Radioimmunotherapy of non-hodgkin's lymphoma

Illidge, Timothy Martin (1999) Radioimmunotherapy of non-hodgkin's lymphoma. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

The work described in this thesis has focused on clarifying some of the important determinants and mechanisms of effective RIT of syngeneic B-cell lymphoma, both in vivo and in vitro. A successful animal model of RIT in B cell lymphomas was established by initially generating a panel of antibodies against mouse B cell antigens. The in vitro characteristics of these antibodies have been compared with their subsequent performance, in biodistribution studies and RIT in vivo. For the first time in an in vivo model the relative contributions of antibody and irradiation are described. Some antibodies including anti-MHC Class II were shown to be effective delivery vehicles of low doses of Iondine-131. These antibodies, which appear to be inactive delivery vehicles can cure animals with low burdens of tumour. However antibodies such as anti-idiotype and anti-CD40 which are active as "naked" antibodies are required to eradicate larger tumour burdens and to cure animals. For anti-idiotype antibodies the antibody and irradiation were shown to have an additive effect in vitro and in vivo in increasing the amount of tumour apoptosis. This increased therapeutic efficacy translated into animals with large tumour burdens being cured. These results strongly imply that RIT is much more than targeted irradiation and suggest potential mechanisms for the successes in the clinic.

During the course of this work a new in vivo and in vitro variant of the BCL₁ tumour was isolated Π-BCL₁. In contrast to the BCL₁ tumour this variant establishes as a syngeneic nodular lymphoma in vivo and grows in free suspension in vitro. This tumour model has provided a useful tool to investigate the induction of apoptosis both in vitro and in vivo.

Finally apoptosis induced by irradiation and antibody were investigated in murine and human lymphoma cells in vitro. The murine radiosensitive B- and T-cell lymphomas were demonstrated to induce large amounts of early apoptosis within 24 hours.

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