|
Abstract
Lung cancer is the most lethal tumor type in the US and Europe, with small cell lung cancer (SCLC) accounting for 15 to 18% of these cases (1, 2). SCLC is one of the most aggressive of all cancers, with up to 70% of patients presenting with distant metastasis at time of diagnosis (3, 4). Despite being initially responsive to therapy, currently the average survival for SCLC cases with limited disease is about 18 months, while patients with extensive disease survive about 9 months from the date of diagnosis (5). New treatment modalities are therefore urgently needed.
The search for antigenic targets that could be utilized as part of a vaccine therapy in cancer has been an area of intense research. Identifying the array of antigenic targets in SCLC and understanding whether such responses can result in anti-tumor immunity is critical, and may lead to successful immune vaccination against SCLC. We identified SOX Group B and ZIC2 proteins as highly immunogenic neuro-ectodermal antigens in SCLC by SEREX (6). We recently completed the analysis of 90 SCLC patients, 42 (47%) of whom had antibodies to either SOX1 or ZIC2. None had autoimmune paraneoplastic disease. SOX1, 2 and 3 antibodies were present in 28, 22 and 16% of patients respectively and 28% had ZIC2 antibodies. All patients with SOX2 and/or SOX3 antibodies were SOX1 seropositive. In contrast, only 8 patients (9%) had both SOX and ZIC2 antibodies. 36% of SOX1 seropositive patients had titers equal to or greater than 1:106. Antibody titers against all antigens were highest at time of diagnosis and stable up to 6 months after. Seroreactivity against either SOX1 or ZIC2 showed statistically significant correlations with younger age, female gender, lower LDH levels and better response to initial therapy. Trends towards better overall survival, a larger proportion of limited stage disease and longer times to progression were observed for all seropositive patients when compared to seronegatives.
A significant number of neuro-ectodermal antigenic proteins were independently isolated as immune targets in autoimmune paraneoplastic neurological disease (PND) associated with SCLC (7). Despite the infrequent occurrence of autoimmune PND, antibodies to neuro-ectodermal antigens associated with PND, such as Hu or VGCC occur in up to 25% of SCLC patients (8, 9, 10, 11). The presence of anti-neuro-ectodermal antigens in SCLC has been associated with clinical parameters of less aggressive disease (9, 12). Thus, immune responses directed against multiple neuro-endocrine tumor antigens might relate to a better prognosis in SCLC (13).
References
1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics. CA Cancer J Clin 2003; 53: 5-26. (PMID: 12568441)
2. Janssen-Heijnen ML, Coebergh JW. The changing epidemiology of lung cancer in Europe. Lung Cancer 2003; 41: 245-58. (PMID: 12928116)
3. Elias AD. Small cell lung cancer: state-of-the-art therapy in 1996. Chest 1997; 112: 251S-258S. (PMID: 9337299)
4. Loehrer PJ Sr. Palliative therapy: extensive small cell lung cancer. Semin Oncol 1995; 22: 40-4. (PMID: 7537903)
5. Simon GR, Wagner H. Small cell lung cancer. Chest 2003; 123: 259S-271S. (PMID: 12527584)
6. Gure AO, Stockert E, Scanlan MJ, Keresztes RS, Jager D, Altorki NK, Old LJ, Chen YT. Serological identification of embryonic neural proteins as highly immunogenic tumor antigens in small cell lung cancer. Proc Natl Acad Sci U S A 2000; 97: 4198-4203. (PMID: 10760287)
7. Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003; 349: 1543-54. (PMID: 14561798)
8. Lennon VA, Kryzer TJ, Griesmann GE, O’Suilleabhain PE, Windebank AJ, Woppmann A, Miljanich GP, Lambert EH. Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 1995; 332: 1467-74. (PMID: 7739683)
9. Graus F, Dalmau J, Rene R, Tora M, Malats N, Verschuuren JJ, Cardenal F, Vinolas N, Garcia del Muro J, Vadell C, Mason WP, Rosell R, Posner JB, Real FX. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 1997; 15: 2866-72. (PMID: 9256130)
10. Verschuuren JJ, Dalmau J, Tunkel R, Lang B, Graus F, Schramm L, Posner JB, Newsom-Davis J, Rosenfeld MR. Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic syndrome. Neurology 1998; 50: 475-9. (PMID: 9484375)
11. Monstad SE, Drivsholm L, Storstein A, Aarseth JH, Haugen M, Lang B, Vincent A, Vedeler CA. Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer. J Clin Oncol 2004; 22: 795-800. (PMID: 14990634)
12. Dalmau J, Furneaux HM, Gralla RJ, Kris MG, Posner J. B. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer - a quantitative western blot analysis. Ann Neurol 1990; 27: 544-52. (PMID: 2163235)
13. Winter SF, Sekido Y, Minna JD, McIntire D, Johnson BE, Gazdar AF, Carbone DP. Antibodies against autologous tumor cell proteins in patients with small-cell lung cancer: association with improved survival. J Natl Cancer Inst 1993; 85: 2012-8. (PMID: 8246287)
|
