D, Parihar R,Castillo P, Liu H, Brenner MK, Metelitsa LS, Gottschalk S, Rooney CM.Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells. Cancer Discov. 2017;7(11):1238-47; PMCID: PMC5669830.
Improving the Outcome of Stem Cell Transplantation for Cancer
Basic Leader: Ann Leen, Ph.D.
Clinical/Translational Leader: Helen Heslop, M.D.
Our clinical researchers run the adult and (in collaboration with the Pediatric Oncology Program) pediatric hemopoietic stem cell transplant programs and are extending the applicability of transplantation for malignancy by using monoclonal antibodies in subablative conditioning regimens and using post transplant immunotherapy to reduce GVHD while augmenting graft versus tumor activity and reconstituting anti-viral immunity. Based on preclinical data, NCI-funded clinical trials have emerged from these studies that prepare donor T lymphocytes depleted of alloreactive cells to enhance immune recovery after mismatched allogeneic SCT and administer virus specific T cells to reconstitute antiviral immunity. Investigators are also developing approaches to render T cells resistant to immunosuppressive drugs and developing strategies to promote recovery of T regulatory cells.
Selected Recent Publications
Tzannou I, Papadopoulou A, Naik S, Leung K, Martinez CA, Ramos CA, Carrum G, Sasa G, Lulla P,Watanabe A, Kuvalekar M, Gee AP, Wu MF, Liu H, Grilley BJ, Krance RA, Gottschalk S, Brenner MK, Rooney CM, Heslop HE, Leen AM, Omer B. Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol. 2017;35(31):3547-57; PMCID: PMC5662844.
Di Stasi A., Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011;365:1673-83. PMC3236370
Papadopoulou A, Gerdemann U, Katari U, Tzannou I, Liu H, Martinez C, Leung K, Carrum G, Gee AP, Vera JF, Krance RA, Brenner MK, Rooney CM, Heslop HE, Leen AM. Activity of rapidly-generated broad-spectrum T cells as treatment for AdV, EBV, CMV, BK virus and HHV6 infections after allogeneic HSCT. Sci Transl Med. 2014;6:242ra83
Zhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT, Durett AG, Dakhova O, Savoldo B,Di Stasi A, Spencer DM, Lin YF,Liu H, Grilley BJ, Gee AP, Rooney CM, Heslop HE, Brenner MK. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood. 2015;125(26):4103-13; PMCID: PMC4481597.
These activities are supported by two manufacturing laboratories which prepare gene transfer vectors and purified and modified cells made to meet current Good Manufacturing or Good Tissue Practice guidelines. The cell therapy laboratory is an NHLBI-funded National Centers which supplies cells to other NIH investigators.
For more information, visit the Center for Cell and Gene Therapy web site.