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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1402-1403 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.2843
Are Vaccines Making a Comeback in Non–Small-Cell Lung Cancer?Mary Crowley Cancer Research Centers; Texas Oncology PA; and Sammons Cancer Center, Baylor University Medical Center, Dallas, TX For decades we have investigated immune-based therapies in other types of cancer, namely melanoma, prostate, renal cell, non-Hodgkin's lymphoma, bladder cancer, and renal cell carcinoma.1-6 However, lung cancer has historically not been considered to be an immunogenic group of tumors. Therefore, the foundation of any lung cancer immunotherapy must rest on a solid rationale for activating and directing the immune system to recognize subtle differences between cancer cells and normal cells. The article by Neninger Vinageras et al6a focuses on the successes of therapies targeting epidermal growth factor receptor to identify one such difference. The results support a unique strategy involving both immune activation and targeted therapy. The investigators constructed a conjugated vaccine product involving a yeast-derived human recombinant epidermal growth factor (EGF) protein and an Escherichia coli–derived P64K Neisseria meningitides protein. Within 4 weeks of completion of frontline platinum-based chemotherapy advanced non–small-cell lung cancer (NSCLC), patients (50 stage IIIB; 30 stage IV) were randomly assigned to receive vaccine or supportive care. Results demonstrated significant correlation of survival in the vaccinated patients (n = 40) to two surrogate parameters: induction of anti EGF antibodies (immune effect) and reduction in serum EGF concentration (targeted effect). Results also suggested overall survival advantage in vaccine-treated patients compared with controls at 60 years or younger. Historically, there have been several hypotheses to explain potential lack of anticancer immune activity in NSCLC. These include ineffective priming of tumor-specific T cells, lack of high-avidity of primed tumor-specific T cells, and physical or functional disabling of primed tumor-specific T cells by the primary host and or tumor-related mechanism. For example, in NSCLC a high proportion of the tumor-infiltrating lymphocytes are immunosuppressive T regulatory cells (CD4+ CD25+) that secrete transforming growth factor-β (TFG-β) and express a high level of cytotoxic T-lymphocyte antigen-4.7 These cells have been shown to impede immune activation by facilitating T-cell tolerance to tumor associated antigens rather than cross-priming CD8+ T cells resulting in the nonproliferation of killer T cells that recognize the tumor without attacking it.7-9 Elevated levels of interleukin (IL)-10 and TFG-β are found in patients with NSCLC. Animal models have shown immune suppression is mediated by these cytokines serving as a defense for malignant T cells against the body's immune system.10-12 Other vaccines in NSCLC have focused on methods of enhancing tumor antigen recognition. Most notable approaches already involved in phase III investigation in NSCLC include Belagenpumatucel-L, L-BLP 25, and MAGE-3 vaccines.
Belagenpumatucel-L is a nonviral gene-based allogeneic vaccine that incorporates the TFG-β2 antisense gene into a cocktail of four different NSCLC cell lines.13 A recent randomized phase II trial involving 75 patients was recently completed. A dose-related survival advantage to belagenpumatucel-L was demonstrated.13 Furthermore, patients who achieved stable disease or better with vaccination had increased production of relevant immunostimulatory cytokines (interferon- The L-BLP 25 liposome vaccine consists of a lipoprotein that is slightly larger that one tandem-repeat of the MUC1 backbone and an immunoadjuvant, monophosphoral lipid-A contained in a liposomal formulation.14 Trials of the L-BLP-25 vaccine in stage III and IV NSCLC patients demonstrated safety of the vaccine but did not demonstrate a statistically significant survival benefit. However, a subset of patients (n = 75) with IIIB disease demonstrated a trend towards improved survival (P =. 09).15 MAGE-3 is aberrantly expressed in a wide variety of tumors, including NSCLC.16 Several CD8+ T-cell epitopes of MAGE-3 have been identified in vitro.17-19 Based on these findings, synthetic peptides corresponding to these epitopes have been introduced into clinical vaccination studies. A recent randomized phase II trial was conducted20 involving 182 stage IB or II NSCLC MAGE-A3 positive patients (122 vaccine and 60 placebo). Results demonstrated a trend towards improved survival in the stage II patients receiving the vaccine compared with placebo. Within the next two years it is likely that the phase III trials involving belagenpumatucel-L, MAGE-3 vaccine and L-BLP 25 will be completed. Other vaccines in NSCLC demonstrating evidence of activity in phase I/II trials include GVAX, B7.1, EP2101, L523S and telomerase GV1001.21 It is hoped that over the next few years our knowledge of the immune system's role against cancer will further improve and our clinical experience with the use of various vaccines involving different stages of disease in NSCLC will enable a "toolbox" of these nontoxic therapeutics to be expanded into the management of NCSLC. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Alexandroff AB, Jackson AM, O'Donnell MA, et al: BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689-1694, 1999[CrossRef][Medline] 2. Coppin C, Porzsolt F, Awa A, et al: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 3:CD001425, 2005 3. Eton O, Legha SS, Bedikian AY, et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: Results from a phase III randomized trial. J Clin Oncol 20:2045-2052, 2002 4. Kaufman HL, Wang W, Manola J, et al: Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): A trial of the Eastern Cooperative Oncology Group. J Clin Oncol 22:2122-2132, 2004 5. Kwak LW: Translational development of active immunotherapy for hematologic malignancies. Semin Oncol 30:17-22, 2003[Medline] 6. Quan WD, Dean Jr GE, Spears L, et al: Active specific immunotherapy of metastatic melanoma with an antiidiotype vaccine: A phase I/II trial of I-Mel-2 plus SAF-m. J Clin Oncol 15:2103-2110, 1997 6. Neninger Vinageras EN, de la Torre A, Osorio Rodríguez M, et al: Phase II randomized controlled trial of epidermal growth factor vaccine in advanced non–small-cell lung cancer. J Clin Oncol 26:1452-1458, 2008 7. Woo EY, Yeh H, Chu CS, et al: Cutting edge: Regulatory T-cells from lung cancer patients directly inhibit autologous T-cell proliferation. J Immunol 168:4272-4276, 2002 8. Dohadwala M, Luo J, Zhu L, et al: Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem 276:20809-20812, 2001 9. Neuner A, Schindel M, Wildenberg U, et al: Prognostic significance of cytokine modulation in non-small cell lung cancer. Int J Cancer 101:287-292, 2002[CrossRef][Medline] 10. Fontana A, Frei K, Bodmer S, et al: Transforming growth factor-beta inhibits the generation of cytotoxic T-cells in virus-infected mice. J Immunol 143:3230-3234, 1989[Abstract] 11. Rook AH, Kehrl JH, Wakefield LM, et al: Effects of transforming growth factor beta on the functions of natural killer cells: Depressed cytolytic activity and blunting of interferon responsiveness. J Immunol 136:3916-3920, 1986[Abstract] 12. Tsunawaki S, Sporn M, Ding A, et al: Deactivation of macrophages by transforming growth factor-beta. Nature 334:260-262, 1988[CrossRef][Medline] 13. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al: Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol 24:4721-4730, 2006 14. Palmer M, Parker J, Modi S, et al: Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer. Clin Lung Cancer 3:49-58, 2001[Medline] 15. Butts C, Murray N, Maksymiuk A, et al: Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol 23:6674-6681, 2005 16. Van den Eynde BJ, van der Bruggen P: T-cell defined tumor antigens. Curr Opin Immunol 9:684-693, 1997[CrossRef][Medline] 17. Fleischhauer K, Fruci D, Van Endert P, et al: Characterization of antigenic peptides presented by HLA-B44 molecules on tumor cells expressing the gene MAGE-3. Int J Cancer 68:622-628, 1996[CrossRef][Medline] 18. Keogh E, Fikes J, Southwood S, et al: Identification of new epitopes from four different tumor-associated antigens: Recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity. J Immunol 167:787-796, 2001 19. Russo V, Tanzarella S, Dalerba P, et al: Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce a class I-restricted T-cell response. Proc Natl Acad Sci U S A 97:2185-2190, 2000 20. Halmos BH: Lung Cancer II. ASCO Annual Meeting Summaries. Alexandria, VA, ASCO, 2006, pp 156-160 21. Nemunaitis J, Nemunaitis J: A review of vaccine clinical trials for non-small cell lung cancer. Expert Opin Biol Ther 7:89-102, 2007[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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; IL-6; IL-4) and positive clinical outcomes were correlated with development of human leukocyte antigen antibody response as well as T-lymphocyte activation. 
