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CDX-301 and Plerixafor Combination in Stem Cell Mobilization for Transplantation

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41OD018403-01
Agency Tracking Number: R41OD018403
Amount: $100,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: OD
Solicitation Number: PA12-089
Solicitation Year: 2013
Award Year: 2013
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
119 4th Avenue
NEEDHAM, MA 02494-2725
United States
DUNS: 40793114
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (781) 433-3160
Business Contact
Phone: (781) 433-3148
Research Institution
Office of Sponsored Programs 1960 Kenny Road
United States

 () -
 Nonprofit College or University

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to evaluate a novel method to mobilize and procure a hematopoietic stem cell (HSC) allograft which we hypothesize will lead to rapid hematopoietic engraftment but cause less graft versus host disease (GVHD) compared to G-CSF mobilized peripheral blood stem cells (G-PBSC) following allogeneic HSC transplantation (HSCT). We plan to study the combination of the CXCR4 antagonist plerixafor and Flt3 ligand (CDX-301). This combination has not previously been studied but based on characteristics of both agents, we hypothesize the combination will safely mobilize a more favorable balance of HSC, conventional T-cells, regulatory T-cells (Treg), and natural killer (NK) cells which will optimize favorable graft versus leukemia (GVL) effects while mitigating deleterious GVHD reactions. A series of studies proposed in preclinical murine and non-human primate models will test our hypotheses. Despite curative potential, HSCT is associated with serious complications such as GVHD and disease relapse which compromise its success. Recently, G-PBSC has replaced bone marrow (BM) as the most commonly used donor graft source, but this trend may have been premature as emerging data suggest G-PBSC is associated with higher rates of chronic GVHD, and in pediatric patients and those with aplastic anemia, worse survival. The higher rates of GVHD observed following transplantation of G-PBSC may be due to the higher quantity of T-cells or other less well characterized factors compared to BM. In this proposal, we hypothesize that the combination of plerixafor and CDX-301 will lead to more robust hematopoietic stem/progenitor and NK-cell cell mobilization compared to plerixafor, G-CSF, or CDX-301 alone and will promote rapid hematopoietic reconstitution following transplantation with reduced risk of GVHD compared with G-PBSC. We will test these hypotheses using three specific aims. In Specific Aim 1, we will study the efficacy of the combination of CDX-301 and plerixafor in mobilization and expansion of hematopoietic stem cells and mature immune cell subsets in the peripheral blood of mice. In Specific Aim 2, we will study the potential of donor hematopoietic cells mobilized by the combination of CDX-301 and plerixaforto reduce GVHD and relapse in mismatched murine leukemia transplantation models. In Specific Aim 3: we will compare the mobilization of hematopoietic cells by plerixafor combined with either G-CSF or Flt3L in a clinically relevant non-human primate model.The successful completion of these aims will establish scientific and technical merits and will pave the way for Phase II of the Small Business Technology Transfer (STTR) process. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The transplantationof cells obtained from the blood of sibling or volunteer unrelated donors can cure many patients with serious blood disorders. Unfortunately, many patients receiving such transplants suffer complications or experience relapse of their cancer and do not benefit. This proposal seeks to improve the quality of the blood cells obtained from donors so that more patients can benefit from blood cell transplantation.

* Information listed above is at the time of submission. *

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