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Novel synthetic receptors with improved antigen specificity and specificity for cancer therapy

具有改进的抗原特异性和癌症治疗特异性的新型合成受体

基本信息

批准号：
10365860
负责人：
STANLEY R. RIDDELL
金额：
$ 7.54万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365860
关键词：
Address Adoptive Cell Transfers Antibodies Antigen Targeting Antigens B lymphoid malignancy CD19 gene CD22 gene CD28 gene CD3 Antigens CD8-Positive T-Lymphocytes Cell Differentiation process Cell physiology Cell surface Cells Chronic Lymphocytic Leukemia Clinic Clinical Data Data Development Disease remission FDA approved Foundations Functional disorder Funding Gene Transfer Grant Hematopoietic Neoplasms Heterogeneity Hybrids Immunoglobulin Constant Region Infiltration Knock-in Knock-out Ligands Light Link Logic MS4A1 gene Major Histocompatibility Complex Malignant Neoplasms Modality Multiple Myeloma Normal Cell Outcome Patients Peptides Population Pre-Clinical Model Progress Reports Property Proteins ROR1 gene Receptor Signaling Refractory Relapse Sensitivity and Specificity Signal Pathway Signal Transduction Solid Solid Neoplasm Specific qualifier value Specificity Surface T cell therapy T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte TRA@ gene cluster TRB@ gene cluster Toxic effect Tumor Antigens Tumor Escape Tumor-infiltrating immune cells Universities Washington Work base cancer cell cancer therapy cancer type chimeric antigen receptor chimeric antigen receptor T cells clinically relevant curative treatments cytokine density design engineered T cells exhaustion gamma secretase genomic locus improved in vitro Assay in vivo in vivo Model inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma neoplastic cell next generation novel pre-clinical prevent receptor synaptogenesis targeted treatment tumor tumor heterogeneity tumor microenvironment

项目摘要

Abstract Adoptive cell therapy using T cells modified by gene transfer to express T cell receptors or synthetic chimeric antigen receptors (CARs) that specify T cell recognition of tumor associated antigens can be effective in patients with refractory malignancies. Clinical data has shown that tumor cells that express low levels of antigen or that have heterogeneous antigen expression can escape and cause relapse. To address the barrier of low antigen density on tumor cells, we have designed novel synthetic hybrid receptors based on principles of T cell receptor signaling that have superior properties and may be capable of eliminating tumor cells with low antigen levels. To address the barrier of heterogeneous antigen expression on tumor cells, we designed colocalization-dependent orthogonal protein switches that perform ‘AND’, ‘OR’, and ‘NOT’ Boolean logic at the cell surface. In principle, this approach can instruct T cells to eliminate heterogeneous tumor cell populations and spare normal antigen positive cells, extending the constellation of antigens that can be safely targeted. The studies in this application will advance these two classes of next generation synthetic receptors for multiple clinically relevant target antigens to achieve more effective and safe elimination of tumors with low and/or heterogeneous antigen expression. The specific aims are: Aim 1: To evaluate signaling and function of novel CAR/TCR hybrid receptors in primary T cells. Signaling, synapse formation, antigen sensitivity, and in vivo function and fate of T cells expressing CAR-TCR hybrid receptors introduced by lentiviral transduction or by knock-in to the T cell receptor alpha gene locus, will be compared to T cells expressing CD28/CD3z and 4-1BB/CD3z CARs targeting the same antigens. Aim 2: To evaluate chimeric costimulatory receptors for T cells engineered with CAR/TCRs. We will evaluate whether the addition of costimulation in CAR/TCR engineered T cells by co-expressing chimeric molecules that engage a tumor associated ligand will enhance antitumor function. Aim 3 To design OR and AND gated CARS specific for multiple myeloma (MM) antigens and evaluate their ability to prevent tumor escape. Multiple myeloma is responsive to T cell therapy targeting single antigens, but tumor cell heterogeneity allows escape. Co-localization dependent protein switches that can perform OR and AND logic gated recognition of heterogeneous tumor cells will be developed and evaluated for targeting multiple myeloma antigens.

摘要