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Targeting and Utilizing Primary Tumors As Live Vaccines: Changing Strategies

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Targeting and Utilizing Primary Tumors As Live Vaccines: Changing Strategies Cellular & Molecular Immunology (2012) 9, 20–26 ß 2012 CSI and USTC. All rights reserved 1672-7681/12 $32.00 www.nature.com/cmi REVIEW Targeting and utilizing primary tumors as live vaccines: changing strategies Xuanming Yang, Eric D Mortenson and Yang-Xin Fu Tumor metastases and relapse are the major causes of morbidity and mortality in cancer. Although surgery, chemotherapy and/or radiation therapy can typically control primary tumor growth, metastatic and relapsing tumors are often inaccessible or resistant to these treatments. An adaptive immune response can be generated during these conventional treatments of the primary tumor, and presumably both the primary tumor and secondary metastases share many of the same or similar antigenic characteristics recognized by the immune system. Thus, when established, this response should be able to control metastatic growth and tumor relapse. This review summarizes the mechanisms by which antitumor immune responses are generated, and recent findings supporting the hypothesis that many therapies targeting primary tumors can generate antitumor adaptive immune responses to prevent metastases and tumor relapse. Cellular & Molecular Immunology (2012) 9, 20–26; doi:10.1038/cmi.2011.49; published online 21 November 2011 Keywords: chemotherapy; immunotherapy; metastasis; radiotherapy; tumor vaccine INTRODUCTION tissues.3–5 Thus, overcoming tumor-associated immune-suppressive Conventional treatments such as surgery and chemotherapy are effec- mechanisms to induce potent antitumor immunity is the first step for tive means of eliminating or reducing primary tumor growth, but have effective cancer immunotherapy.5–7 Many mechanisms are involved not proved effective in eradicating metastases. Because metastatic dis- in tumor-associated immune suppression of naive and previously ease may not respond similarly to chemotherapies used in treating the activated T cells. First, tumors create an environment insufficient primary tumor,1 recent research has focused on the importance of for expansion and maturation of effector tumor-specific T cells. generating an antitumor immune response to control metastatic dis- Second, effector T cells must be capable of reaching the site of the ease. Presumably, both the primary tumor and secondary metastases malignancy, and many tumors have physical and chemical barriers share many of the same or similar antigenic characteristics recognized preventing lymphocyte infiltration. Finally, tumors downregulate by the immune system; yet, there has been no clear strategy formulated receptors or find other means to prevent lymphocytes within the in which a patient’s own tumor tissues is used to generate an antitu- tumor microenvironment from appropriately executing effector func- mor adaptive immune response for the eradication of metastases and tions to destroy cancer cells. Multiple mechanisms employed by prevention of relapse. Once tumors metastasize, curing the disease is tumors to hinder the immune response at each of these steps have difficult and rare. This review summarizes recent findings supporting been identified. the hypothesis that targeting primary tumors with both conventional and new therapies can potentially generate antitumor adaptive THE CURRENT STRATEGIES FOR CANCER IMMUNOTHERAPY immune responses that prevent metastases and relapse. Active immunization and adoptive T-cell transfer therapy are cur- Due to the vast number of genetic changes associated with carcino- rently the main cancer immunotherapy strategies used. Both of these genesis, tumors express many neo-antigens and mutated antigens. strategies are designed to overcome deficiencies in priming of tumor Indeed, much evidence exists to indicate that many cancers are anti- antigen-specific T cells in cancer-bearing hosts. Cancer vaccines rely genic and thus recognizable by the adaptive immune system.2 Mere on immunization of patients with antigenic peptides, proteins or DNA recognition by adaptive immunity, however, is insufficient, given that expressed by the tumor directly or delivered by some other vehicle these antigenic cancers rarely regress spontaneously. Effective antitu- such as dendritic cells (DCs) or virus. Despite its relative simplicity mor immunity depends on both the presence of tumor-reactive and safety, vaccine treatments have shown very limited success.8 lymphocyte precursors and means by which these precursor lympho- Although tetramer or ELISPOT assays revealed the generation of cytes can be activated. Most T cells with high affinity to tissue-specific in vivo antitumor T cells in vaccinated patients,9–11 clinical respon- antigens are deleted in the thymus or later tolerized in the peripheral ses observed from these trials were few.8 This was consistent with Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL, USA Correspondence: Dr XM Yang, Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. E-mail: [email protected] or Dr Y-X Fu, Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. E-mail: [email protected] Received 10 August 2011; revised 27 September 2011; accepted 28 September 2011 Utilizing primary tumor as in situ vaccine XM Yang et al 21 observations in murine models where the presence of large numbers of Indeed, the number of studies demonstrating that antibody therapy antigen-specific T cells was insufficient to mediate tumor regression in can induce both cellular and humoral immunity is rapidly increasing. tumor-bearing mice.12,13 There are a multitude of explanations for For instance, Trastuzumab treatment can induce antitumor cytotoxic this observation: an inadequate number or avidity of immune cells, T lymphocytes (CTLs) in patients.21 Similarly, it was demonstrated an inability of lymphocytes to migrate into the tumor microenviron- that a mouse anti-epidermal growth factor receptor antibody could ment, or a reduced activation of quiescent or precursor lymphocytes control metastasis in a CD4 and CD8 T cell-dependent manner.22 may all prevent successful vaccination. In addition, tolerance mechan- However, the mechanisms by which antibody therapy generates activ- isms induced by the tumor, including the lack of costimulation leading ate adaptive immunity has remained largely unclear. Our current to anergy induction and/or active suppressive mechanisms, create a findings demonstrated that anti-neu antibody treatment induced anti- great barrier to productive vaccination. These obstacles must be tumor adaptive immunity and this is essential for the therapeutic overcome if cancer vaccines are to be effective in mediating cancer effect in a syngenic mouse tumor model. This study revealed an essen- regression. tial role for the adaptive immune system in the therapeutic effect of Adoptive transfer therapies in which tumor-infiltrating lympho- antibody treatment on HER2/neu tumors. Given the fact that the cytes are isolated from the tumor, or peripheral blood in some cases, antibody mediated blockade of oncogenic signals and the induction expanded in an antigen-specific way, and adoptively transferred back of ADCC had been previously demonstrated, we proposed that both into the patient,14 have been effective in a small number of highly of these outcomes lead to a significant release of danger signals selected melanoma patients.15 Although many tumor-specific and (such as High-mobility group protein 1 (HMGB1)) to activate DCs -associated antigens have been identified, few of these antigens in and promote cytokine production. Furthermore, FcR-mediated sig- human tumors have been confirmed to be rejecting antigens. In addi- naling and phagocytosis could induce additional cytokine and danger tion, the rejecting antigen may vary greatly among different tumors. signal production, leading to MyD88-enhanced cross-presentation for Moreover, the best adjuvants for ex vivo expansion of cytotoxic T cells more effective activation of the adaptive immune system for enhanced are still uncertain. Therefore, the limited knowledge regarding the tumor control. Most importantly, the adaptive immunity induced by rejecting tumor antigens for T-cell expansion and the potential inab- targeting primary tumors could protect from tumor rechallenge which ility to physically isolate or expand these T cells, is preventing this is indicative of a response to metastatic disease and relapse.23 Recently, therapy from being applied to a wide variety of cancers. As a result, it was reported that the therapeutic effect of anti-HER2/neu did not understanding how immune responses are generated in vivo during require CD41 T cells, but did depend on both type I and type II conventional antitumor therapies and how to enhance these res- interferon.24 In other models of oncogenic blockade, however, it was ponses, is of great importance. reported that tumor regression did require CD41 T cells.25 Thus, the detailed mechanism of CD41 T-cell activation and the role of these CONVENTIONAL TREATMENTS ON PRIMARY TUMORS cells in antibody-mediated tumor regression are unclear. INDUCE IMMUNE RESPONSES Total control or elimination of tumor metastases by antibody Antibody therapy alone is rare. Most antibodies only partially delay the disease pro- The first antibody approved for cancer treatment was Rituximab in cess. Thus, improving the efficiency of antibody therapies is a great 1997. Now, there are more than 10 antibodies approved by the Food challenge in this field of study. Many companies
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