: An area of increasing interest, and potentially significant clinical use, is performing mismatched stem cell transplants for high-risk and refractory hematological malignancies using related donors. Such patients currently undergo transplants using HLA matched sibling or unrelated donor stem cells. Using haplotype-mismatched donors from siblings, parents or children would permit the availability of suitable donors for more than 90-95% of candidate patients. However, the main limitation is graft-versus-host disease (GVHD). GVHD can be almost eliminated by extensive T-cell depletion (>5 logs). While T cell depletion increases the risk of graft rejection, this can be overcome by the use of very large doses of stem cells. Therefore, it is desirable to have a system where very large numbers of stem cells can be efficiently processed to deplete T-cells, and with minimal loss of these stem cells. A second area of increasing interest, and potentially significant clinical use, is the isolation of Natural Killer (NK) Cells for Immunotherapy. NK cells are important cells of the innate immune system that are not involved in specific antigen recognition. These cells are important in the defense against infections, but also have potent anti-tumor effects. Currently, there is growing interest in the use of both autologous and allogeneic activated NK cells for cancer immunotherapy. In particular, the use of allogeneic NK cells mismatched for HLA-C alleles of the recipient can exert very potent anti-leukemic effect in vitro. Infusion of NK cells may also assist engraftment of stem cells in the bone marrow transplant setting. This project will focus on the development/application of a high throughput, flow through immunomagnetic cell separation system currently under development for clinical scale T-cell depletion and NK isolation. While several systems have been developed, none are currently approved for these indications, and their performance is generally suboptimal. With respect to the recovery of stem cells during T-cell depletion, a significant increase in stem cell recovery is needed, from reported mean values of 41 to over 80%, to facilitate 'mega-dose' CD34 cell therapy in mismatched transplants. Less research has been carried out for clinical scale NK cell separation technology, with current methods performing sub-optimally due to loss of over 50% of the NK cells. Specifically, therefore, our objectives are: 1.To demonstrate significantly superior performance for T-cell depletion with the aim of achieving 5 log10 depletion of T cells, with >90% recovery of CD34+ cells in greater than or equal too 80% of clinical apheresis samples obtained from normal donors. 2. To demonstrate significantly superior performance of NK cell isolation with the aim of isolating CD56+ CD3- NK cells with > 90% recovery and with <1 x 10/5 CD3+ cell contamination in greater than or equal to 90% of peripheral blood apheresis products processed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA097391-01A1
Application #
6601768
Study Section
Special Emphasis Panel (ZRG1-SSS-4 (10))
Program Officer
Mccarthy, Susan A
Project Start
2003-07-21
Project End
2007-03-31
Budget Start
2003-07-21
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$472,579
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071650709
City
Columbus
State
OH
Country
United States
Zip Code
43210
Lustberg, Maryam B; Stover, Daniel G; Chalmers, Jeffrey J (2018) Implementing Liquid Biopsies in Clinical Trials: State of Affairs, Opportunities, and Challenges. Cancer J 24:61-64
Jatana, Kris R; Balasubramanian, Priya; McMullen, Kyle P et al. (2016) Effect of surgical intervention on circulating tumor cells in patients with squamous cell carcinoma of the head and neck using a negative enrichment technology. Head Neck 38:1799-1803
McMullen, Kyle P; Chalmers, Jeffrey J; Lang, Jas C et al. (2016) Circulating tumor cells in head and neck cancer: A review. World J Otorhinolaryngol Head Neck Surg 2:109-116
Lustberg, Maryam B; Balasubramanian, Priya; Miller, Brandon et al. (2014) Heterogeneous atypical cell populations are present in blood of metastatic breast cancer patients. Breast Cancer Res 16:R23
Wu, Yongqi; Deighan, Clayton J; Miller, Brandon L et al. (2013) Isolation and analysis of rare cells in the blood of cancer patients using a negative depletion methodology. Methods 64:169-82
Xu, Jie; Mahajan, Kalpesh; Xue, Wei et al. (2012) Simultaneous, single particle, magnetization and size measurements of micron sized, magnetic particles. J Magn Magn Mater 324:4189-4199
Garcia-Villa, Alejandra; Balasubramanian, Priya; Miller, Brandon L et al. (2012) Assessment of ?-H2AX levels in circulating tumor cells from patients receiving chemotherapy. Front Oncol 2:128
Balasubramanian, Priya; Lang, James C; Jatana, Kris R et al. (2012) Multiparameter analysis, including EMT markers, on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck. PLoS One 7:e42048
Sun, Jianxin; Zborowski, Maciej; Chalmers, Jeffrey J (2011) Quantification of both the presence, and oxidation state, of Mn in Bacillus atrophaeus spores and its imparting of magnetic susceptibility to the spores. Biotechnol Bioeng 108:1119-29
Zborowski, Maciej; Chalmers, Jeffrey J (2011) Rare cell separation and analysis by magnetic sorting. Anal Chem 83:8050-6

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