Phase I Amount
$1,059,489
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 TZ101. TZ101 is comprised of the enzyme α 1, 3 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 "regulatory T cells" reveals over 400 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: 1) Production of cGMP TZ101 reagents (FTVI and GDP-fucose) 2) Phase I: examination of the safety of dose level 1: fuocsylated T-regs at 1x106 /kg patient weight. We will use three co-primary outcomes measures for safety: 1) time to severe infusional toxicity, 2) grade 3, 4 GVHD and 3) death. 3) Phase IIa: examination of preliminary efficacy at a single dose of fucosylated T-regss at 1x107 cells/kg patient weight. We will use the primary outcome T = the time to severe (grade 3 or 4) GVH to death, monitored over the first 100 days post allotransplant for efficacy 4) 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 Statement: 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 3rd party cord blood-derived regulatory T-cells (Tregs) pretreated with TZ101 which is a kit comprised of the enzyme α 1, 3 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 TZ101 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.
NIH Spending Category: Cancer; Clinical Research; Clinical Trials and Supportive Activities; Hematology; Prevention; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation
Project Terms: Acute; Address; Affect; Allogenic; allotransplant; Anti-inflammatory; Anti-Inflammatory Agents; Autoimmune Process; base; Binding (Molecular Function); Calcineurin inhibitor; Cancer Center; CD44 gene; cell type; Cells; Cessation of life; cGMP production; Chronic; Chronic Graft Versus Host Disease; Clinic; Clinical; Clinical Management; Clinical Research; Clinical Trials; Collaborations; Contracts; Cyclic GMP; Cyclosporine; cytokine; Dendritic Cells; Disease; Dose; E-Selectin; Economic Burden; Engraftment; Enrollment; Enzymes; Florida; follow-up; Fucose; Funding; Future; galactoside 3-fucosyltransferase; Glycoproteins; Graft-vs-Host Disease; Grant; Guanosine Diphosphate Fucose; Hematologic Neoplasms; Hematopoietic stem cells; Home environment; Homing; Immune; immune function; improved; In Vitro; in vivo; Inborn Genetic Diseases; Incubated; Infusion procedures; innovation; Killer Cells; Lead; Ligands; Lymphoproliferative Disorders; Mediating; Membrane Glycoproteins; Minnesota; Monitor; Mortality Vital Statistics; Multicenter Trials; Natural immunosuppression; novel; novel strategies; open label; Outcome; Outcome Measure; P-Selectin; patient population; Patients; Phase; phase I trial; Population; pre-clinical; Pre-Clinical Model; preclinical study; Prevention; Prevention approach; primary outcome; public health relevance; Quality of life; Reagent; Recovery; Regulatory T-Lymphocyte; Research Personnel; response; Risk; Safety; safety study; Selectins; Series; Site; Staging; stem; Stem cell transplant; Stem cells; sugar; T-Lymphocyte; Tacrolimus; Therapeutic; Time; TimeLine; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation; treatment planning; Umbilical Cord Blood; Universities; Up-Regulation (Physiology); Weigh
