Dr. Di Stasi is Assistant Professor of Medicine in the Bone Marrow Transplantation and Cell Therapy Program Unit, where he performs both clinical and translational research activities. His primary research focus involves the pre-clinical validation of adoptive T cell immunotherapy strategies for hematologic malignancies.
Specifically, Dr. Di Stasi is concentrating on genetic modification of T cells with chimeric artificial receptors targeting tumor associated antigens, and the incorporation of a novel inducible Caspase9 suicide gene to grant safety of cellular approaches, including donor lymphocytes infused after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
As post-doctoral fellow Dr. Di Stasi successfully completed a pre-clinical translational projects involving the generation of chimeric antigen receptor cytotoxic T-cells redirected to target the CD30 molecule on the surface of Hodgkin lymphoma (HL). To overcome the hostile immune-environment to T cells, he over-expressed the CCR4 chemokine receptor in the T-cells, based on the tumor's secretion of the chemokine TARC which is bound by CCR4.
This modification increased migration and anti-tumor activity in an in vivo HL model, and will soon be tested in a phase-I clinical trial. Dr. Di Stasi also led a team to clinically test a novel inducible Caspase9 (iC9) suicide gene; haploidentical donor T-cells were administered to patients after allo-HSCT, in order to boost anti-viral and anti-cancer immunity. This technology allowed prompt elimination of infused donor T cells in patients who developed graft versus host disease (GVHD) after infusion of the iC9 dimerizer molecule, AP 1903.
This technology is currently investigated in several phase I/II clinical studies in the US and abroad, and has the potential to reduce the morbidity and mortality burden of GVHD, and UAB is now compiling a phase-I clinical trial for patients undergoing matched related allo-HSCT.
Abstract
Adoptive transfer of donor-derived T lymphocytes expressing a safety switch may promote immune reconstitution in patients undergoing haploidentical hematopoietic stem cell transplant (haplo-HSCT) without the risk for uncontrolled graft versus host disease (GvHD). Thus, patients who develop GvHD after infusion of allodepleted donor-derived T cells expressing an inducible human caspase 9 (iC9) had their disease effectively controlled by a single administration of a small-molecule drug (AP1903) that dimerizes and activates the iC9 transgene. We now report the long-term follow-up of 10 patients infused with such safety switch-modified T cells. We find long-term persistence of iC9-modified (iC9-T) T cells in vivo in the absence of emerging oligoclonality and a robust immunologic benefit, mediated initially by the infused cells themselves and subsequently by an apparently accelerated reconstitution of endogenous naive T lymphocytes. As a consequence, these patients have immediate and sustained protection from major pathogens, including cytomegalovirus, adenovirus, BK virus, and Epstein-Barr virus in the absence of acute or chronic GvHD, supporting the beneficial effects of this approach to immune reconstitution after haplo-HSCT. This study was registered at www.clinicaltrials.gov as #NCT00710892.
