Identification of biomarkers of fatty acid intake

Harvard University (Sch Of Public Hlth), Boston MA

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Abstract

Fatty acids in the blood and more recently in adipose tissue are widely used as biomarkers of fatty acid intake in individuals and populations. Feeding studies show that dietary fat composition markedly influences the fatty acid distribution of blood components and adipose tissue. Nevertheless, the relationships between specific fatty acid intake and their levels in blood and adipose tissue are scarce in epidemiologic studies. Technological advances in gas chromatography and fatty acid peak identification software now make it possible to study specific fatty acids in large population studies at a new level of sophistication. The overall goal of this project is to identify suitable blood biomarkers of specific fatty acid intake in 180 free-living subjects (90 men and 90 women). Over thirty-five fatty acids and their isomers will be identified in all study participants to: 1) Compare the ability of non-endogenously synthesized fatty acids in plasma, erythrocytes, whole blood and adipose tissue to reflect fatty acid intake, 2) Determine the distribution of individual fatty acids in these biological specimens and compare it to that of dietary fatty acid intake, and 3) Identify whether endogenously synthesized fatty acids can be suitable biomarkers of fatty acid intake. In secondary analyses we will explore specific fatty acids that may serve as indicators of food intake. The study subjects represent a subgroup of controls from an ongoing case-control study on gene-diet interactions and heart disease in Costa Rica. The composition of the diet in this population is similar to that in the United States (see preliminary results). Most importantly, all the fatty acids that are present in the biological samples from the United States can be identified in the Costa Rican samples. Our proposed study offers a unique opportunity to compare dietary intake, blood constituents and adipose tissue in the same population. Dietary assessment tools have been validated and all the biological specimens and dietary intake information have already been collected and adequately archived. This study will provide the most complete data set to validate the use of biochemical markers of specific fatty acid intake and improve our understanding of their role in carcinogenesis. Relapsed B cell lymphomas are incurable with conventional therapies except stem cell transplantation, a toxic treatment modality which salvages only 20-50% of patients with recurrent disease. Innovative new treatment approaches are therefore clearly necessary for this disease. This project will evaluate the feasibility, safety, toxicity, and efficacy of treating patients with relapsed follicular lymphomas with autologous CD8+ cytotoxic T lymphocytes (CTL) which have been genetically modified to express a chimeric T cell receptor recognizing the CD20 antigen present on B cell lymphomas. In Aim 1, we will perform preclinical studies transfecting autologous cytotoxic T lymphocytes obtained by apheresis with an scFvFc:zeta chimeric T cell receptor recognizing the CD20 antigen, clone and expand the transfected T cells, and document their specific cytotoxicity for CD20-expressing target cells. Comparative analyses will be performed using cytotoxic T cells transfected with alternative chimeric T cell receptors recognizing the CD19 and CD22 antigens. In Aim 2, we will assess the safety, feasibility, and toxicity of infusing ex-vivo expanded autologous CD8+ T cell clones expressing a CD20-specific scFvFc:zeta chimeric immunoreceptor into patients with relapsed follicular lymphoma in a small Phase I pilot trial. In Aim 3, we will monitor the trafficking of adoptively transferred CD20-specific CD8+ T cell clones to lymph nodes and other tumor sites and their persistence in vivo using serial quantitative Indium-111 gamma camera imaging, quantitative real time PCR and flow cytometric analyses of blood, bone marrow and lymph nodes. In Aim 4, we will rigorously assess the partial and complete response rates, remission durations, and adverse events induced by treatment with CTL bearing a CD20-specific chimeric T cell receptor in a Phase II trial planned to accrue 50 patients over 3 years. We anticipate that these studies will document the technical feasibility of this approach, the safety of administering genetically modified T cells and their ability to induce objective remissions in patients who have failed standard chemotherapy.