Immunotherapeutic approaches to B cell neoplasms

Wrightham, Mark Nicholas (1988) Immunotherapeutic approaches to B cell neoplasms. University of Southampton, Doctoral Thesis.

Abstract

Immunological control of B cell tumours could theoretically be achieved by the administration of exogenous agents such as anti-idiotypic (anti-Id) antibody or lymphokine-activated killer (LAK) cells, or by host suppression of tumour by endogenous effector systems such as natural killer (NK) cells. This thesis examines various aspects of the application of anti-Id or LAK cells to therapy of B cell neoplasms, and the possible anti-tumour action of NK cells in non-Hodgkin's lymphoma (NHL). Tumour cells from patients with B cell neoplasms often secrete small amounts of free idiotypic light chain that can be found in the urine. This offers a potentially useful source of immunogen for the preparation of anti-Id antibody, but the application of such an approach requires that monoclonal anti-light chain Id antibodies should also recognise intact idiotypic Ig. Tumour-derived urinary λ chains from a patient with typical chronic lymphocytic leukaemia (CLL) were used to raise monoclonal antibodies (mAb), and a hybridoma secreting antibody specific for idiotypic, but not normal light chain, was obtained. This mAb also bound to the patient's idiotypic IgMλ, both on neoplastic cells and in soluble form, but did not recognise normal IgM, normal serum or a panel of IgM paraproteins, and did not react with normal tonsillar cells. The epitope recognised by this mAb is characterised and compared with that bound by a conventional anti-Id mAb reactive with a composite (heavy + light chain) determinant. A given mAb to a private idiotope has only limited applicability to the treatment of lymphoma being, by definition, specific for a single tumour. Antibodies to cross-reacting idiotypic determinants (IdX) could theoretically be used to treat more than one patient. A hybridoma screening system to detect such mAbs is described, together with an assay allowing quantitation of the degree of cross-reactivity in each instance. Two examples of anti-IdX mAbs are discussed, in comparison with anti-Id mAbs of more restricted recognition. The waxing and waning of disease often seen in NHL suggests the presence of a mechanism of tumour suppression in vivo. Alternative immunotherapeutic approaches could be based on augmentation of cellular immune responses of the host to the tumour. NK cells have been implicated in such responses, and the potential contribution of this system to the control of NHL in remission has been examined in a comparative study of peripheral blood NK function in patients in the active and quiescent phases of disease. NK activity of patients in remission was significantly elevated by comparison with active NHL, and the functional properties of peripheral NK cells from a single patient in remission are described in more detail. Recent studies have suggested that NK cells may be the precursors of LAK cells generated from peripheral blood, and the anti-tumour activities of LAK from patients with NHL are also examined. LAK cells are shown to mediate ADCC against tumour targets, a finding which suggests novel therapeutic strategies.

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