The design of effective immune therapies to eradicate residual malignant cells following chemotherapy is dependent upon understanding immune and hematopoietic dysfunctions present in this period. Toward this end, we have examined four facets of cellular function in patients with cancer before and after therapy. First, we have determined through preclinical animal models and clinical studies that the majority of CD4 T cells present in the post-chemotherapy period are derived from expansion of mature peripheral T cells. Population of T cells derived from expansion later decline in number and are susceptible to apoptosis. Two clinical studies have been initiated based on these results. The second facet of cellular function concerns the in vitro generation of T lymphocyte populations of defined cytokine phenotype: Type I (Th1, Tc1) and Type II (Th2, Tc2). CD4+ T cells of Th1-type mediated both lethal GVHD and CVL. In contrast, CD8+ cytotoxic T cells secreting either Type I or Type II cytokines were found to mediate potent GVL effects with reduced GVHD. Culture conditions have now been established for the generation of human cytokine-defined T cell subsets as a prelude to clinical studies. The third facet of the work concerns characterizing alterations in hematopoietic cell populations following chemotherapy. It was found that chemotherapy damage to hematopoietic progenitors occurred despite hematopoietic cytokine therapy. Such treatment stimulated production of negative regulators of hematopoiesis. These results have implications for T cell regeneration and for gene manipulation of hematopoietic stem cells. The fourth facet of the work has focused on antigen presenting cell biology. It has been found that cells of monocyte/macrophage lineage ar precursors of dendritic cells, and that calcium ionophore treatment of such cells provokes almost uniform conversion to harvest monocyte cells, provide approaches for new clinical therapies involving tumor antigen vaccines.
