A Phase I/II Clinical Trial to Investigate Fucosylated Tregs in Prevention of GVHD

DESCRIPTION provided by applicant Allogeneic hematopoietic stem cell transplant has the potential to cure various hematological malignancies and inherited disorders but is limited by treatment related mortality which in a majority of cases is directly related to Graft versus Host Disease GVHD Current therapy for GVHD involves prolonged immunosuppression with calcineurin inhibitors such as cyclosporine and tacrolimus However in itself prolonged immunosuppression results in delayed immune function leading to infectious complications as well as a risk of post transplant lymphoproliferative disorders Thus there is a clear need for alternative approaches to mitigate the deleterious effects of GVHD whether acute or chronic With proof of concept preclinical studies completed we are requesting funding to support a pilot two stage Phase I IIa safety and preliminary efficacy clinical trial investigating an innovative cell based approach for prevention of GVHD in a dual cord blood transplant setting Our proposed approach is novel in that it capitalizes on the beneficial and well established anti inflammatory effects of systemically administered regulatory T cells Tregs combined with enhanced homing engraftment following their ex vivo treatment with TZ TZ is comprised of the enzyme fucosyltransferase FTVI and its substrate guanosine diphosphate fucose which when incubated with cells leads to site and stereospecific addition of fucose to cell surface glycoproteins This has been shown by a number of different Investigators to enhance selecting mediated binding for varying cell types Most notably this interaction underlies the homing of stem progenitor cells to sites of upregulated levels of selectins which is a hallmark of inflamed tissue A search on clinical trials gov for andquot regulatory T cellsandquot reveals over clinica trials demonstrating the importance and safety of administration of this immune population Furthermore T regs are endowed with multiple features that can clearly address GVHD across a broad patient population such as lack of stimulation of a proliferative response from alloreactive T cells alteration of cytokine secretion profile of dendritic cells T cells and natual killer cells in vitro inhibition of secretion of proinflammatory cytokines and increased expressio of suppressive cytokines We are proposing four specific aims Production of cGMP TZ reagents FTVI and GDP fucose Phase I examination of the safety of dose level fuocsylated T regs at x kg patient weight We will use three co primary outcomes measures for safety time to severe infusional toxicity grade GVHD and death Phase IIa examination of preliminary efficacy at a single dose of fucosylated T regss at x cells kg patient weight We will use the primary outcome T the time to severe grade or GVH to death monitored over the first days post allotransplant for efficacy Preclinical in
vitro and in vivo studies pursuing the mechanism of action of fucosylated Tregs along with correlating in vivo outcome measures with ongoing clinical results The results from these proposed studies will provide us with sufficient information to assess the merits of advancing this cell based approach for GVHD into a Phase IIb multicenter trial If ultimately successful availability of fucosylated Tregs will provide additional options in the clinical management of GVHD for better patient recovery and improved quality of life Furthermore it will stimulate exploration of this promising new cell therapeutic approach for application with autoimmune and other diseases PUBLIC HEALTH RELEVANCE Acute and chronic graft versus host disease GVHD imposes not only a significant physical and economic burden on transplant patients but also negatively impacts survival in the setting of an allogeneic transplant In the present submission we are proposing a novel cell based therapeutic strategy for GVHD This approach involves the systemic administration of rd party cord blood derived regulatory T cells Tregs pretreated with TZ which is a kit comprised of the enzyme fucosyltransferase and its substrate guanosine diphosphate fucose We are capitalizing on the well established anti inflammatory effects of Tregs and through ex vivo pretreatment of these cells with TZ we are enhancing their ability to home to sites of selectin upregulation such as inflamed tissue This enhanced homing may lead to improved outcomes and possibly circumvent the need for large scale cell expansion efforts Against a background of positive proof of concept preclinical results we are proposing to translate this novel approach to the clinic in a Phase I IIa safety and preliminary efficacy study