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• W2006011881 abstract "Our laboratory has created an Ad-sig-TAA/ecdCD40L vaccine platform designed to activate dendritic cells (DCs). Two subcutaneous (s.c.) injections of the TAA/ecdCD40L protein following the s.c. injection of the Ad-sig-TAA/ecdCD40L vector (TAA/ecdCD40L VPP vaccine) further increases the levels of the tumor-associated antigen (TAA)-specific CD8 effector T cells induced by the vector. We tested the combined effect of chemotherapy-induced destruction of tumor cells and TAA/ecdCD40L VPP vaccine which further increases the levels of TAA available to the DCs at the time of vaccination. The chemotherapy was delivered selectively to the tumor cells using intratumoral (i.t.) injection of the AdCDIRESE1A vector followed by intraperitoneal (i.p.) 5-fluorocytosine (5FC). The 5-fluorouracil (5FU) produced in the vector infected the tumor cells, destroys them and releases the TAA for processing and presentation by the DCs. This mode of delivery spares the TAA CD8 effector T cells from the destructive effect of the 5FU when their proliferation is induced by the vaccine. Test mice treated with both the s.c. administered TAA/ecdCD40L VPP vaccine and the AdCDIRESE1A/5FC chemosensitization vector had the smallest tumor volumes and survived longer than mice treated with either of these agents alone (P < 0.001). Our laboratory has created an Ad-sig-TAA/ecdCD40L vaccine platform designed to activate dendritic cells (DCs). Two subcutaneous (s.c.) injections of the TAA/ecdCD40L protein following the s.c. injection of the Ad-sig-TAA/ecdCD40L vector (TAA/ecdCD40L VPP vaccine) further increases the levels of the tumor-associated antigen (TAA)-specific CD8 effector T cells induced by the vector. We tested the combined effect of chemotherapy-induced destruction of tumor cells and TAA/ecdCD40L VPP vaccine which further increases the levels of TAA available to the DCs at the time of vaccination. The chemotherapy was delivered selectively to the tumor cells using intratumoral (i.t.) injection of the AdCDIRESE1A vector followed by intraperitoneal (i.p.) 5-fluorocytosine (5FC). The 5-fluorouracil (5FU) produced in the vector infected the tumor cells, destroys them and releases the TAA for processing and presentation by the DCs. This mode of delivery spares the TAA CD8 effector T cells from the destructive effect of the 5FU when their proliferation is induced by the vaccine. Test mice treated with both the s.c. administered TAA/ecdCD40L VPP vaccine and the AdCDIRESE1A/5FC chemosensitization vector had the smallest tumor volumes and survived longer than mice treated with either of these agents alone (P < 0.001). One of the factors that limit the immune response to cancer is the poor access of tumor-associated antigens (TAAs) to Class I major histocompatibility complex antigen presentation pathways within antigen-presenting cells or dendritic cells (DCs).1Fanslow WC Srinivasan S Paxton R Gibson MG Spriggs MK Armitage RJ Structural characteristics of CD40 ligand that determine biological function.Semin Immunol. 1994; 6: 267-278Crossref PubMed Scopus (150) Google Scholar,2Wurtzen PA Nissen MH Claesson MH Maturation of dendritic cells by recombinant human CD40L-trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production.Scand J Immunol. 2001; 53: 579-587Crossref PubMed Scopus (30) Google Scholar In order to address this problem, we designed an adenoviral vector system (Ad-sig-TAA/ecdCD40L) for tumor antigen loading and activation of DCs.3Akbulut H Tang Y Maynard J Zhang L Pizzorno G Deisseroth A Vector targeting makes 5-fluorouracil chemotherapy less toxic and more effective in animal models of epithelial neoplasms.Clin Cancer Res. 2004; 10: 7738-7746Crossref PubMed Scopus (28) Google Scholar,4Zhang L Tang Y Akbulut H Zelterman D Linton PJ Deisseroth A An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells.Proc Natl Acad Sci USA. 2003; 100: 15101-15106Crossref PubMed Scopus (63) Google Scholar,5Tang Y Zhang L Yuan J Akbulut H Maynard J Linton PJ et al.Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens.Blood. 2004; 104: 2704-2713Crossref PubMed Scopus (23) Google Scholar,6Tang Y Akbulut H Maynard J Petersen L Fang X Zhang WW et al.Vector prime/protein boost vaccine that overcomes defects acquired during aging and cancer.J Immunol. 2006; 177: 5697-56707Crossref PubMed Scopus (18) Google Scholar In this strategy, the TAA are linked to the extracellular domain (ecd) of the CD40 ligand (CD40L), which is attached to a signal sequence (sig). The TAA/ecdCD40L protein that is released from the vector infected cells binds to the CD40 receptor on the DCs, thereby activating them. The engagement of the CD40 receptor by the TAA/ecdCD40L protein results in internalization of the chimeric protein into the DCs, wherein it is processed through the Class I antigen processing pathway. Our preclinical data have suggested that this strategy results in induction of memory cells, generating TAA-specific immunity for over a year. A second strategy we have used6Tang Y Akbulut H Maynard J Petersen L Fang X Zhang WW et al.Vector prime/protein boost vaccine that overcomes defects acquired during aging and cancer.J Immunol. 2006; 177: 5697-56707Crossref PubMed Scopus (18) Google Scholar for increasing the magnitude of the TAA-specific immune response induced by the Ad-sig-TAA/ecdCD40L vector vaccine is to inject the TAA/ecdCD40L protein subcutaneously (s.c.) 7 and 21 days after the injection of the Ad-sig-TAA/ecdCD40L vector. These protein boosts produced a sixfold increase in the levels of the TAA-specific CD8 effector cells and antibodies as compared to levels generated by the Ad-sig-TAA/ecdCD40L vector alone. In this paper, we report the results of experiments designed to test a third strategy. This strategy seeks to enhance the immune response induced by the Ad-sig-TAA/ecdCD40L vector vaccine against TAA by increasing the level of TAA available to the immune response at the time of vaccination. We tested this by delivering chemotherapy to induce the breakdown of the cancer cells so as to increase the level of TAA available to the antigen-presenting cells. Systemic chemotherapy delivered at the time of vaccination might actually diminish the vaccine response because of the sensitivity of the TAA-specific CD8 effector T cells which proliferate following the vaccination. In order to spare the proliferating TAA-specific CD8 effector T cells from the effects of the chemotherapy, we injected the AdCDIRESE1A vector intratumorally (i.t.) at the time of vaccination.3Akbulut H Tang Y Maynard J Zhang L Pizzorno G Deisseroth A Vector targeting makes 5-fluorouracil chemotherapy less toxic and more effective in animal models of epithelial neoplasms.Clin Cancer Res. 2004; 10: 7738-7746Crossref PubMed Scopus (28) Google Scholar The i.t. vector injection was followed by injections of the nontoxic chemotherapy precursor, 5-fluorocytosine (5FC) intraperitoneally (i.p.) every day for 10 days. In this paper, we report the results of experiments designed to test whether the combination of the TAA/ecdCD40L vaccine with the AdCDIRESE1A/5FC chemosensitization vector induces a systemic immune response that is greater than that induced by the use of either vaccine or chemosensitization alone. Test mice inoculated with s.c. TC-1 tumor explants were separated into four groups: (i) control; (ii) chemotherapy only; (iii) vaccine only; and (iv) chemotherapy plus vaccine. The mice in the vaccine-only and chemotherapy-plus-vaccine groups were immunized with s.c. injections of the Ad-sig-E7/ecdCD40L vector 1 week before tumor inoculation and injected s.c. with the E7/CD40L protein boost recombinant protein once a week for three consecutive weeks. Chemotherapy-only and chemotherapy- plus-vaccine groups were administered the AdCDIRESE1A vector intratumorally on day 7 after tumor inoculation, at which time the average tumor volume was 50 mm3. All these mice were given 5FC i.p. every day for 10 days in the period between day 7 and day 17 after tumor inoculation. The mice treated with both vaccine and AdCDIRESE1A along with i.p. 5FC had the smallest tumor volumes and survived longer than did the other groups (P < 0.001). In conclusion, the study showed that a combination of i.t. injections of the AdCDIRESE1A vector, i.p. 5FC, and concomitant s.c. injection of vector prime and protein boost vaccine yielded more potent immune responses than either vaccine or chemotherapy alone. These results suggest that the combination of the Ad-sig-TAA/ecdCD40L vector-prime-TAA/ ecdCD40L protein boost vaccine with the i.t. injection of the AdCDIRESE1A chemotherapy sensitization vector will increase the vaccine-induced immune response against the tumor cells. Analysis of the expression of the CD gene in the AdCMVCD and AdCMVCDIRESE1A vectors. The following cell lines were seeded at a density of 200,000 cells/well in 6-well plates: TC-1, CCL-51, NT-2, and CRL-2638. Twenty-four hours later these cells were then incubated with the following vectors for a 16-hour period of incubation: AdCMVCDIRESE1A, AdCMVE1A, and AdCMVCD. The cells were then trypsinized and washed with phosphate-buffered saline. Total RNA was isolated from the cells, and cDNA was generated using the primers specific for the CD coding transcripts. Portions of the CD gene were synthesized and amplified from the mRNA of the gene by reverse transcription–PCR. The bands produced by PCR from the CD cDNA of CCL-51 cells are shown in Figure 1b. All the cell lines used in the current study yielded similar results. TC-1 cells were used for the in vivo studies. The analysis of the bands produced by the amplification of the RNA from the AdCMVCD vector-infected cells shows that the expected molecular weight for CD is around 1.2 kb (Figure 1b). These data show that the AdCMVCDIRESE1A and AdCMVCD vectors express CD coding mRNA sequences. Western blot analysis of E1A protein expressed by the tumor cells infected with E1A carrying vectors. Cell lines were seeded at a density of 100,000 cells/well in 6-well plates. Twenty-four hours later, these cells were exposed to the following vectors: AdCMVCD, AdLpE1A, AdCMVE1A, AdCMVCDIRESE1A, and the AdWT virus. After 2 days of incubation, the tumor cells were harvested, and the lysates of these cells were studied for the level of E1A protein expression. The bands produced by western blotting from CCL-51 cells are shown in Figure 1c. All the cell lines used in this study yielded similar results. The bands specific for E1A protein, which were obtained from the AdCMVE1A vector-infected cells, show the expected molecular weight for E1A, which is ~30 kd Figure 1c. In contrast, no protein bands are visible from uninfected control cells or from cells infected with nonreplicating vectors. These data show that adenoviral vectors have the capability of expressing E1A protein in mouse tumor cells. Functional analysis of the CD gene in mouse tumor cell lines. We then analyzed the cytotoxicity generated in vitro by vectors at different multiplicities of infection in tumor cell lines derived from mouse carcinomas of the breast, colon, and lung. In this study, in vitro cytotoxicity tests were carried out with the replication-competent AdCMVCDIRESE1A vector to test the efficacy of the vector in various mouse tumor cells. As shown in Figure 1, the TC-1 and CCL-51 cells were the mouse tumor cells that were found to be most sensitive to the vector. As shown by the dotted line in Figure 1d, the addition of 5FC caused a significant increase in cytotoxicity in the TC-1 cells used in the animal model (P < 0.01). The roles of the two therapeutic transcription units (CD and E1A) appear to be additive in the total effect of the vector in both human and mouse tumor cells in the NT-2 and TC-1 cells but not in the CCL-51 nor in the CRL-2638 cell (see Figure 1d). Cytokine release from the activated splenic T cells. In order to test the efficacy of the various treatment strategies for inducing an immune response, we measured the cytokine release from the activated splenic T cells in the treatment groups, as shown in Table 1. As shown in Figure 2a and Table 2, the T cells from mice injected with the combination of the vaccine and the AdCDIRESE1A chemotherapy sensitization vector released significantly more interferon-γ (IFN-γ) than groups injected with the AdCDIRESE1A alone and the control group. There were no significant differences in the levels of interleukin-4 (IL-4) among the groups (see Table 2 and Figure 2a).Table 1The treatment groupsGroupsTreatments• Group 1 (control)• PBS• Group 2 [chemotherapy (CT)]• AdCDIRESE1A + 5FC only• Group 3 (vaccine)• Ad-sig-E7-CD40L + E7CD40L• Group 4 (CT + vaccine)• AdCDIRESE1A + 5FC +Ad-sig-E7-CD40L + E7CD40LAbbreviations: 5FC, 5-fluorocytosine; PBS, phosphate-buffered saline. Open table in a new tab Table 2The IFN-γ and IL-4 secretion from activated splenic τ cells (mean ± SD)GroupsIFN-γ(pg/ml)IL-4 (pg/ml)Control64.2 ± 2.112.4 ± 1.2CT96.8 ± 5.916.5 ± 3.6Vaccine379.7 ± 6.812.2 ± 0.6CT + vaccine1,294.2 ± 266.213.5 ± 0.8CT, chemotherapy; IFN-γ, interferon-γ; IL-4, interleukin-4. Open table in a new tab Abbreviations: 5FC, 5-fluorocytosine; PBS, phosphate-buffered saline. CT, chemotherapy; IFN-γ, interferon-γ; IL-4, interleukin-4. The tumor-specific effector T cells. The IFN-γ- and IL-4-secreting splenic T cells of the experimental treatment groups of mice were assessed using enzyme-linked immunospot ELISPOT) assay. We also quantified the ratio of E7+ tumor-specific CD8 cells to total CD8 cells in the tumor tissues, tumor-draining lymph nodes, and spleens from the treatment groups of mice, using flow cytometry. The CD8+ cells were the major subgroup of lymphocytes infiltrating the tumor nodules in all the groups. The vaccine-only group had the highest ratio of E7-specific CD8+ cells to total CD8 cells (Table 3, P < 0.01). The ratio of E7-specific CD8+ cells to total CD8 cells in the chemo-plus-vaccine group was also higher than those in the chemo-only and control groups (Table 3, P < 0.001). Thus, the ratio of E7 tetramer-positive CD8 cells to total CD8 cells infiltrating the tumor nodule in the vaccine-only group was significantly higher than in the other groups (Figure 2b). Likewise, the ratio of the E7+-specific CD8 cells to total CD8 cells in the tumor-draining lymph nodes of mice in the vaccine-only group was significantly higher than the corresponding ratios in the tumor tissue and tumor-draining lymph nodes of animals in the chemotherapy-only and chemotherapy-plus-vaccination groups. These latter, in turn, were similar and significantly higher than the ratio in the control group. Interestingly, the chemotherapy- plus-vaccine group had the highest ratio of E7+-specific CD8 cells to total CD8 cells in the spleen (Figure 2c).Table 3The ratio of the subgroup of lymphocytes infiltrating the tumor nodules in the treatment groupsGroupsCD8+(%)CD4+ (%)Control0.04 ± 0.020.012 ± 0.008CT0.24 ± 0.020.046 ± 0.019Vaccine1.21 ± 0.110.062 ± 0.030CT + vaccine0.55 ± 0.030.027 ± 0.010CT, chemotherapy. Open table in a new tab CT, chemotherapy. As shown in Figure 2d, mice treated with a combination of vaccine and the AdCMVCDIRESE1A chemotherapy vector (group 4) had significantly more IFN-γ (2,004 ± 603 mm2)-secreting T cells when compared with mice treated with vaccine only (1,402 ± 380 mm2) or chemo only (267 ± 29 mm2), or with control mice (167 ± 32 mm2) (P < 0.001). Likewise, IL-4-secreting T cells were significantly higher in the mice treated with chemo-plus-vaccine when compared with the other treatment groups (Figure 2d). The smaller area of spots denoting IL-4-secreting cells as compared to the area occupied by IFN-γ spots suggests that the vaccination-plus-AdCMVCDIRESE1A vector treatment stimulates a Th1 rather than a Th2 immune response. Cell-mediated cytotoxicity assay of splenic T cells. Cell-mediated cytotoxicity was assayed by measuring the levels of the active caspase-3 antibody apoptosis by flow cytometry at day 7 after the last injection of E7-CD40L protein boost. The CD8+ cells from mice treated with the AdCDIRESE1A chemotherapy vector-plus-vaccination showed significantly higher cytotoxicity against E7+ TC-1 tumor cells than did the CD8+ cells from mice in the vaccine-alone, chemotherapy-alone, or control groups (see Figure 2e) (E:T cell ratio: 1:1; 5:1; 10:1). VPP vaccination induces anti-E7 antibodies. As shown in Figure 2f, vaccination induced high levels of E7-specific antibodies in both vaccine-alone and chemotherapy-plus-vaccine groups of mice at day 7 after the last injection of E7-CD40L protein boost. The serum E7-specific antibody titer was almost similar in tumor-bearing control mice and in normal mice without tumor inoculation. The chemotherapy-only group had a very low level of E7-specific antibody response. Negative regulatory T cells. Negative regulatory T cells (Tregs), which are CD4+CD25+FoxP3+, have been reported to limit the degree of immune response to vaccination. We have already reported that the level of Tregs decreased with hMUC-1/ ecdCD40L.6Tang Y Akbulut H Maynard J Petersen L Fang X Zhang WW et al.Vector prime/protein boost vaccine that overcomes defects acquired during aging and cancer.J Immunol. 2006; 177: 5697-56707Crossref PubMed Scopus (18) Google Scholar We quantified the levels of CD4+CD36+FoxP3+ T cells in the tumor tissue, tumor-draining lymph nodes and spleens of mice from the treatment groups, using flow cytometry. The percentage of Tregs in the total CD4 T cells infiltrating the tumor nodules of the control mice was almost five times higher than in the group of mice receiving both the vaccine and the chemotherapy sensitization vector with 5FC, as shown in Figure 3a (P < 0.001). The levels of Tregs in the tumor tissues, tumor-draining lymph nodes, and spleens of mice in the vaccine-alone and chemotherapy-plus-vaccine groups were lower than the corresponding levels in the chemotherapy-only group (Figure 3a). Immunosuppressive cytokine release. The levels of IL-10 and transforming growth factor-β (TGF-β), which have significant suppressive effects on immune cell functions, in tumor tissue and sera of the vaccine- and chemotherapy-treated groups were significantly lower than in the control group. Among all the test groups, the chemotherapy-plus-vaccine group had the lowest levels of these cytokines (Figure 3b and c). Likewise, the TGF-β levels from the activated splenic T cells in the vaccine-treated groups were lower than in the groups without vaccine treatment (Figure 3d). However, no significant differences were found among the treatment groups in respect of the levels of IL-10 in activated T cells (P > 0.05). Chemotherapy plus vaccination suppresses tumor growth. The efficacy of i.t. injection of the AdCDIRESE1A replication-competent chemotherapy vector/5FC system in combination with s.c. injection of Ad-sig-E7-CD40L followed by three sequential weekly injections of E7-CD40L protein was tested in C57BL/6 mice bearing s.c. tumor nodules derived from TC-1 cells. On the day 7 after injection of CCL-51 cells, the tumor volumes were measured and the mice were randomly divided into four groups: 1. Mice injected i.t. with phosphate-buffered saline served as the control group (group 1—control), 2. Mice injected i.t. with AdCDIRESE1A followed 10 days later with i.p. 5FC injection (group 2—chemotherapy), 3. Mice injected s.c. with Ad-sig-E7-CD40L vaccine vector 1 week before the tumor inoculation followed by three weekly, sequential s.c. injections of E7-CD40L protein (group 3—vaccine only), and 4. Mice injected i.t. with AdCDIRESE1A chemotherapy vector followed by 10 days of i.p. 5FC injections, s.c. injection with Ad-sig-E7-CD40L vaccine vector, and three weekly sequential s.c. injections of E7-CD40L protein (group 4—chemotherapy plus vaccine). The mice in all the groups were followed until their death or until they had to be killed because of large tumor volume. The tumor nodules of most of the mice disappeared after the second week of treatment with the combination of i.t. injection of chemotherapy vector and s.c. injection of vaccine vector followed by protein boosting (chemotherapy plus vaccine—group 4). Although there was significant delay in tumor growth in the vaccine-only and chemotherapy-only groups as compared to the control group, no complete remissions were observed in mice from either of these groups (Figure 4a). The mice in the chemotherapy-plus-vaccine group produced the best survival pattern (Figure 4b). The median survival of the mice in the chemotherapy-only and vaccine-only groups was almost two times that of the control group (31 ± 1 and 25 ± 1 days versus 15 ± 1 days; P < 0.001), but less that that seen in the group which received both the chemotherapy and the vaccine. The immune response diminishes with advancing age, and most epithelial cancers occur in persons in the older age group.This is because of a decline in the ratio of the antigen-naive T cells/ memory cells as the chronological age advances, and because of the acquisition of functional defects in the CD4 T cells.7Eaton SM Burns EM Kusser K Randall TD Haynes L Age-related defects in CD4 cell cognate helper function lead to reductions in humoral responses.J Exp Med. 2004; 200: 1613-1622Crossref PubMed Scopus (211) Google Scholar,8Dong L More I Hossain MJ Liu B Kimura Y An immunostimulatory oligodeoxynucleotide containing a cytodine-guanosine motif protects senescence-accelerated mice from lethal influenza virus by augmenting the T helper type 1 response.J Gen Virol. 2003; 84: 1623-1628Crossref PubMed Scopus (47) Google Scholar One of these functional defects is the loss of expression of the CD40L at the time of activation of CD4 T cells.7Eaton SM Burns EM Kusser K Randall TD Haynes L Age-related defects in CD4 cell cognate helper function lead to reductions in humoral responses.J Exp Med. 2004; 200: 1613-1622Crossref PubMed Scopus (211) Google Scholar,8Dong L More I Hossain MJ Liu B Kimura Y An immunostimulatory oligodeoxynucleotide containing a cytodine-guanosine motif protects senescence-accelerated mice from lethal influenza virus by augmenting the T helper type 1 response.J Gen Virol. 2003; 84: 1623-1628Crossref PubMed Scopus (47) Google Scholar The expression of the CD40L is absolutely essential to the proliferation induced in antigen-specific B cells and T cells at the time of an inflammatory response to a viral infection or any other inflammatory responses. As shown in Figure 5, we linked the E7 target antigen to the CD40L and embedded this chimeric transcription unit in an adenoviral vector. The attachment of the E7 antigen to the CD40L helps internalize the E7 TAA into the DCs so that the E7 is presented on the Class I major histocompatibility complex. The presence of the CD40L in the vaccine vector and in the booster protein also replaces the missing CD40L signal in the aged immune system. As shown in Figure 5, this results in the expansion of antigen-specific T cells, which then pour out from the lymph nodes into the blood stream and then migrate into the tumor tissue where they lower the number of TAA-specific tumor cells. This TAA/ecdCD40L VPP vaccine is unique in the following ways: 1. The ligation of the ecd of the CD40L potent immunostimulatory signal to the TAA delivers the TAA to the CD40 receptor of the DCs; this activates the DCs followed by internalization of the TAA/ecdCD40L protein so that the TAA peptides are eventually presented on Class I major histocompatibility complex;4Zhang L Tang Y Akbulut H Zelterman D Linton PJ Deisseroth A An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells.Proc Natl Acad Sci USA. 2003; 100: 15101-15106Crossref PubMed Scopus (63) Google Scholar,6Tang Y Akbulut H Maynard J Petersen L Fang X Zhang WW et al.Vector prime/protein boost vaccine that overcomes defects acquired during aging and cancer.J Immunol. 2006; 177: 5697-56707Crossref PubMed Scopus (18) Google Scholar 2. In older individuals, the CD4 T cells no longer express CD40L which is needed for the vaccine induced expansion of TAA-specific B cells and TAA-specific CD8 effector cells.1Fanslow WC Srinivasan S Paxton R Gibson MG Spriggs MK Armitage RJ Structural characteristics of CD40 ligand that determine biological function.Semin Immunol. 1994; 6: 267-278Crossref PubMed Scopus (150) Google Scholar,2Wurtzen PA Nissen MH Claesson MH Maturation of dendritic cells by recombinant human CD40L-trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production.Scand J Immunol. 2001; 53: 579-587Crossref PubMed Scopus (30) Google Scholar The addition of CD40L in the form of the TAA/ecdCD40L vaccine produces a robust expansion of the TAA-specific B cells and CD8 T cells.4Zhang L Tang Y Akbulut H Zelterman D Linton PJ Deisseroth A An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells.Proc Natl Acad Sci USA. 2003; 100: 15101-15106Crossref PubMed Scopus (63) Google Scholar,5Tang Y Zhang L Yuan J Akbulut H Maynard J Linton PJ et al.Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens.Blood. 2004; 104: 2704-2713Crossref PubMed Scopus (23) Google Scholar,6Tang Y Akbulut H Maynard J Petersen L Fang X Zhang WW et al.Vector prime/protein boost vaccine that overcomes defects acquired during aging and cancer.J Immunol. 2006; 177: 5697-56707Crossref PubMed Scopus (18) Google Scholar 3. The TAA/ecdCD40L transcription unit is embedded in a replication incompetent adenoviral vector, which is injected s.c. as the first injection of the vaccine. The vector-infected cells secrete the TAA/ecdCD40L protein for 10–14 days. The binding of this protein activates and antigen-loads the DCs.The presence of the adenoviral DNA and protein motifs also immediately activates the innate immune response through engagement of these motifs with the Toll-like receptors. 4. The use of the TAA/ecdCD40L protein boost following the vector injection further expands the numbers of the TAA-specific B cells and the TAA-specific CD8 effector cells.5Tang Y Zhang L Yuan J Akbulut H Maynard J Linton PJ et al.Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens.Blood. 2004; 104: 2704-2713Crossref PubMed Scopus (23) Google Scholar,6Tang Y Akbulut H Maynard J Petersen L Fang X Zhang WW et al.Vector prime/protein boost vaccine that overcomes defects acquired during aging and cancer.J Immunol. 2006; 177: 5697-56707Crossref PubMed Scopus (18) Google Scholar It has been known that the apoptosis seen in tumor cells induced by conventional chemotherapy is often associated with the induction of a tumor-specific immune response. The tumor cells themselves could serve as adjuvants in inducing an immune response.9Tan PH Beutelspacher SC Xue SA Wang YH Mitchell P McAlister JC et al.Modulation of human dendritic cell function following transduction with viral vectors: implications for gene therapy.Blood. 2005; 105: 3824-3832Crossref PubMed Scopus (131) Google Scholar It has been proposed that the dying cells might provide a danger signal that alerts the immune system, not unlike that generated by bacterial or viral infections.10Matzinger P Tolerance, danger, and the extended family.Annu Rev Immunol. 1994; 12: 991-1045Crossref PubMed Scopus (4035) Google Scholar Dying tumor cells serve as a source of tumor antigens, inducing the maturation of DCs and tumor immunity.11Banchereau J Briere F Caux C Davoust J Lebecque S Liu Y et al.Immunobiology of dendritic cells.Annu Rev Immunol. 2000; 18: 767-811Crossref PubMed Scopus (5665) Google Scholar This adjuvant activity is increased in the dying cells.12Shi Y Zheng W Rock KL Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses.Proc Natl Acad Sci USA. 2000; 97: 14590-14595Crossref PubMed Scopus (193) Google Scholar We have therefore tested whether it is possible to increase the efficacy of the TAA/ecdCD40L VPP vaccine by the addition of chemotherapy targeted to the tumor cells by means of a chemotherapy sensitization vector (AdCDIRESE1A) along with systemic administration of the chemotherapy precursor, 5FC. In order to deliver the chemotherapy specifically to the tumor cells, and to spare the TAA-specific T cells that would be undergoing a proliferative response to the TAA/ecdCD40L vaccine at the time of vaccination, we used a pro-drug activation transcription unit, cytosine deaminase, to convert a harmless chemotherapy precursor, 5FC, into the chemotherapeutic 5-fluorouracil (5FU). The levels of 5FU that are generated by this system in infected cells are so high that even nondividing cells die of the therapy. Previous reports have shown the tumor-suppressive effects of adenoviral vectors carrying the CD gene/5FC system on various tumor cell lines and in vivo models.13Akbulut H Zhang L Tang Y Deisseroth A The cytotoxic effect of replication competent adenoviral vectors carrying L-plastin promoter regulated E1A and cytosine deaminase genes in cancers of the breast, ovary and colon.Cancer Gene Ther. 2003; 10: 388-395Crossref PubMed Scopus (54) Google Scholar,14Peng XY Won JH Rutherford T Fujii T Zelterman D Pizzorno G et al.The use of the L-plastin promoter for adenoviral-mediated, tumor-specific gene expression in ovarian and bladder cancer cell lines.Cancer Res. 2001; 61: 4405-4413PubMed Google Scholar,15Kievit E Nyati MK Ng E Stegman LD Parsels J Ross BD et al.Yeast cytosine deaminase i" @default.
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• W2006011881 date "2008-10-01" @default.
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• W2006011881 title "Chemotherapy Targeted to Cancer Tissue Potentiates Antigen-specific Immune Response Induced by Vaccine for In Vivo Antigen Loading and Activation of Dendritic Cells" @default.
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• W2006011881 doi "https://doi.org/10.1038/mt.2008.158" @default.
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