Therapeutic DNA vaccination in follicular lymphoma

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



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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