Unfortunately few human or animal studies have focused on the role of the immune system in surveillance for lung cancer. Such lack of data leads to controversy in this field. A recently published European study of immunosuppressed patients demonstrated no increase in lung cancer in kidney or liver transplant recipients but an increase in those receiving a heart allograft (13). Based on this data it is possible to conclude that in the population as a whole immunosurveillance for lung cancer may not occur. Alternatively one could conceive that differences in cancer incidence may be unmasked only in patients with a significant smoking history, such as those requiring heart transplantation for coronary artery disease. Other observational studies, however, do not demonstrate an increase in lung cancer in heart transplant recipients, despite an increase in other cancers such as malignant melanoma and cervical carcinoma (14). Similar controversy exists in small animal models of lung cancer. Kobayashi and colleagues, for example, demonstrated that the incidence of chemically induced lung cancer is similar in immunocompetent and T cell deficient littermates while other investigators, using similar methodology, have demonstrated the importance of T cells in immunosurveillance for fibrosarcoma (15-17). Based on these and other data one must conclude that the existence of immunosurveillance for lung cancer is not rigorously supported by clinical or animal data. Thus, unlike clinical trials of immune based therapy for melanoma and renal cell carcinoma, the rationale for immunotherapy in the treatment of lung cancer deserves more background investigation. Since lung cancer, especially non small cell lung cancer (NSCLC), is the leading form of cancer related death (18,19), funding and execution of such trials is a critical priority to our field.

Adoptive cell transfer is a form of passive immunotherapy that involves identification, isolation, expansion and subsequential re-infusion of autologous lymphocytes with anti-tumor activity into patients. This form of therapy has been used with or without administration of appropriate growth factors to enhance T cell survival and expansion in vivo. Such an approach also has the theoretic advantage that identification and isolation of only a few tumor reactive lymphocytes is sufficient for therapy as these cells can be expanded significantly in ex vivo prior to reinfusion (40). The genetic modification of isolated cells and the introduction of T cell receptors with high avidity for tumor specific antigens also creates exciting therapeutic possibilities (26).

Unlike NSCLC, small-cell lung cancer (SCLC) represents only 15-20% of all primary malignancies the lung. SCLC is usually a systemic disease at the time of diagnosis and only anecdotal long-term survival has been reported. Even limited disease, although initially responsive to chemo and radiation therapy, often recurs (64,65). Based on these reasons biologic therapy, such as immunotherapy, that can offer a long-term tumor-specific response may be an ideal treatment modality for this malignancy. Gangliosides are glycolipid components of the plasma membrane that play an integral role in multiple biologic functions. Compared to the normal cellular components of the lung, neutral glycolipids are more prevalent in SCLC (66). While poorly immunogenic in and of themselves, these antigens can be successfully targeted by anti-idiotypic antibodies. This form of immunotherapy takes advantage of the fact that “secondary” antibodies raised against a primary antibody to a defined antigen, even one of low affinity, will mimic epitopes present in the original antigen in the hypervariable region of the immunoglobulin. Administration of such anti-idiotypic antibodies can then be used to generate both a humeral and cellular TAA-specific immune response as the antibody itself acts as an antigen (67,68). GD3 is a ganglioside present in tumors of neuroectodermal origin including small cell lung cancer. While itself poorly immunogenic (69), the anti-idiotype antibody to this antigen (Bec2) produces a detectable anti-GD3 immune response in as many as one-third of the treated patients (70,71). A small pilot study of Bec2 vaccination combined with BCG performed at Memorial Sloan-Kettering Cancer Center, revealed a surprisingly positive response in the 15 treated patients and acted as a nidus for a large randomized prospective trial (72). Such a study was performed between 1998 and 2002 as 515 patients from 120 institutions in 17 countries with limited SCLC were prospectively randomized to receive either vaccination with Bec2 and a BCG adjuvant or observation alone after completing induction chemoradiotherapy. When published in 2005 the investigators were unable to detect an improvement in overall survival, progression-free survival, or quality of life in those in the vaccination arm (4). While a trend towards prolonged survival was detected in the one third of patients who developed a detectable humoral immune response to the vaccination, this did not reach statistical significance. Toxicity was mostly related to local skin-site irritation with occasional systemic effects such as lethargy, arthralgia, and myalgia. Thus while this Bec2 vaccination trial presented an overall negative result the potential for vaccination and immune-based therapy as an adjuvant method for treating SCLC remains a future possibility if vaccines capable of producing a better immunologic response can be developed.

Inbred mice offer an efficient and reproducible method to study carcinogen-induced lung cancer as a highly reliable model of lung adenocarcinoma exists. A single injection of urethane leads to the development of early adenomatous tumors in the lung within 10 weeks with progression to fully invasive adenocarcinoma after 32 weeks (84). The progression of such cancers from hyperplasia to benign adenoma to fully invasive adenocarcinoma with metastatic potential mimics progression of human disease. Interestingly multiple studies have defined different strains of mice as either tumor-susceptible “high-responders” (A/J for example) or tumor resistant “low responders” (C3H He/J for example) with 100% of susceptible animals and few resistant ones developing tumors after injection of carcinogen (85). This variability in strain susceptibility to induction of lung adenocarcinoma suggests that inherent genetic factors may alter the development and/or progression of NSCLC independent of carcinogen administration or the environment (85). The use of such models to develop a better understanding of lung cancer immunology and immune evasion, as has been done for malignant melanoma, might facilitate a more rational approach toward lung cancer immunotherapy.