Clinical outcomes of unresectable stage III NSCLC are universally poor. Survival with combination chemo-radiotherapy is 11-18 months. Investigation of additional therapies is warranted. Immunotherapies, specifically cancer vaccines, have therapeutic potential. Preliminary data indicate that autologous dendritic cells, pulsed with allogeneic tumor antigens can induce measurable immune responses in individuals with NSCLC. Responses have been seen irrespective of stage or prior therapy, and the spectrum includes responders and nonresponders. The host environment appears to play a significant role in regulating T cell responses to vaccines. We postulate that physiologic (inducible) and pathologic (constitutive expression by NSCLC tumor cells) COX-2 activity can mediate immune regulation. COX-2 is the enzyme responsible for PGE-2 production, a prominent immunosuppressive cytokine with numerous direct and indirect effects that polarize the immune response towards suppression or tolerance. Specifically, PGE-2 and monocyte-derived IL 10 induced by PGE2 may significantly suppress antigen presentation and proliferation of NSCLC specific T cells, as well as lead to premature death of DCs. Modifying the host environment with COX-2 inhibitors is feasible and a rational strategy to enhance T cell responses to DC vaccines. Literature and preliminary data support these precepts. Thus, studies are designed to test the routine effectiveness of DC vaccines in unresectable stage III NSCLC and further evaluate the immune modulating effects of COX-2 inhibitors used in concert with tumor vaccines. Postulating an inverse relationship between COX-2 activity and immunologic response to vaccines, biomarkers of COX-2 activity will be evaluated as correlative markers of immune reactivity. Markers will also be used to track biologic effects of the COX-2 inhibitor Celebrex in NSCLC.
| Hirschowitz, Edward A; Foody, Terry; Hidalgo, Giovanna E et al. (2007) Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. Lung Cancer 57:365-72 |
