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Preclinical Models and Clinical Situation 41 Chemotherapy Plus Active Immunotherapy Chemotherapeutic agents have been tested with cancer vaccines and have demonstrated synergy in several models. For instance, docetaxel administered two days prior to each of the three vaccinations of GM-CSF-secreting B16 melanoma cells results in 50% long-term survival of B16 tumor–bearing mice compared to 10% survival with either agent alone (76). While docetaxel was shown to induce neutropenia and lymphopenia, the expansion and survival of antigen-specific T cells (examined in OT-1 TCR transgenic mice using OVAtransfected B16 cells) was not impaired. In another study using neu transgenic mice, three different chemotherapeutic drugs (cyclophosphamide, doxorubicin, and paclitaxel) were tested in combination with a HER-2/neu expressing tumor vaccine and showed enhanced activity in a therapeutic setting (77). Whether drug was administered before or after vaccination affected the outcome and the optimal order of administration was found to vary from one drug to the next. Some recent clinical studies provide yet another somewhat surprising perspective on how active immunotherapy might synergize with chemotherapy. With the caveat associated with retrospective analysis, 25 patients with glioblastoma multiforme were vaccinated with DCs loaded with autologous tumor HLA-eluted peptides or tumor lysate (78). Thirteen of these patients went on to receive subsequent chemotherapy. An additional 13 nonvaccinated patients analyzed in this study also received chemotherapy. Of the vaccine plus chemotherapy-treated patients, 42% were two-year survivors while only 8% of patients treated with chemotherapy alone or vaccine alone survived this long. It is hypothesized that infiltrating CD8þ T cells may upregulate markers on the tumor (e.g., Fas), which render cells more susceptible to chemotherapeutic drugs that kill targets via induction of apoptosis. In another study, a striking response rate of 62% among 21 extensive-stage small cell lung cancer patients treated with second-line chemotherapy was observed after vaccination with DCs transduced with full-length p53 (79). Thirteen of the 21 patients were platinum-resistant and 61.5% of these were responders. In a third study of patients with various metastatic cancers treated with a DNA vaccine encoding a common tumor antigen, five of six immune responders who received subsequent salvage therapy experienced unexpected clinical benefit (80). Among those benefiting from the salvage therapy were four patients with progressive disease after vaccination. Among eight patients who did not demonstrate immunity to vaccination and who survived to receive additional therapy, only one derived clinical benefit. Clearly, determining the optimal mode of administration represents a challenge to clinical applications of vaccine/chemotherapy combinations, as the best regimen may only be understood through an extensive matrix of combination testing in clinical trials. Furthermore, as discussed by Lake and Robinson, delivery of more antigen by vaccination may not be necessary in cases where the chemotherapeutic agent alone results in sufficient antigen release via tumor cell
42 Levey apoptosis and secondary necrosis (81). In these situations, amplification of endogenous responses to cross-presented antigen using antibodies against, e.g., CD40, may be sufficient to realize clinical benefit (82). Nonspecific Immune Modulation Plus Active Immunotherapy Another trend emerging in the practice of active immunotherapy with personalized (and nonpersonalized) cancer vaccines is their use in combination with other nonspecific immunomodulatory agents. Again, these combination approaches are likely to be necessary in any setting more advanced than minimal residual disease (83). Moreover, if the nonspecific agents prove to be well tolerated with minimal toxicity, there may be incentive to employ them even in the setting of minimal disease burden to further decrease the likelihood of disease recurrence. The nonspecific agents include antibodies against CTLA-4 that are designed to prevent effector T cell downregulation and a large number of agents that address the problem of immune suppression in tumor-bearing hosts. With emphases on preclinical testing, these various agents are discussed in turn below. Striking synergy between anti-CTLA-4 antibody and autologous GM-CSFsecreting B16 melanoma and SM1 breast tumor vaccines against established disease in mice has been observed, and the antibody has also been tested in combination with an off-the-shelf GM-CSF-secreting prostate cancer vaccine, with promising results in preclinical studies (84–86). In a preliminary study in human cancer patients previously treated with either autologous or off-the-shelf cancer vaccines who went on to receive infusion with anti-CTLA-4 antibody, only those patients who received the autologous vaccine demonstrated signals of clinical activity (87). Many additional clinical trials are underway testing anti-CTLA-4 antibody either as monotherapy or in combination with off-the-shelf peptide vaccines, GM-CSF, and off-the-shelf whole cell vaccines (88,89 and http://www.clinicaltrials.gov/). Unfortunately, there are no clinical trials currently underway testing anti-CTLA-4 antibody with personalized cancer vaccines despite the suggestion that autologous vaccines may be a particularly potent partner for this antibody. Will the dose of antibody required vary depending on what vaccine type is employed? This later question is of interest given the autoimmune-like toxicities associated with the antibody (90). In the last 10 to 15 years, the issue of specific immune suppression in tumor-bearing hosts has moved from a concept with few tangible toe holds from which to direct therapeutic intervention to remarkable progress in identifying molecular structures and cell types that are ripe for targeting in preclinical and clinical settings. One can envision that just as different chemotherapeutics have been combined in the clinic based on unique mechanisms of action, multiple agents each working to address distinct pathways of immune suppression will be utilized in combination. A nonexhaustive list of agents, their biological targets and evidence, where available, for utility in combination with cancer vaccines are presented in Table 3. Two agents that address the problem posed by accumulation of regulatory T cells (Tregs) are discussed in some detail.
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Page 8 and 9: Preface Throughout the last 20 year
Page 10 and 11: Preface vii Table 1 A Diverse Techn
Page 12 and 13: Preface . . . . v Contributors . .
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104 Luptrawan et al. antigens (84,8
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108 Luptrawan et al. 66. Dunn GP, B
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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Development of Novel Immunotherapeu
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206 Index Antigenic peptides degrad
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208 Index Chromogens, enzymatic act
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210 Index Freund’s adjuvants. See
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212 Index Langerhans cells, 133, 13
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214 Index [Peptide vaccines] invest
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216 Index TCRL. See TCR-like immuno
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Oncology and Immunology about the b
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