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Dan L. Duncan Cancer Center

Houston, Texas

BCM has 25 departments and more than 90 research and patient-care centers.
Dan L. Duncan Cancer Center
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Cell and Gene Therapy Program

Malcolm K. Brenner, M.D., Ph.D., Leader

(Malcolm K. Brenner, M.D., Ph.D., Leader;
Helen Heslop, M.D., Co-Leader)

The program has 18 research members, 12 members and three clinical investigators. All 18 research members are funded by National Institutes of Health for cancer related studies, and focus on mechanistic analyses of cancer stem cell biology, on active and adoptive immunotherapy of malignancy and on developing approaches to improve the safety and effectiveness of allogeneic stem cell transplantation.

Helen Heslop, M.D. - Co-leader

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 has three main themes:

Normal and malignant stem cell biology

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-orientated aspects of their work are appropriately acknowledged and explored. Recent research highlights include identification of Ronin, as a central player in the control of embryogenesis and ES cell differentiation, identification of HSC-specific genes that control HSC proliferation and clinical correlation of antitumor responses with targeting of tumor stem cell populations.

Selected recent publications:

Chambers SM, Boles NC, Lin KY, Tierney MP, Bowman TV, Bradfute SB, Chen AJ, Merchant AA, Sirin O, Weksberg DC, Merchant MG, Fisk CJ, Shaw CA, Goodell MA. Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny. Cell Stem Cell. 2007;1:578-591.

Dejosez M, Krumenacker JS, Zitur LJ, Passeri M, Chu LF, Songyang Z, Thomson JA, Zwaka TP. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell. 2008;133:1162-1174.

Fujita J, Crane AM, Souza MK, Dejosez M, Kyba M, Flavell RA, Thomson JA, Zwaka TP. Caspase activity mediates the differentiation of embryonic stem cells. Cell Stem Cell. 2008;2:595-601.

Feng CG, Weksberg DC, Taylor GA, Sher A, Goodell MA. The p47 GTPase Lrg-47 (Irgm1) links host defense and hematopoietic stem cell proliferation. Cell Stem Cell. 2008;2:83-89.

Foster AE, Okur FV, Biagi E, Lu A, Dotti G, Yvon E, Savoldo B, Carrum G, Andreeff M, Goodell MA, Heslop HE, Brenner MK. Selective depletion of a minor subpopulation of B-chronic lymphocytic leukemia cells is followed by a delayed but progressive loss of bulk tumor cells and disease regression. Mol Cancer. 2009;8:106.

Adoptive cellular immunotherapy of cancer

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 (resulting in an orphan drug designation for EBV CTLs for post transplant lymphoma) and studies showing the anti-tumor activity of genetically modified T cells in subjects with neuroblastoma and lymphoma.

Selected recent publications:

Bollard CM, Gottschalk S, Leen AM, Weiss H, Straathof KC, Carrum G, Khalil M, Wu MF, Huls MH, Chang CC, Gresik MV, Gee AP, Brenner MK, Rooney CM, Heslop HE. Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood. 2007;110:2838-2845.

Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF. Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity. 2007;27:334-348.

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. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14:1264-1270.

Di Stasi AB, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, Savoldo B. T lymphocytes co-expressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and anti-tumor activity in a Hodgkin's tumor model. Blood. 2009. 113:6392-402.

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. Long term outcome of EBV specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2009e pub

Improving the outcome of stem cell transplantation for cancer

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 whilst augmenting graft versus tumor activity and reconstituting anti-viral immunity. Based on pre-clinical 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 extending these strategies to cord blood transplant, developing approaches to render T cells resistant to immunosuppressive drugs and developing strategies to promote recovery of T regulatory cells.

Selected recent publications:
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;12:1160-1166.

De Angelis B., Dotti G, Quintarelli C, Huye L, Zhang L, Zhang M, Pane F, Heslop HE, Brenner MK, Rooney CM, Savoldo B. Generation of Epstein-Barr-Virus-specific Cytotoxic T lymphocytes Resistant to the Immunosuppressive Drug Tacrolimus (FK506). Blood. 2009 113:6392-6402

Hanley PJ, Cruz CR, Savoldo B, Leen AM, Stanojevic M, Khalil M, Decker W, Molldrem JJ, Liu H, Gee AP, Rooney CM, Heslop HE, Dotti G, Brenner MK, Shpall EJ, Bollard CM. Functionally active virus-specific T-cells that target CMV, adenovirus and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood. 2009 114:1958-67

Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley PJ, Kennedy-Nasser AA, Leung KS, Gee A, Krance R, Brenner MK, Heslop HE, Rooney CM, Bollard CM. Cytotoxic T-lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infection after haploidentical and matched unrelated stem cell transplant. Blood. 2009 epub.

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.

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