Therapeutic DNA vaccination in follicular lymphoma

Jennings, Nicola (2006). Therapeutic DNA vaccination in follicular lymphoma. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000faf8

Abstract

The experiments described in the chapters of this thesis were part of a collaborative project with colleagues at the Universities of Bournemouth, Manchester and Southampton. This Cancer Research-UK and National Blood Service (NBS) sponsored clinical trial reports on one of the first DNA vaccine trials in humans in patients with low-grade follicular lymphoma. Twenty-five patients were enrolled and the V genes encoding the V domains of their surface immunoglobulin (sIg) on the dominant malignant clone were isolated from a lymph node biopsy and single chain variable domain antibody fragments (scFv) were constructed. The V gene cassettes were cloned into the vaccine plasmid, pVAC2. pVAC2 fuses the scFv gene cassette in open reading frame to the gene for fragment C of tetanus toxoid. Each patient vaccine was produced to GMP standards and subjected to pre-release quality and sterility controls. In parallel with the clinical trial all the vaccines were administered to Dutch rabbits and antibody responses were measured. To measure anti-idiotypic responses an inducible/secretable Drosophila expression system was modified and calmodulin (CaM) tagged scFv was produced. The scFv-CaM fusion proteins were then used to measure the anti-idiotypic responses in the patients pre- and post-vaccination.The variable domains from another FL patient (but not enrolled in the trial) with an IgM paraprotein and suffering from severe autoimmune thrombocytopenia, were isolated, the scFv constructed, a DNA vaccine prepared and idiotypic antibodies raised. These reagents were used to determine whether the IgM paraprotein produced by the dominant Lymphoma clone was exhibiting anti-platelet reactivity.

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