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Therapeutic and Prophylactic Cancer Vaccines 63 reversible phenomenon. Tumor load is another consideration for the success of a vaccine. Studies from mice models for cervical cancer have indicated that the antitumor therapeutic effects targeting the E7 subunit are better achieved when tumor burden is low. In addition, studies in patients have indicated that precursor lesions have been associated with a CTL response, while no CTL activity is detected when these become established cancers. Several other methods of augmenting an immune response to tumor antigens have been studied. Examples of prime-boost strategies and use of immune modulators are among a few. Immune modulators such as Toll-like receptor (TLR) agonists to enhance antigen uptake and presentation by DCs, activation of B7 family of costimulators on DCs, and dampening of negative costimulatory molecules such as CTLA-4 on T cells have all been used separately. A probable chance of success would be achieved when using some of these modulators in combination and timing them appropriately in the vaccination schedule to obtain a robust immune response. Among clinical studies, more thought is required into the type of patient population that should be enrolled in the study. Several clinical studies have indicted that therapeutic cancer vaccines are not effective in bulky disease, or in late- or end-stage patients. This is probably due to tumor-induced immune suppression caused by soluble factors such as TGF-b. Several studies now indicate the role of CD4 þ CD25 þ T regulatory cells and their role in inducing tolerance. These cells depend on TGF-b for their survival and suppress T effector cytolytic function, which is considered crucial for the killing of tumor. The probability of this approach becoming a treatment option is most likely in a minimal disease setting or as an adjuvant where one would expect to find minimal tumor-induced immune suppression. Also, an aspect of the success of pivotal trials depends on results from controlled phase 2 studies. This would eliminate an assumption that similarities exist between the two groups of patients studied at different points in time and in the face of continuous assessments and improvements on disease staging/classification and clinical/immunological monitoring. Patients may be randomized to an observation or follow-up arm, or an intent-to-treat arm of the trial, depending on the vaccine, staging of the disease, and the clinical end point. While efficacy data were often compared with historical controls, more and more phase 2 trials are now being randomized. Of importance is the development of biomarkers and imaging techniques in aiding diagnosis and disease monitoring during treatment. In a recent study using molecular-genetic imaging techniques, the investigators showed that they could induce EBV tyrosine kinase expression within tumors by treating with Velcade 1 , a proteosome inhibitor, followed by radiolabeled 2 0 -fluoro-2 0 -deoxy-beta-D-5iodouracil-arabinofuranoside (FIAU) to image and potentially kill these tumors (75). Like imaging, the use of biomarkers will be an important tool to aid monitoring in clinical trials. To name a few, markers such as prostate-specific antigen (PSA) and CA-125 are currently available to monitor the disease status of
64 Srinivasan patients with prostate or ovarian carcinomas, respectively, indicating the need to identify more of these. The development of cancer vaccines has clearly been fraught with challenges. Nevertheless, the wealth of information acquired from preclinical and clinical studies has guided us to a level where much has been learnt and new insights gained. All these lessons can potentially be exploited to chalk out various avenues to develop successful therapeutic cancer vaccines. REFERENCES 1. Gardasil F. FDA Licenses New Vaccine for Prevention of Cervical Cancer and Other Diseases in Females Caused by Human Papillomavirus. FDA; 2006. 2. Matzinger P. The danger model: a renewed sense of self. Science 2002; 296(5566): 301–305. 3. Challis GB, Stam HJ. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol 1990; 29(5):545–550. 4. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348(3):203–213. 5. Srinivasan R, Wolchok JD. Tumor antigens for cancer immunotherapy: therapeutic potential of xenogeneic DNA vaccines. J Transl Med 2004; 2(1):12. 6. Srinivasan R, Van Epps D. Specific active immunotherapy of cancer: potential and perspectives. Rev Recent Clin Trials 2006; 1:283–292. 7. Uyl-de Groot CA, Vermorken JB, Hanna MG Jr., et al. Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits. Vaccine 2005; 23(17–18):2379–2387. 8. Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 2004; 363(9409): 594–599. 9. Hege KM, Jooss K, Pardoll D. GM-CSF gene-modified cancer cell immunotherapies: of mice and men. Int Rev Immunol 2006; 25(5–6):321–352. 10. Shaif-Muthana M, McIntyre C, Sisley K, et al. Dead or alive: immunogenicity of human melanoma cells when presented by dendritic cells. Cancer Res 2000; 60(22): 6441–6447. 11. Barth A, Hoon DS, Foshag LJ, et al. Polyvalent melanoma cell vaccine induces delayed-type hypersensitivity and in vitro cellular immune response. Cancer Res 1994; 54(13):3342–3345. 12. Van Epps D. Characterization of polyvalent allogeneic vaccines. Dev Biol (Basel) 2004; 116:79–90; discussion 133–143. 13. Morton DL, Hoon DS, Nizze JA, et al. Polyvalent melanoma vaccine improves survival of patients with metastatic melanoma. Ann N Y Acad Sci 1993; 690:120–134. 14. Morton DL, Foshag LJ, Hoon DS, et al. Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg 1992; 216(4):463–482. 15. Hsueh EC, Famatiga E, Gupta RK, et al. Enhancement of complement-dependent cytotoxicity by polyvalent melanoma cell vaccine (CancerVax): correlation with survival. Ann Surg Oncol 1998; 5(7):595–602.
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
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Preface Throughout the last 20 year
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Preface vii Table 1 A Diverse Techn
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Preface . . . . v Contributors . .
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Contributors Pedro Alves Ludwig Ins
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1 Factoring in Antigen Processing i
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Factoring in Antigen Processing in
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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206 Index Antigenic peptides degrad
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212 Index Langerhans cells, 133, 13
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Oncology and Immunology about the b
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