Laurence J. N. Cooper, M.D, Ph.D.
Pediatrics - Patient Care
University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 0907, SCR1.2028
Houston, TX 77030
(713) 404-3764 pager
We have used gene therapy to improve the potency of immunotherapy and to target tumor antigens for which there is immunological tolerance. This is achieved by combining two technologies to genetically modify clinical-grade T cells, (i) namely electro-transfer of Sleeping Beauty (SB) system and (ii) selective propagation on artificial antigen presenting cells (aAPC). This has resulted in our launching a suite of gene therapy trials infusing tumor-specific T cells.
T-cell specificity can be redirected through the expression of single-chain chimeric antigen receptors (CARs) that recognize cell-surface molecules independent of MHC. For example, a CD19-specific CAR can be expressed to render T cells capable of targeting malignant B cells and we are undertaking a first-in-human trial to infuse such genetically modified T cells after autologous hematopoietic stem-cell transplantation (HSCT). CAR+ T cells can also be readily generated with specificity for other antigens, such as the ancient retroviral protein HERV-K expressed on breast cancer, CD56 expressed on neuroblastoma, and c-Met expressed on many hypoxic tumors. Since the therapeutic effect is dependent on T-cell persistence we have adapted the CAR itself, co-expressed co-stimulatory molecules, as well as altered the culturing environment to reprogram T cells for sustained persistence. To infuse donor-derived CAR+ T cells after allogeneic HSCT and avoid graft-versus-host-disease we have expressed CAR in T cells that have been anergized against allo-antigen and used designer zinc finger nucleases (ZFNs) to eliminate expression of endogenous ab T-cell receptor (TCR) on CAR+ T cells. To build upon data showing the persistence and anti-tumor effect of adoptive transfer of human CAR+ T cells in immunocompromised mice we are using two large animal models. We have demonstrated that the infusion of autologous T cells in companion dogs with spontaneous B-lineage lymphoma can help restore immunity, traffick to lymph nodes and improve survival. We are using Rhesus monkeys to model the persistence of CAR+ T cells and effects of targeting a B-lineage antigen on normal B cells in non-human primates. To non-invasively image infused T cells we have (i) co-expressed thymidine kinase (TK) as a reporter gene for positron emission tomography (PET) and (ii) electro-transferred, using our proprietary high throughput device, 64Cu-labeled gold nanoparticles. To improve the safety of CAR+ T cells we have adapted the SB system to express multiple transposons to co-express CAR with TK to render T cells sensitive to conditional ablation in vivo with ganciclovir. Furthermore, we have introduced a molecular sensor for oxygen so that the CAR is conditionally expressed on T cells in the hypoxic tumor microenvironment. To target pathogens in addition to malignancies we are developing CARs that recognize CMV and Aspergillus. Since the aAPC supports the outgrowth of CAR+ T cells, we have adapted this platform for the numeric expansion of antigen-specific T cells that recognize pathogens and malignancies via TCR. To combine T-cell therapy with vaccine therapy we have genetically modified T cells to express immunodominant antigens from tumors and pathogens and demonstrated that these can serve as T-cell derived antigen presenting cells (T-APC). To broaden the appeal of T-cell therapy, we have generated ZFNs to eliminate MHC expression so that allogeneic CAR+ T cells can be pre-prepared and infused as an “off-the-shelf” reagent across transplantation barriers.
Interested TRIUMPH scholars will work on translational aspects of immunology adapting basic science into clinical trials. The scholar will not only undertake cutting-edge research in this fast-paced laboratory, but will be mentored in the conduct of clinical trials including regulatory affairs governing the manufacture of clinical-grade cells and in performing correlative studies. The laboratory training is supported by didactic sessions during laboratory meetings and journal clubs. Additional educational opportunities occur at seminars and meetings both in and outside MDACC’s campus. The successful TRIUMPH scholar at the end of their training will have expertise in applied immunology having taken an idea from the bench to the bedside. He or she will have the tools to be able to lead others not only in terms of laboratory science, but also in the generation and application of critical clinical-grade reagents for the treatment of malignancies and complications.