Immunity and lung cancer: perspectives for an antitumor vaccine

The founding hypothesis of the anti-tumor vaccine is the following: anti-tumor immunity results from the expression of specific antigens by cancer cells which differentiate them from normal cells. These antigens would be able to stimulate the immune system and become targets for mediated rejection. Several observations can be pur forward in support of this hypothesis: 1) patients with early stage lung cancer have an activated immune system as is evidenced by the activation of tumor infiltrating lymphocytes or the increased serum level of soluble IL-2 receptor. This immune system activation contrasts with the generally observed immune deficiency in advanced stages; 2) antibodies directed against cancer cell antigens (for example, anti-mutant-p53 antigens) are detected in the serum of patients with lung cancer. In this setting, several monoclonal antibodies have been generated against lung cancer tumor cell lines. Some recognize tumor-associated antigens while others are directed against tumor marker oncogene products, or growth factors. Monoclonal antibodies can be used coupled with radioisotopes, antimitotic agents or toxins, mainly ricin. The goal is to use the monoclonal antibody selectivity to vehicle the active anticancer substance to the site of the tumor. For small-cell cancer, studies are now being conducted to assess the efficacy of monoclonal antibodies directed against NCAM glycoproteins or GRP. Among the different cell effectors of anti-cancer immunity, NK cells have a spontaneous cytotoxic effect against several histologically distinct tumor cell lines. This activity is independent of previous antigenic sensitization. However, administration of interleukin-2 or intratumoral injection of BCG can stimulate NK activity. In addition, NK cells express a receptor for the Fc portion of IgG immunoglobulins recognized by CD16 antibodies. Via the Fc receptor NK cells can induce antibody-dependent cytotoxic activity. Other major effectors, LAK cells, result mainly from interleukin-2 activation of NK cells. Injected at high doses, interleukin-2, associated or not with in vitro amplified LAK autologs, provokes tumor response in patients with several types of solid tumors. Unfortunately, it is much less active in lung cancer Conversely, combining autologous tumor infiltrating lymphocytes (TIL) and interleukin-2 could be an adjuvant treatment for operated lung cancer patient. The greatest hopes for anti-tumor vaccine are placed in one final effector, probably the most important: the cytotoxic T lymphocyte. These lymphocytes can be stimulated in vitro by autologous tumor cells and produce a specific cytotoxic response against the stimulating tumor. They are activated in the presence of interferon-gamma and tumor rejection antigens. These antigens are produced by the tumor and result either from the expression of normally silent genes in the non-cancerous cells, or from the expression of genes carrying point mutations. Among the tumor rejection antigens detected in patients with lung disease, products of IMAGE genes (which are silent in normal cells) and products of the oncogene HER2/neu are noteworthy. The main challenge today is to make these antigens sufficiently "immunogenic" so they can stimulate in vivo a specific tumor rejection response. This is the aim of specific immunotherapy using antigenic peptide vaccines.