The design of effective immune therapies to eradicate residual malignant cells following chemotherapy is dependent on understanding immune and hematopoietic dysfunctions present in this period. Toward this end, we have examined cellular populations and their function in patients with cancer before and after therapy. First, we carried out preclinical studies to established approaches for investigating T cell immune reconsitution after chemotherapy. We then used these approaches to characterize pathways of T cell regeneration in patients and found that the majority of CD4+ T cells present in the post-chemotherapy period are derived in adults from expansion of mature peripheral T cells. Populations of T cells derived from expansion are susceptible to apoptosis in vitro and, after partial reconstitution of peripheral CD4+ T cell counts, decline in number. The resulting T cell repertoire is oligoclonal with clonal deficits as well as clonal over-representations. Efforts are in progress to determine if thymic recovery occurs at late time points in adults following acute T cell depletion, and to characterize thymic regulation. Two clinical studies have been initiated based on the results described with the intent to derive strategies to maximize T cell immunocompetence in adult patients treated with chemotherapy and to investigate NK cell biology and regeneration. A third study is being constructed to combine vaccines with transplant therapy based on information regarding immune reconstitution. A second facet of the work focused on immune reconstitution concerns characterizing alterations that may occur in hematopoietic/pre-thymocyte stem 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. The chemokine Mig has been identified as one such negative regulator. These results have implications for T cell regeneration and for gene manipulation of hematopoietic stem cells.
