The primary goal of this grant application is to support a mentored career development program that provides the necessary training and environment to successfully translate novel preclinical laboratory findings into a human clinical trial of adoptive cellular immunotherapy of cancer. It is the intent of this application to provide instruction in the conduct of translational research through a Master's program of Clinical Research at Case Western Reserve University which will provide fundamental knowledge for development of an investigator-initiated clinical trial. Preclinical data, generated from our laboratory utilizing a murine model of adoptive cellular immunotherapy suggests that T cells with common antigen-binding CDR3 regions of the T cell receptor undergo clonal expansion within sentinel lymph nodes. These T cell clones share identical T cell receptor CDR3 regions confirmed by DNA sequencing and are characterized by tumor specific immune reactivity. We propose to test the hypothesis that """"""""sentinel lymph nodes contain clonally-expanded tumor-specific T cells which can be identified by CDR3 gene sequencing and expanded for use in adoptive immunotherapy"""""""". In order to test our hypothesis, we propose the following:
Specific aim 1). Determine the frequency of T cells clones detected by CDR3 spectratyping in sentinel lymph nodes from patients with breast cancer and melanoma.
Specific aim 2). Identify common CDR3 regions within sentinel lymph nodes which are shared among patients with similar HLA type.
Specific aim 3). Develop a method of generating tumor-specific VB T cell clonotypes from fresh sentinel lymph nodes based upon CDR3 analysis.
Specific aim 4). Design and begin implementation of a Phase I study of adoptive immunotherapy using specific VB T cell clonotypes from tumor-draining lymph nodes in patients with advanced breast cancer or melanoma. The proposed career development plan will provide the critical additional training and expertise that is necessary for the applicant to develop a career as an independent translational clinician investigator.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA109115-05
Application #
7920256
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
2006-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2010
Total Cost
$134,460
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Zhang, Mei; Graor, Hallie; Yan, Lu et al. (2016) Identification of Melanoma-reactive CD4+ T-Cell Subsets From Human Melanoma Draining Lymph Nodes. J Immunother 39:15-26
Zhang, Mei; Graor, Hallie; Visioni, Anthony et al. (2015) T Cells Derived From Human Melanoma Draining Lymph Nodes Mediate Melanoma-specific Antitumor Responses In Vitro and In Vivo in Human Melanoma Xenograft Model. J Immunother 38:229-38
Zhang, Mei; Gao, Yunxiang; Caja, Kevin et al. (2015) Non-viral nanoparticle delivers small interfering RNA to macrophages in vitro and in vivo. PLoS One 10:e0118472
Kim, Julian A; Choi, Audrey H (2013) Effect of radiation therapy on survival in patients with resected Merkel cell carcinoma: a propensity score surveillance, epidemiology, and end results database analysis. JAMA Dermatol 149:831-8
Visioni, Anthony; Zhang, Mei; Graor, Hallie et al. (2012) Expansion of melanoma-specific T cells from lymph nodes of patients in stage III: implications for adoptive immunotherapy in treating cancer. Surgery 152:557-65; discussion 565-6
Zhang, Mei; Kim, Julian A (2012) Effect of molecular size and modification pattern on the internalization of water soluble ?-(1 ? 3)-(1 ? 4)-glucan by primary murine macrophages. Int J Biochem Cell Biol 44:914-27
Choi, A H; Barnholtz-Sloan, J S; Kim, J A (2012) Effect of radiation therapy on survival in surgically resected retroperitoneal sarcoma: a propensity score-adjusted SEER analysis. Ann Oncol 23:2449-57
Liao, Xudong; Sharma, Nikunj; Kapadia, Fehmida et al. (2011) Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest 121:2736-49
Wu, Xiao-Cheng; Eide, Melody J; King, Jessica et al. (2011) Racial and ethnic variations in incidence and survival of cutaneous melanoma in the United States, 1999-2006. J Am Acad Dermatol 65:S26-37
Weir, Hannah K; Marrett, Loraine D; Cokkinides, Vilma et al. (2011) Melanoma in adolescents and young adults (ages 15-39 years): United States, 1999-2006. J Am Acad Dermatol 65:S38-49

Showing the most recent 10 out of 14 publications