Immunophenotypic and functional analyses of a cyclophosphamide-induced LGL population in immunised rats : potential for chemoimmunotherapy of tumours
In principle, immunotherapy of cancer can be achieved by administration of agents such as interleukin-2 (IL-2), or by lymphokine-regulated anti-tumour effectors such as lymphokine-activated killer (LAK) cells or natural killer (NK) cells. Modalities currently available, however, achieve only limited success and may be severely toxic. Augmented generation of the above factors in vivo, perhaps in combination with chemotherapy, might significantly improve anti-tumour efficacy. This thesis describes a marked, relative increase in spleen NK activity in rats after high-dose cyclophosphamide (CY) administration, followed by systemic immunisation with a T-dependent antigen in adjuvant. This effect was not detected after CY alone or immunisation alone, and was not inhibited by cyclosporin A, a drug which, at least in vitro, blocks T cell production of various lymphokines capable of augmenting NK activity. Enhanced cytoloxicity was related to the dose of CY. It was detected within days of treatment and persisted for several weeks. Detailed immunophenotypic analyses of concomitant changes in other lymphocyte subsets, measured by flow cytometry, are also reported. Recent studies indicate that NK cells are the precursors of LAK cells. The capacity for host LAK generation in vitro after CY/immunisation was thus examined. This was severely compromised early after treatment, when NK activity within the lymphoid population was higher than normal, but recovered within 2-3 weeks. Efforts to detect enhanced NK and LAK activities after high-dose recombinant IL-2 (R.IL-2) administration to normal rats were unsuccessful, but immunophenotypic and histotogical changes indicative of cellular activation in vivo are described. NK cells have been implicated in host responses to malignancy, particularly under conditions of minimal tumour burden. The anti-tumour efficacy of the CY/immunisation protocol was therefore tested in rats bearing advanced pulmonary metastases of an NK-sensitive carcinosarcoma. Immunisation alone had no anti-tumour effects, whilst CY alone significantly extended survival time; long-term survival was rarely achieved. By contrast, tumour growth was eradicated in the majority of CY/immunised rats, a finding which suggests that efforts to maximise this novel therapeutic strategy, such as by combining it with subsequent R.IL-2 administration, would be worthwhile.