The candidate's objective is to become the principal investigator of a laboratory equipped to perform translational studies focusing on novel ways to modulate the immune system to target cancer. As she has obtained a large part of the relevant training to achieve this goal, the K08 would allow her to complete the final strides before achieving independent Assistant Professor status. Specifically, the candidate aspires to address relapse after allogeneic hematopoietic cell transplantation (HCT) in patients with high-risk leukemias as this remains a significant cause of treatment failure and death. CD8+ T-cell clones specific for WT1, a protein that is over-expressed in leukemic cells with the highest levels expressed in leukemic stem cells (LSC), generated from HLA-matched donors have been administered after HCT without significant toxicity and observed to preferentially localize to the marrow. However, anti-leukemic efficacy was limited in some patients by the lack of long-term in vivo T-cell persistence, low avidity for the WT1 target, and may have been enhanced by simultaneously targeting additional epitopes. To address these obstacles, this project proposes in a Phase I/II trial, to generate EBV- or CMV-specific memory T cells from matched donors and transduce them to express a high affinity WT1-specific TCR before infusion in patients with high-risk AML, CML and MDS post-HCT. The candidate will assess the safety, persistence, localization and function of the transferred cells and correlate the parameters with the efficacy o preventing relapse in post-HCT patients who are in CR (Clinical Study Arm 1), and the potential antileukemic activity of transferred cells in patients with detectable disease (Clinical Study Arm 2). She then proposes to explore the feasibility of targeting the newly identified LSC and cancer testis antigen CCNA1 with T cell therapy by testing if non-gene modified T-cell products from leukemic donors can be generated for use in future clinical trials to assess safety. In parallel, she will screen for CCNA1-specific high-avidity/affinity CD8+ T cell clones, and isolate their TCR for potential use as 'off the shelf' reagents. If safety of targeting either antigen alone is demonstrated, these reagents could be used concurrently in future clinical trials. The candidate will receive advanced training in recently developed novel mass spectrometry- based methods to assess multiple parameters simultaneously on infused T-cells in addition to flow cytometry- based methods, biostatistics, molecular immunology, and FDA related regulatory conduct of gene-modified clinical trials. The research and training activities will be primarily conducted at the Fred Hutchinson Cancer Research Center, which is a superb environment for basic, clinical and translational research, particularly in the field of HCT. The candidate will be mentored by Dr Phil Greenberg, an experienced and successful mentor who has an established career in the field of translational immunology and immunotherapy. The proposed translational studies are aimed at developing potent, non-toxic treatments for patients with AML, MDS and CML, determining immunologic parameters for successful leukemia eradication, and guiding the design and safe deployment of high-affinity T cells targeting LSC proteins.
The Specific Aims are: 1. Evaluate in a phase I/II trial the safety and potential efficacy of donor-derived C4-CTL in preventing relapse in remission patients at high risk of AML/MDS/CML recurrence. 2. Evaluate in a Phase I/II the safety, efficacy and potential limitations to the anti-leukemic activity of donr- derived C4-CTL in patients with MRD or recurrent AML/MDS/CML. 3. Explore the potential for targeting CCNA1 with T cell therapy as an alternate target antigen to WT1.
In an attempt to eradicate recurrent leukemia after hematopoietic cell transplantation (HCT) which is associated with a very poor outcome, patients will receive infused white blood cells that are specific for common viruses (EBV and CMV), as they have the ability to survive longer, and that are genetically modified with a strong receptor for WT1, which is a protein contained by leukemia cells. This project then proposes to examine the safety of targeting a protein called CCNA1, which is contained in leukemia stem cells, and then perform the initial steps necessary to target this protein with a strong receptor that could be used for patients in the future. This research may help patients fight recurrent leukemia with a non-toxic approach that could be used to offset or delay HCT in future studies.
