Cellular immunodeficiency is associated with human
cancer. Extensive reviews on
cancer of the head and neck, lung, esophagus and breast convince the author that for these diseases the immunodeficiency is reasonably well established yet the mechanisms are poorly understood. Evidence indicates that other
tumors are similarly associated with cellular immune deficiency. The advent of recombinant
cytokines and of antitumor
monoclonal antibodies has served to focus attention toward direct tumoricidal mechanisms. As
tumor antigens relating to cellular and humoral immune mechanisms are being defined and
vaccine strategies are increasingly being attempted, it is critical to confront issues of the mechanism of anergy and effective immunorestoration in order to maximize the potential of cellular immune response to address these
tumor antigens. Intrinsic to this approach is the introduction of contrasuppressive
therapy to alleviate the
tumor-associated immune suppression. Encouraging attempts have been made with
plasmapheresis,
indomethacin, low-dose
cyclophosphamide, anti CTLA-4, anti
FAS ligand and, perhaps in the future, more judiciously applied
chemotherapy. In contrast to the popular notion that thymic involution cannot be reversed in the adult, studies from the author's laboratory indicate that in aged
hydrocortisone stressed mice, a natural Type 1-cytokine mixture (IRX-2) hastens the reversal of thymic involution and promotes T-cell responses to
cytokines and
mitogens. Recombinant
IL-1 and
IL-2 by themselves, and in combination, were inactive. Similar positive effects were observed with oral
zinc,
zinc-
thymulin and
thymosin alpha(1). The combination of a natural
cytokine mixture (IRX-2) with
thymosin alpha1 had a very large effect and increased the absolute number of peripheral T lymphocytes as measured in the spleen. In studies of combination
immunotherapy in lymphocytopenic squamous cell
head and neck cancer patients using
IRX-2 (18 patients) and
IRX-2 plus
thymosin alpha(1) (IRX-3) in IRX-2-refractory patients (7 patients), marked increases in CD(45)RA(+) 'naïve' T cells (>250/mm(3)) were observed. These are among the first insights into how to generate T lymphocyte replacement in the adult. These and many other experimental efforts point to ways to achieve more effective
immunotherapy of human
cancer in the future, particularly if
tumor-induced immune deficiency can be effectively addressed.