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. ? ? ?
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