Joint Fellowship Training Program
Mentor:
Steven R. Bauer, Ph.D.
Organizational Affiliation and Position:
Biologist
Laboratory of Stem Cell Biology, Division of Cell and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration
Email:
steven.bauer@fda.hhs.gov
Telephone:
301-827-0684
Title of Research Program:
Safety and efficacy of ex-vivo cell and gene therapy
Project Summary:
We have established a model system to study the multipstep process of virally mediated tumorigenesis 1 with the ultimate goal of assuring safer combination cellular and gene therapies. The combination of cell plus gene therapies holds tremendous potential for the treatment or cure of cancer. Many cell therapies rely on ex vivo gene transduction followed by selection and expansion to achieve the desired number of cells with the desired therapeutic properties. Unfortunately, three out of eleven patients in a SCID gene therapy trial received retrovirally-transduced hematopoietic stem cells and subsequently came down with T cell leukemia. This illustrates the importance of understanding mechanisms of tumorigenesis when considering risks and benefits of combined cellular and gene therapy.
Proposed Project for IOTF Fellow:
In this lab, fellows would utilize a model system that we have established to increase our understanding of the multistep transformation1 process with the ultimate goal of assuring safer combination cellular and gene therapies. Our lab uses normal mouse precursor B-cells cultured with recombinant IL-7 and bone-marrow stroma. These cells are normal but proliferate indefinitely in the presence of IL-7 and the stromal cells. We have demonstrated that these pre-B cells can be infected and transformed in vitro by dual oncogene retroviruses carrying c-myc with either v-abl or v-raf1. We have used this model to study some of the important steps that lead to leukemia including mechanisms that lead to constitutive activation of growth factor signal transduction pathways1 and mechanisms that lead to loss of sensitivity to growth inhibition factors, specifically TGF-beta. However, many questions remain and more global approaches such as micro array and proteomics techniques could be used by IOTF fellows to compare and contrast the effects of different oncogenes introduced into normal cells using oncogenic retroviruses. We expect that knowledge gained will ultimately enhance our ability to safely use vector-transduced precursor cell populations for use in treatment of a variety of human diseases. We also expect that a better understanding of oncogenic subversion of growth pathway signaling will lead to safer and a greater range of therapeutic approaches to lymphoid lineage pathologies and tumors in general.
Regulatory Activity:
The PI has extensive experience in regulation of cellular and gene therapies (since 1991) and will mentor the fellow in the investigational new drug (IND) review process in the areas of cell and gene therapies, especially those related to cancer (e.g., gene-transduced stem cells, allogeneic stem cells for hematopoietic reconstitution). The fellow will gradually accumulate experience and spend up to 50% of their time in reviewing manufacturing, production, and characterization of cell or gene therapy products. M.D.s can also spend a portion of their time learning and performing clinical reviews within the clinical/pharmacology/toxicology review division.
Reference(s):
Hilbert DM, Theisen PW, Rudikoff EK, Bauer SR. Interaction of abl and raf with IL-7 signaling pathway and transformation of pre-B cells from resistant mice. Oncogene 1998 Oct 22;17(16):2125-35.
