Editorial Multimodality treatment warranted for ovarian cancer: immunotherapy, a prerequisite to improve prognosis for this vicious disease “...we envision a multimodality approach for ovarian cancer where immunotherapy directed towards multiple well-defined antigens is combined with cytoreductive surgery, (immunomodulatory) classic chemotherapy and targeted drugs intended to prevent and/or reverse immune escape by the tumor.”
Although not the most frequently occurring type of gynecological malignancy, ovarian cancer is the primary cause of death from gynecological malignancies. The high mortality is best attributed to the lack of specific symptoms and effective screening methods, which in general results in diagnosis of advanced-stage disease. Despite changes in standard therapy, cytoreductive surgery and platinum-based chemotherapy, 5-year survival has only modestly improved over the last decades and remains low at approximately 40%. To improve prognosis, new treatment modalities are being explored. Immunotherapy is one of these strategies.
An increasing body of evidence indicates that the presence of tumor-infiltrating lymphocytes is associated with more favorable prognosis of ovarian cancer. Although this observation has been described for T lymphocytes in general [1] , it seems that different T‑lymphocyte subsets contribute in diverse ways [2–4] . Rather, the prognostic effect of lymphocytes depends on the ratio of the different T‑lymphocyte subsets present [3,4] . The presence of intratumoral lymphocytes and the associated favorable prognosis are generally ascribed to tumor-specific immune responses and form the rationale for the development of immunotherapy for ovarian cancer. Ideally, a vaccine is highly immunogenic, easily manufactured and universally applicable. Antigen-specific immunotherapy strategies include administration of: proteins/peptides with or without adjuvant; dendritic cells (DCs; transfected with DNA- or RNA-encoding tumor antigens, or loaded with peptides, whole
proteins or tumor lysates); recombinant viruses encoding tumor antigens; and autologous or allogeneic tumor cells [5] . Antigen-restricted strategies have the distinct advantage that antigen-specific immune responses can be easily monitored as a tool to improve the vaccine or vaccination strategy. Yet, short-peptide vaccines induce either T helper or cytotoxic T-cells and are limited to patients with certain HLA genotypes corresponding to the peptide used. By contrast, whole-protein or long-peptide vaccines may contain epitopes for both T helper and cytotoxic T-cells and can be applied irrespective of HLA genotype. DC vaccines are laborious in production and restricted to individual patients, but have the advantage that DCs are highly efficient professional antigen-presenting cells. Type and maturation status of DCs are issues to be solved in this vaccination approach. The most important challenge facing viral vector vaccines is antigenic competition between the target antigen and the viral vector itself. Tumor cell-derived vaccines and vaccines consisting of DCs loaded with tumor lysates contain multiple unknown antigens that, on the one hand may include patient-specific strong antigenic epitopes, but on the other hand may contain epitopes for which tolerance was created, thus diluting an effective immune response. Which vaccine type will ultimately result in the best trade-off between clinical applicability and immunogenicity and/or clinical efficacy remains to be elucidated. As for most human tumors with unknown etiology, no tumor-specific antigens have been identified for ovarian cancer. Nevertheless, antigenic targets for the immune system do exist in the form of tumor-associated antigens (i.e., self-antigens with an altered expression in tumor cells as compared with normal body cells) [6] . Several types of tumor-associated antigens have been identified and targeted in ovarian cancer,
10.2217/1750-743X.1.2.163 © 2009 Future Medicine Ltd
Immunotherapy (2009) 1(2), 163–165
“The most important challenge facing
viral vector vaccines is antigenic competition between the target antigen and the viral vector itself.”
Ninke Leffers University of Groningen, The Netherlands
Toos Daemen University of Groningen, The Netherlands
Ate GJ van der Zee University of Groningen, The Netherlands
Hans W Nijman† Author for correspondence: Department of Gynecological Oncology, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands Tel.: +31 503 611 649 Fax: +31 503 611 860
[email protected] †
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for example, upregulation and/or mutation in oncogenes and/or tumor-suppressor genes (Her-2/Neu and p53), expression of cancer testis antigens (NY-ESO-1, MAGE and LAGE-1) and glycolipid antigens (MUC1 and CA125) [5] . None of the antigens identified thus far are universally expressed by epithelial ovarian malignancies. Moreover, heterogeneous antigen expression within a single tumor nodule or between primary tumors and metastases may exist. For any immunotherapeutic strategy to be clinically successful, it would most likely have to target multiple known antigens and should possibly even be patient tailored, based on antigen-expression profiling.
“In light of these numerous immune evasion strategies, it can be inferred that it is unlikely that immunotherapy by itself will ever attain high success rates. The key to success, therefore, probably lies in combinatorial strategies.” Although most tumor-associated vaccines induce immunological responses, clinical responses are incidental, with response rates far smaller than those for second-line chemo therapy. A possible explanation may be that patients participating in immunotherapeutic trials frequently have established recurrent disease, which may simply be too substantial to be eradicated by induced immune responses. Better results might be obtained by immunizing patients with pre-malignant disease (a stage that currently cannot be detected in ovarian cancer) or concurrent with or shortly after successful primary therapy. The latter options are supported by the observation that chemotherapeutic agents currently or previously used in the primary treatment of ovarian cancer (i.e., docetaxel or cyclophosphamide) have been shown to enhance antigen-specific immune responses to immunotherapy [7,8] . An additional factor for failure of currently available immunization protocols could be that cellular responses induced are inadequate (e.g., Th2‑type or regulatory CD4 + T-cells). Possibly, the addition of adjuvants to the cancer vaccine may improve the polarization of induced responses, thus enhancing the likelihood of clinical efficacy. Possible candidates would be Toll-like receptor (TLR) agonists as these ligands activate DC maturation, induce secretion of inflammatory cytokines by innate immune cells and have been suggested to help overcome tolerance to self-antigens as well as to promote responses to tumor antigens [9] . 164
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The success of immunotherapy for (ovarian) cancer may be further hampered by strategies ‘employed’ by tumors to escape destruction by the immune system. These approaches have been categorized as: evasion of recognition by the immune system (e.g., downregulation of MHC class I, tumor antigens and/or other components of the antigen presentation machinery); expression and/or secretion of immunosuppressive substances (e.g., IDO, IL-10 and TGF-β); upregulation of negative costimulatory signals (e.g., PD-L1 and Fas-L); recruitment of immunosuppressive cells (e.g., regulatory T cells and myeloid-derived suppressor cells); and interference with extravasation and/or homing of lymphocytes [10–13] . In light of these numerous immune evasion strategies, it can be inferred that it is unlikely that immunotherapy by itself will ever attain high success rates. The key to success, therefore, probably lies in combinatorial strategies (i.e., immunotherapy to induce antitumor immune responses together with drugs that target the above-mentioned immune-escape mechanisms) [12] . Promising results have, for example, been attained by the addition of an endothelial receptor B antagonist to previously clinically ineffective immunotherapeutic strategies in murine models, thereby promoting lymphocyte recruitment and tumor responses [10] . Other agents that may possibly be included in such a multimodality approach include agents interfering with negative costimulatory signals (e.g., anti-CTLA‑4 antibodies) that induced tumor-specific immune cells independent of antigen-specific immunotherapy in metastatic melanoma patients [14] , and drugs resulting in MHC class I upregulation (e.g., 5‑aza-2´-deoxycytidine [15]). In addition, drugs that directly target processes pivotal to tumor growth and survival may also contribute to such a regimen, for example, agents that disrupt tumor vasculature or inhibit angiogenesis (e.g., bevacuzimab) [16] .
“For any immunotherapeutic strategy to be
clinically successful, it most likely would have to target multiple known antigens and should possibly even be patient-tailored, based on antigen-expression profiling.” In summary, although significant advances have been made in the field of immunot herapy for ovarian cancer, important challenges remaining are when to immunize, what antigens are best targeted, what vaccine-type combined with what adjuvant has the best trade-off future science group
Multimodality treatment warranted for ovarian cancer
between immunogenicity and clinical applicability and how to overcome immune escape by tumor cells. For the future, we envision a multimodality approach for ovarian cancer where immunotherapy directed towards multiple welldefined antigens is combined with cytoreductive surgery, (immunomodulatory) classic chemotherapy and targeted drugs intended to prevent and/or reverse immune escape by the tumor. Bibliography 1
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Leffers N, Gooden MJ, de Jong RA et al.: Prognostic significance of tumorinfiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol. Immunother. 58(3), 449–459 (2009). Sato E, Olson SH, Ahn J et al.: Intraepithelial CD8 + tumor-infiltrating lymphocytes and a high CD8 +/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102(51), 18538–18543 (2005). Sabbatini P, Odunsi K: Immunologic approaches to ovarian cancer treatment. J. Clin. Oncol. 25(20), 2884–2893 (2007).
future science group
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Laheru D, Lutz E, Burke J et al.: Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin. Cancer Res. 14(5), 1455–1463 (2008). Conroy H, Marshall NA, Mills KH: TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours. Oncogene 27(2), 168–180 (2008). Buckanovich RJ, Facciabene A, Kim S et al.: Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14(1), 28–36 (2008).
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improve tumor immunotherapy. Clin. Cancer Res. 14(14), 4385–4391 (2008). 13 Whiteside TL: The tumor microenvironment
and its role in promoting tumor growth. Oncogene 27(45), 5904–5912 (2008). 14
Yuan J, Gnjatic S, Li H et al.: CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc. Natl Acad. Sci. USA 105(51), 20410–20415 (2008).
15
Adair SJ, Hogan KT: Treatment of ovarian cancer cell lines with 5-aza-2´-deoxycytidine upregulates the expression of cancer-testis antigens and class I major histocompatibility complex-encoded molecules. Cancer Immunol. Immunother. 58(4), 589–601 (2009)
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