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Abstract
The development of strategies for actively stimulating immunological rejection of tumors, previously an elusive goal, has been accelerated by recent improved understanding of the molecular basis of immune recognition and immune regulation of cancer cells. This has led to the identification of several tumor antigens with immunogenic potential. The translation of these advances into the clinic as cancer vaccines requires carefully conducted, well-coordinated but discovery-oriented research in the form of clinical trials that can quickly assess alternative vaccine strategies for each tumor type, immuno-monitoring, and tumor escape mechanisms. In this regard, the Cancer Vaccine Collaborative (CVC), an innovative partnership between Ludwig Institute for Cancer Research (LICR) and the Cancer Research Institute (CRI), is a promising paradigm for the advancement of cancer vaccines. The CVC utilizes a unique academic structure that plans, sponsors, and conducts early-phase cancer vaccine trials. The standardized monitoring employed by the CVC enables the comparison of single vaccine variables such as the constitution of an antigen (protein, peptide, viral vectors, or DNA), the method, frequency, and intensity of antigen delivery, and the addition of different adjuvants. In the first part of my talk, I will give an overview of progress made by the CVC in the last few years.
In the second part of my talk, I will illustrate the activities of the CVC by using our ovarian cancer program. The long-range goal of our studies is to harness the potential of cellular immune responses for improving the outcome for patients with epithelial ovarian cancer (EOC). Although most patients with EOC initially demonstrate excellent response to frontline therapies, the relapse rate is approximately 85%. Within 2 years of surgery and systemic chemotherapy, tumors usually reoccur and once relapse occurs, there is no known curative therapy. A proposed strategy for minimizing the risk of recurrent disease is immunotherapy. Patients who demonstrate complete response to frontline therapies could be considered for immunotherapy, with the presumption that the majority do in fact have micrometastases. This approach necessitates the identification of targets with tissue-restricted expression and immunogenic potential, and the development of strategies to improve the immunogenicity of these antigens.
Based on these considerations, in collaboration with the NY Branch of the LICR (1, 2, 3, 4), we have characterized the repertoire of "cancer-testis" (CT) antigens expressed in EOC (including NY-ESO-1, LAGE-1, MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, CT7, CT10, CT16, CT17, BAGE, OY-TES-1, SCP-1, AKAP3, SSX-1, SSX-2 and SSX-4). The results demonstrate that most EOC express at least one of these CT antigens and there is some inter-relationship in the pattern of expression. In addition, we have determined the relationship between immune cell infiltration, CT antigen expression and clinical outcome in EOC. Our study indicates that the prognostic significance of TILs is attributable to intraepithelial CD8+ TILs, while overall T-TIL (CD3+ TIL), CD20+ TIL and CD4+ TIL subtypes were not significantly prognostic. Further, a high intraepithelial CD8+/CD4+ T-cell ratio is a favorable prognostic variable in EOC suggesting that the amount of CD4+ TILs may play a role in determining the prognostic significance of CD8+ TILs in EOC. Since this effect may be attributed to the CD4+ CD25+ regulatory T (Treg) cells, we have also characterized the phenotype and effector functions of NY-ESO-1 specific T cells in the tumor microenvironment, and examined the interaction of these cells with autologous tumor derived CD4+ CD25+ T cells.
In the final part of the talk, preliminary results from a phase 1 clinical trial of NY-ESO-1DP4 p157-170 (NY-ESO-1DP4), a peptide of potentially dual MHC class I and class II specificities, in patients with EOC will be presented.
References
1. Odunsi K, Jungbluth A, Stockert E, Qian F, Gnajtic S, Tammela J, Intengan M, Beck A, Keitz B, Santiago D, Williamson B, Scanlan MJ, Ritter G, Chen YT, Driscoll D, Sood A, Lele S, Old LJ. NY-ESO-1 and LAGE-1 cancer-testis antigens are potential targets for immunotherapy in epithelial ovarian cancer. Cancer Res 2003; 63: 6076-83. (PMID: 14522938)
2. Tammela J, Jungbluth AA, Qian F, Santiago D, Scanlan M, Keitz B, Driscoll D, Rodabaugh K, Lele S, Old LJ, Odunsi K. SCP-1 "Cancer / Testis" antigen is a prognostic indicator and a candidate target for immunotherapy in epithelial ovarian cancer. Cancer Immun 2004; 4: 10. (PMID: 15487888)
3. Qian F, Gnjatic S, Jager E, Darren Santiago D, Jungbluth A, Grande C, Schneider S, Keitz B, Ritter G, Lele S, Sood A, Old LJ, Odunsi K. T Helper Type1 (Th1)/Th2 CD4+ T-cell responses against NY-ESO-1 in HLA-DPB1*0401/0402 patients with epithelial ovarian cancer. Cancer Immun 2004; 4: 12. (PMID: 15521719)
4. Sato E, Olson S, Ahn J, Jungbluth A, Frosina D, Bundy B, Qian F, Gnjatic S, Ambrosone A, Kepner J, Keitz B, Odunsi T, Ritter G, Lele S, Chen YT, Old LJ, Odunsi K. Prognostic Significance Of Intraepithelial CD8+ Lymphocytes: Relationship With "Cancer-Testis" Antigen Expression In Ovarian Cancer. Manuscript submitted for publication.
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