Rosenberg SA, Yang JC, Restifo NPCancer immunotherapy: moving beyond current vaccines. Nat Med 10:909-915

Surgery Branch of the Center for Cancer Research at the National Cancer Institute, Building 10, Room 2B42, 10 Center Drive, MSC 1502 Bethesda, Maryland 20892-1502, USA.
Nature Medicine (Impact Factor: 27.36). 10/2004; 10(9):909-15. DOI: 10.1038/nm1100
Source: PubMed


Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.

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Available from: Nicholas P Restifo,
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    • "Despite this, CD8 + T cells specific for tumorassociated self-antigens, such as gp100, tyrosinase and MART, do exist in patients with malignant melanoma (Bakker et al., 1994; Boon et al., 2006; Kawakami et al., 2000). For this reason, clinical studies are using melanosomal antigens for vaccination approaches (Rosenberg et al., 2004). "
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    ABSTRACT: Murine tumor models that closely reflect human diseases are important tools to investigate carcinogenesis and tumor immunity. The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In the present study, we characterized the immune status and functional properties of immune cells in tumor-bearing mice. Melanoma development was accompanied by a reduction in percentages of CD4(+) T cells including regulatory T cells (Tregs) in CD45(+) leukocytes present in tumor tissue and draining lymph nodes (LN). In contrast, percentages of CD8(+) T cells were unchanged and these cells showed an activated phenotype in tumor mice. Endogenous melanoma-associated antigen glycoprotein (gp)100-specific CD8(+) T cells were not deleted during tumor-development, as revealed by pentamer staining in skin and draining LN. They, however, were unresponsive to ex vivo gp100 peptide stimulation in late-stage tumor mice. Interestingly, immunosuppressive myeloid-derived suppressor cells (MDSC) were recruited to tumor tissue with a preferential accumulation of granulocytic MDSC (grMDSC) over monocytic MDSC (moMDSC). Both subsets produced Arginase-1, inducible nitric oxide synthase (iNOS) and TGF-β and suppressed T cell proliferation in vitro. In this work, we describe the immune status of a spontaneous melanoma mouse model that provides an interesting tool to develop future immunotherapeutical strategies.Journal of Investigative Dermatology accepted article preview online, 29 June 2015. doi:10.1038/jid.2015.241.
    Journal of Investigative Dermatology 06/2015; DOI:10.1038/jid.2015.241 · 7.22 Impact Factor
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    • "Numerous studies testing the ability of therapeutic vaccines to eliminate chronic infections have shown only limited success in clinical trials for HIV, HBV and HCV [3] [27]. Vaccine-induced immune responses do not sustain and are ineffective in eliminating the pathogens [28] [29] [30] and cancers. Interleukin 10 (IL-10) is a cytokine that is expressed by many cell types including innate and adaptive immune cells [31]. "
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    ABSTRACT: Interleukin 10 is a cytokine with the ability to reduce or terminate inflammation. Chronic viral infection, such as infection of chronic hepatitis B, hepatitis C and HIV, has increased levels of interleukin 10 in peripheral blood. Serum IL-10 levels are also high in certain cancers. Blocking IL-10 signalling at the time of immunisation clears chronic viral infection and prevents tumour growth in animal models. We review recent advances in this area, with the emphasis on potential use of this novel strategy to treat chronic viral infection and cancer in human. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cellular Immunology 01/2015; 293(2):126-129. DOI:10.1016/j.cellimm.2014.12.012 · 1.92 Impact Factor
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    • "Unfortunately immune responses were transient and clinical outcomes have been poor. The best results were obtained in patients with melanoma at cutaneous or lymphatic sites [13]. Recently the FDA has approved the first DC-based vaccine against human metastatic prostate cancer [14]. "
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    ABSTRACT: Dendritic cells (DC) presenting tumor antigens are crucial to induce potent T cell-mediated anti-tumor immune responses. Therefore DC-based cancer vaccines have been established for therapy, however clinical outcomes are often poor and need improvement. Using a mouse model of B16 melanoma, we found that the route of preventive DC vaccination critically determined tumor control. While repeated DC vaccination did not show an impact of the route of DC application on the prevention of tumor growth, a single DC vaccination revealed that both the imprinting of skin homing receptors and an enhanced proliferation state of effector T cells was seen only upon intracutaneous but not intravenous or intraperitoneal immunization. Tumor growth was prevented only by intracutaneous DC vaccination. Our results indicate that under suboptimal conditions the route of DC vaccination crucially determines the efficiency of tumor defense. DC-based strategies for immunotherapy of cancer should take into account the immunization route in order to optimize tissue targeting of tumor antigen specific T cells.
    PLoS ONE 08/2014; 9(8):e105266. DOI:10.1371/journal.pone.0105266 · 3.23 Impact Factor
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