Department of Surgery
David J. Cole, MD Research
David J. Cole, MD
My laboratory is focused on identifying novel anti-cancer approaches and translating the most successful strategies into clinical trials. There are 3 main areas efforts:
Adoptive T cell therapy for cancer treatment. Adoptive T cell therapy has shown incredible efficacy in treating select cancer patients with metastatic disease. Patients with otherwise no hope have been cured. Unfortunately, this technique only works for some patients (for example, a subset of metastatic melanoma patients) and not in more common cancers such as breast or pancreatic cancer. It is not known why adoptive T cell therapy is more effective for some types of cancers, but a major focus of my laboratory is expanding the efficacy of this therapy to a broader range of patients. Our focus is on three elements related to adoptive T cell therapy: 1) improving the source of the T cells, 2) polarizing the T cells prior to adoptive transfer, and 3) making the host environment more conducive to supporting T cell expansion. In terms of the source of the T cells, we are genetically modifying peripheral blood T cells with tumor-reactive T-cell receptors (TCR) and chimeric antigen receptors (CAR). To make these cells more effective against tumor, we have found that polarization with IL-12 dramatically improves anti-tumor efficacy. Finally, we are focused on identifying alternatives to chemotherapy and radiation for supporting T cell expansion after adoptive transfer into patients. Our efforts to optimize all three of these elements are ongoing with collaborations at MUSC as well as Loyola University (Chicago).
Gene therapy for the treatment of pancreatic cancer. Another major effort in my laboratory is the development of novel gene therapy strategies for the treatment of pancreatic cancer. This cancer has proven particularly resistant to treatment with conventional therapies. However, recent advances in genetics have identified the expression of many genes critical to the progression of pancreatic cancer. Using various gene transfer techniques, we are developing novel strategies to specifically modulate gene expression in pancreatic tumor cells, with the goal of blocking metastatic progression of this disease and also inducing a natural immune-based response against the tumor. My MUSC collaborator on this project is Dr. Ramsay Camp.
Translational research. The overall goal of my laboratory is to take basic research findings and translate these into the clinic. To aid in this endeavor, my laboratory is a member of the MUSC immunotherapy translational research group composed of basic researchers and clinicians. In addition to the people, one of the unique resources we have at MUSC is the center for cellular therapy which allows the production of cell-based products such as autologous dendritic cells and T cells for transfusion into patients. As part of the translational group, my group has led the initiation of three clinical trials involving the use of dendritic cells as a vaccination platform for treating patients with metastatic melanoma and pancreatic cancer. These three trials developed from research in my lab showing that showed the use of novel adjuvant (poly I:C) could dramatically enhance efficacy of dendritic cells to induce T cell-mediated immune responses. As of early 2013, about eight MUSC patients have been treated with our autologous dendritic cell-based vaccine. In addition to these dendritic cell trials, my group is currently preparing for the initiation of an adoptive T cell therapy trial for the treatment of metastatic melanoma patients with a target start date of mid-2014.
1. Cole, D.J., and M.P. Rubinstein. 2012. Soluble IL-15/IL-15Ralpha complexes in human serum. Blood 120:1-2.
2. Rubinstein, M.P., C.A. Cloud, T.E. Garrett, C.J. Moore, K.M. Schwartz, C.B. Johnson, D.H. Craig, M.L. Salem, C.M. Paulos, and D.J. Cole. 2012. Ex vivo interleukin-12-priming during CD8(+) T cell activation dramatically improves adoptive T cell transfer antitumor efficacy in a lymphodepleted host. J Am Coll Surg 214:700-707; discussion 707-708.
3. Mehrotra, S., A.A. Al-Khami, J. Klarquist, S. Husain, O. Naga, J.M. Eby, A.K. Murali, G.E. Lyons, M. Li, N.D. Spivey, H. Norell, T. Martins da Palma, G. Onicescu, C.M. Diaz-Montero, E. Garrett-Mayer, D.J. Cole, I.C. Le Poole, and M.I. Nishimura. 2012. A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice. J Immunol 189:1627-1638.
4. Little, E.C., C. Wang, P.M. Watson, D.K. Watson, D.J. Cole, and E.R. Camp. 2012. Novel immunocompetent murine models representing advanced local and metastatic pancreatic cancer. J Surg Res 176:359-366.
5. Salem, M.L., A.A. Al-Khami, S.A. El-Nagaar, A.A. Zidan, I.M. Al-Sharkawi, C. Marcela Diaz-Montero, and D.J. Cole. 2012. Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide. Cell Immunol 276:67-74.
6. Kohlhapp, F.J., A. Zloza, J.A. O'Sullivan, T.V. Moore, A.T. Lacek, M.C. Jagoda, J. McCracken, D.J. Cole, and J.A. Guevara-Patino. 2012. CD8(+) T cells sabotage their own memory potential through IFN-gamma-dependent modification of the IL-12/IL-15 receptor alpha axis on dendritic cells. J Immunol 188:3639-3647.
- Cole DJ, Sanda MG, Yang JC, Schwarkenruber DS, Weber J, Ettinghausen SE, PockaJ BA, Kim Hl, Levin RD, Pogrebniak HW, Balkissoon J, Fenton RM, DeBarge, LR, Kaye J, Rosenberg SA, Parkinson DR: Phase I open trial of continuous intravenous rhM-CSF in patients with metastatic cancer. J Natl Cancer Inst, Vol 86(1): 39-45, 1994.
- Cole DJ, Nishimura M, ShDyansky J, Yannelli J, Custer M, Rosenberg SA: Identification and transfer of funtional TCR alpha and beta chains frc1n tumor specific murine T-cell clones to alternative effector cells (current investigation).
|The Surgical Molecular Oncology Group (December 2012)|