The long-term objective of both the proposal and candidate is to better understand the interaction of malignancies and tumor specific T cell reconstitution in the setting of hematopoietic transplantation, such that improved immunotherapeutic strategies can be developed. This proposal describes a 5-year mentored training program for the principal investigator, who has completed residency training in both internal medicine and pediatrics and fellowship training in hematology/oncology and bone marrow transplantation. The applicant now seeks to acquire additional training and expanded research skills with the goal of preparation for independence as a physician scientist. This program will promote the development of skills in hematopoietic stem cell biology as applied towards transplantation immunology and development of a novel strategy of hematopoietic stem cell (HSC) derived immunotherapy. Dr. Irving Weissman, a recognized leader in the field of stem cell biology who has trained numerous postdoctoral students and graduate students will mentor the principal investigator's scientific development with additional guidance provided by a selected advisory committee. The long range goal of this project is to address the question of whether hematopoietic stem cells carrying genes encoding anti-tumor T cell receptors (TCR) can generate tumor reactive T cells and generate a directed graft versus malignacy effect without graft versus host disease (GVHD). Such antigen specific TCR transduced HSC could, with a single inoculum of modified stem cells provide cancer patients with a continuously renewing and expanding pure population of tumor reactive T cells. The central hypothesis of this work is that stem cell derived immunotherapy can provide a powerful, long acting and tumor specific immune response following transplantation. To explore proof of principle of such a strategy we propose to (1) Develop a murine model of Acute Myeloid Leukemia (AMI), modified to express 2 model tumor/leukemia associated antigens, (2) Determine the ability of HSC and common lymphocyte progenitors (CLP) derived from TCR transgenic mice which express TCR specific to model antigens to engraft into non-transgenic recipients and generate Class I or Class II restricted antigen-specific T cells; (3) Define the reactivity of naive and activated TCR transgenic donor derived T-cells in-vitro as well as following adoptive transfer into mice bearing AML expressing the target model tumor antigens; (4) Determine the ability of transplanted TCR-transgenic HSC to generate tumor antigen specific T-cells and affect tumor specific GVL in recipients bearing AML at the time of and following transplantation. Proof of principle of such a stem cell-derived immunotherapy strategy could lead to translation to the clinic, where patients receiving ablative and non-myeloablative transplants could engender a specific GVL response without GVHD, thereby effecting long term cure and prevention of relapse from minimal residual disease present at the time of transplant.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL076335-04
Application #
7436303
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M2))
Program Officer
Mondoro, Traci
Project Start
2005-07-04
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$123,471
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Chan, Charles K F; Chen, Ching-Cheng; Luppen, Cynthia A et al. (2009) Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature 457:490-4
Czechowicz, Agnieszka; Kraft, Daniel; Weissman, Irving L et al. (2007) Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science 318:1296-9