Introduction. W Song 1, Y Tong 1, H Carpenter 1, H-L Kong 1 and RG Crystal 1,2 1

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1 (2000) 7, Macmillan Publishers Ltd All rights reserved /00 $ ACQUIRED DISEASES RESEARCH ARTICLE Persistent, antigen-specific, therapeutic antitumor immunity by dendritic cells genetically modified with an adenoviral vector to express a model tumor antigen W Song 1, Y Tong 1, H Carpenter 1, H-L Kong 1 and RG Crystal 1,2 1 Division of Pulmonary and Critical Care Medicine, and 2 Institute of Genetic Medicine, Weill Medical College of Cornell University, New York, NY, USA Dendritic cells (DC) are potent antigen-presenting cells that play a critical role in the initiation of cellular immune responses. Using a BALB/c syngeneic colon carcinoma cell line expressing a model tumor antigen -galactosidase ( gal), we previously reported (Song et al, J Exp Med 1997; 186: ) that immunization of mice with a single injection of DCs genetically modified with an adenovirus vector expressing gal confers potent protection against a lethal intravenous tumor challenge, as well as suppression of preestablished lung tumors, resulting in a significant survival advantage. In the present study, we have addressed the question: how long does the memory of tumor antigenspecific immunity persists after DC priming in vivo using this genetically modified DC-based cancer vaccination strategy? To accomplish this, two groups of mice were evaluated: (1) mice surviving 400 days following protection from an initial intravenous tumor challenge after immunization with DC genetically modified to express gal; and (2) mice surviving 300 days that had previously demonstrated regression of pre-established lung tumors after treatment with DC immunization. By analyzing the antigen-specific cytotoxic T lymphocyte response and challenging these long-term survival mice with a second subcutaneous tumor administration, the data demonstrate that a single administration of DC genetically modified to express a model antigen induces long-lasting, antigen-specific antitumor immunity in both naive and tumorbearing hosts, observations that have important implications in the development of genetically modified DC-based antitumor vaccination strategies. (2000) 7, Keywords: dendritic cells; tumor immunity; T cell memory; gene therapy; adenovirus Introduction Many tumor cells express epitopes on their surface that provide a potential target for therapeutic vaccine strategies that boost natural immune-mediated tumor defense mechanisms. 1 3 Host immune responses to tumors are generally ineffective in generating antitumor immunity sufficient to eliminate the tumor. 1 3 Although there are many mechanisms underlying this, emerging evidence indicates that the ineffective tumor antigenspecific antitumor immunity in tumor-bearing hosts might be circumvented by presenting the tumor antigens by dendritic cells (DC), the potent antigen presenting cells that play a critical role in the initiation of cellular immune responses. 4 8 Recent advances in DC biology, tumor antigen identification, and protein and gene transfer technology have made it possible to modify genetically DC ex vivo to express tumor antigens as a cancer vaccine strategy A number of delivery strategies are being used to load tumor antigens into DC ex vivo including pulsing DC with defined antigenic peptides, tumor lysate or tumor RNA, transducing DC with viral Correspondence: RG Crystal, The New York Hospital-Cornell Medical Center, 520 East 70th Street, ST 505, New York, New York 10021, USA Received 5 February 2000; accepted 19 September 2000 vectors, and coculturing or fusing DC with tumor cells. 25,26 All of these strategies have been shown to induce short-term protective and therapeutic antitumor immunity There has been little information, however, on long-term T cell memory after DC priming in vivo using DC-based cancer vaccination strategies. 7 The present study was designed to question the extent of long-term T cell memory induced by DC genetically modified with an adenovirus (Ad) vector expressing a model tumor antigen. To accomplish this, we have utilized a model of BALB/c syngeneic colon carcinoma cell line expressing a model antigen -galactosidase ( gal) that we have previously used to demonstrate that immunization of mice with a single injection of DC genetically modified with an Ad vector expressing gal (DC- Ad gal) confers potent protection against a lethal intravenous (i.v.) tumor challenge as well as suppression of pre-established lung tumors, resulting in a significant survival advantage. 20 We have utilized long-term survival mice from two different groups: (1) mice surviving 400 days following protection from an initial i.v. tumor challenge after immunization with DC genetically modified with an Ad vector expressing gal; and (2) mice surviving 300 days that had previously demonstrated regression of pre-established lung tumors after treatment with immunization with DC modified by Ad gal. By analyzing the antigen-specific cytotoxic T lymphocyte

2 (CTL) response and challenging these long-term survival mice with a second subcutaneous tumor administration, the data demonstrated that a single administration of DC genetically modified to express a model antigen induced long-lasting antigen-specific CTL responses in both naive and tumor-bearing hosts. Results Long-term protection against lethal i.v. tumor challenge after DC immunization As previously reported, 20 BALB/c mice that were immunized with DC-Ad gal ( ) before challenge with tumor cells were effectively protected against intravenous tumor challenge, with all animals surviving over the 140 day observation period. For the present study, these mice were followed on a long-term basis. Strikingly, there was a prolonged survival ( 400 days) in the DC-Ad gal group compared with the DC-AdNull group (P ; not shown ). In contrast, mice immunized with DC-Ad gal were not protected against a challenge by CT26.WT cells (P 0.9; not shown), indicating that the immune response was antigen ( gal)-specific. Titration of the dose of DC-Ad gal used for immunization revealed that as few as 10 4 DC-Ad gal were as potent as 10 6 DC-Ad gal in tumor protection (not shown). Long-term suppression of pre-established lung metastases by DC immunization We previously reported 20 that immunization with DC genetically modified to express gal could suppress preestablished gal-expressing tumors in tumor-bearing hosts, with prolonged survival of at least 100 days. These same surviving mice were observed in the present study as a long-term follow-up of the ability of the genetically modified DC-induced immunity to persist. Mice with pre-existing lung metastases which received DC-Ad gal ( ) treatment lived significantly longer ( 300 days) than the DC-AdNull control group (P ; data not shown). As in the prevention experiment, DC-Ad gal immunization had no therapeutic effect on CT26.WT tumors which did not express gal (not shown), suggesting that the antitumor effect of the genetically modified DC was antigen ( gal)-specific. Also similar to the prevention study, a therapeutic effect is mediated by genetically modified DC at doses from 10 4 to 10 6 (not shown). Persistence of the CTL response in long-term survival mice To determine whether antigen ( gal)-specific CTL responses persisted in these long-term survival mice, splenocytes from those mice were restimulated in vitro with gal peptide and were then evaluated for specific cell lysis in a standard 51 Cr-release assay. As with nontumor bearing mice evaluated 300 days after DC- Ad gal immunization (Figure 1a, b), gal-specific CTL were easily detected, in long-term ( 300 days) survival mice that were protected from the initial i.v. tumor challenge (Figure 1c), as well as in long-term survival mice that demonstrated regression of pre-established lung tumors (Figure 1d). The cellular immune response was gal-specific since the CT26.WT target exhibited negligible lysis. The specific cytotoxicity was mediated pre- Persistent antitumor immunity induced by genetically modified DC dominantly by MHC-restricted CTL rather than natural killer cells since E22, an MHC-mismatched gal-expressing murine tumor cell line, was not significantly lysed in the same assay. Adoptive CTL transfer for tumor prevention To determine whether the gal-specific CTL induced by DC-Ad gal immunization were responsible for the protection of mice from tumor challenge or regression of preestablished lung tumors, gal-specific CTL were generated from DC-Ad gal immunized mice and transferred to naive mice. Naive mice that received CTL from DC- Ad gal immunized mice, but not from DC-AdNull immunized mice, were protected from either a subsequent subcutaneous (P , all observations, Figure 2a) or intravenous tumor challenge of CT26.CL25 (P 0.004, all observations; Figure 2b). Naive mice that received CTL from DC-Ad gal immunized mice were not protected from CT26.WT challenge, consistent with the concept that it was the gal-specific CTL that were responsible for the in vivo tumor protection. Similar observations were made using adoptive transfer to naive mice of CTL derived from long-term survivor mice (previously immunized with DC-Ad gal) and then subcutaneously challenged with CT26.WT (Figure 2c) or with CT26.CL25 (Figure 2d). In this context, adoptive transfer from long-term survivors did not afford protection against CT26.WT (P 0.1, all observations, Figure 2c) while adoptive transfer from long-term survivors did provide protection again CT26.CL25 (P 0.03, all observations, Figure 2d). Second bilateral tumor challenge in long-term survival mice To evaluate further the long-term memory of antitumor immunity in vivo after genetically modified DC immunization, the long-term survival mice ( 400 days) that were protected from an i.v. tumor challenge, and long-term survival mice ( 300 days) that demonstrated regressed pre-existing tumor after genetically modified DC immunization were rechallenged in the lower flank with subcutaneous bilateral 10 5 CT26.WT (left flank) and CT26.CL25 (right flank) tumors. As controls, naive mice of comparable age and mice immunized with DC-Ad gal for 300 days were also rechallenged under identical conditions. As in the control mice immunized with DC- Ad gal, both groups of long-term survival mice were protected from the second subcutaneous tumor challenge with CT26.CL25 tumor cells (Figure 3a), but were not protected from the challenge with CT26.WT cells (Figure 3b), indicating the tumor protection was mediated by long-lasting gal-specific antitumor immunity. It was of interest to note that both groups of longterm survival mice were not protected from the CT26.WT challenge despite their previous in vivo killing of CT26.CL25 by gal-specific CTL. However, the long-term survival mice that were protected from the initial intravenous CT26.CL25 challenge had a significantly slower growth rate of CT26.WT compared with the naive mice group (P 0.02; Figure 3b). This suggests that cross-priming was not operant, in that the antigens released by CT26.CL25 after being killed by CTL were not efficiently processed and presented in vivo by enough DC to prime the immune system. 2081

3 Persistent antitumor immunity induced by genetically modified DC 2082 Figure 1 Persistence of long-lasting cytotoxic T lymphocyte (CTL) response induced following immunization with DC genetically modified with an adenovirus (Ad) vector expressing -galactosidase. To determine the extent of persistence of the model antigen ( gal)-specific CTL response in vivo after DC immunization, a standard 51 Cr-release assay was performed using CTL splenocytes derived from naive mice, mice immunized with DC-Ad gal ( 300 days), long-term survival mice that were protected from an intravneous (i.v.) tumor challenge ( 400 days), and long-term survival mice that demonstrated regression of pre-existing tumor after DC-Ad gal immunization 300 days previously. The splenocytes were stimulated in vitro for 5 days with irradiated syngeneic SVBalb cells pulsed with a gal peptide, and then assayed for specific cell lysis against three syngeneic target cells (parental CT26.WT, gal-expressing CT26.CL25, or CT26.WT pulsed with gal peptide CT26.WT- gal peptide) as well as the E22 gal-expressing allogeneic tumor cell line. (a) CTL response in naive mice matched by age to the control mice. (b) CTL response in mice after long-term DC-Ad gal immunization. (c) CTL in DC-Ad gal-immunized mice that survived long-term after an i.v. tumor challenge. (d) CTL in tumor-bearing mice that survived long term after treatment with DC-Ad gal immunization. Antigen-loss escape tumor variant Although DC-Ad gal-based vaccination was effective in protecting mice against subsequent subcutaneous tumor challenge, we observed that a minority of DC-Ad gal immunized mice (two of 17 mice in three separate experiments) initially protected from a lethal subcutaneous tumor challenge for more than 80 days eventually succumbed to regrowth of tumor. Interestingly, analysis of one of these tumors showed that it was gal negative, as demonstrated by RT-PCR for gal mrna and DNA- PCR for the gal gene (not shown). Discussion Immunization using DC loaded with tumor antigen represents a powerful method of inducing specific antitumor immunity. This study evaluates the chronicity of antitumor immunity memory induced by immunization of genetically modified DC. The data demonstrated that a single subcutaneous immunization of genetically modified DC induced long-lasting antigen-specific CTL immunity (300 to 400 days, the length of the experiments) in both naive and tumor-bearing hosts. With the discovery of more tumor antigens, the strategy of genetic modification of DC with adenovirus gene transfer vectors to express specific tumor antigens may be useful in the treatment of malignancy, particularly in applications to suppress the growth of micrometastases using vaccinations with tumor antigen-expressing DC as adjuvant treatment after primary therapy. The observations in the present study are striking in the persistence of the antitumor immunity generated by a single administration of DC genetically modified by ex vivo adenovirus-mediated transfer of a model antigen known to be expressed by the tumor. The data demonstrate that for the majority of experimental animals, antitumor immunity and concomitant suppression of tumor growth lasted for 300 to 400 days, the length of the experiments. Interestingly, although immunization with DC expressing a model tumor antigen was effective, it was of interest to note that a minority of the mice in this study that initially remained tumor-free for 80 days eventually succumbed to regrowth of tumor. The mechanism for this is unknown, although assessment of one of these regrowth tumors demonstrated a loss of the gene coding for the model antigen, a phenomenon that has been previously noted in antigen-loss tumor variants in human melanoma and murine P815 and SV40-transformed tumor models It is tempting to speculate that a vigorous antigen-specific antitumor CTL response in vivo might facilitate the generation of antigen-loss variants by eradicating tumor cells expressing the tumor antigen, permitting small numbers of tumor cells not expressing the targeted antigen to regrow. This observation supports the critical importance of T cell selective pressure against tumor progression and has important implications for the

4 Persistent antitumor immunity induced by genetically modified DC 2083 Figure 2 Adoptive cytotoxic T lymphocyte transfer for tumor prevention. To determine whether the gal-specific CTL induced by DC-Ad gal immunization were responsible in vivo for the protection of mice from tumor challenge or regression of pre-established lung tumors, gal-specific CTL were generated from DC-immunized mice as described in Figure 1. CTL ( ) were infused i.v. into naive mice. One day later, the mice were challenged either subcutaneously or intravenously with 10 5 CT26.CL25 or CT26.WT cells. As a control, a group of DC-Ad gal-immunized mice were also challenged by tumor. For subcutaneous tumor challenge, the mice were followed for tumor growth by measuring tumor size in two dimensions using calipers (product = width length). The data are expressed as the mean ± standard error. For intravenous tumor challenge, the mice were followed for survival and the data expressed as percent survival as a function of time. (a) Protection of mice from subcutaneous tumor challenge with adoptive transfer of CTL from short-term (2 week) DC-immunized mice. (b) Similar to (a), but protection of tumor from intravenous tumor challenge. (c) Similar to (a), but with adoptive transfer from long-term survivor mice and then challenged subcutaneously with CT26.WT. (d) Similar to (c), but challenged subcutaneously with CT26.CL25. development of DC-based tumor vaccines. In this context, it underlies the possible need to develop DC-based vaccines that are armed with a spectrum of antigens from tumor cells in order to treat effectively the heterogenous human tumors. While the present study argues strongly for the use of genetically modified DC as a strategy to achieve longterm suppression against tumor cells expressing a model antigen, it depends on the identification of specific tumor antigens, and the use of gene sequences coding for these antigens to modify autologous DC. Because the identification of tumor-specific antigens has been a challenge for many tumor types, the applicability of using genetically modified DC to suppress tumor growth would be markedly broadened if it was not necessary to identify the specific antigen(s) to express in the DC. In this context, previous studies have shown that the in vivo generation of immune response against tumor cells generally occurs through cross-priming, with tumor antigen presentation to MHC class I molecules being dependent on bone marrow-derived antigen-presenting cells of the host Relevant to DC tumor strategies, there is evidence that DC can efficiently acquire antigens from apoptotic cells or irradiated tumor cells in vitro and induce MHC class I- restricted CTL responses, and this may account for the in vivo phenomenon of cross-priming. 25,26 In this regard, it is interesting to note that in the present study, the longterm survival mice protected from an initial CT26.CL25 challenge were not protected from the secondary challenge with parental tumor CT26.WT. This suggests that the antigens released by CT26.CL25 after being killed by CTL in vivo were not efficiently presented by DC to the immune system, ie cross-priming was not operant, at least to the extent detected by this experimental system.

5 Persistent antitumor immunity induced by genetically modified DC 2084 Figure 3 Evaluation of growth of a second subcutaneous tumor challenge in long-term survival mice that were protected from lung tumor challenge more than 10 months previously. To determine the extent of persistence of antitumor immunity in vivo, the long-term survival mice that were protected from an intravenous tumor challenge ( 400 days), and long-term survival mice that demonstrated regressed pre-existing tumor after DC immunization ( 300 days), were rechallenged subcutaneously bilaterally in the lower flank with 10 5 CT26.WT (left flank) and CT26.CL25 (right flank). As controls, comparable old naive mice and mice immunized with DC-Ad gal 300 days previously were rechallenged in a parallel fashion. The mice were then followed for tumor growth as described for Figure 3a. The data are expressed as mean ± standard error. (a) CT26.WT subcutaneous tumor challenge (left side) in all groups. (b) CT26.CL25 subcutaneous tumor challenge (right side) in all groups. This observation also reinforces the concept that inefficient tumor antigen presentation by DC in vivo is an important mechanism by which tumors may escape immune surveillance, and suggests that strategies designed to enhance in vivo DC cross-priming and/or to achieve more efficient in vitro DC cross-priming needs to be explored further before assuming such strategies will work in human applications of these strategies. Materials and methods Mice and cell lines Six- to eight-week-old male BALB/c (H-2 d ) mice were obtained from the Jackson Laboratory (Bar Harbor, ME, USA). Animals were housed under specific pathogen-free conditions and treated according to National Institutes of Health guidelines. CT26.WT (H-2 d ) is a clone of the N-nitroso-N-methylurethane-induced BALB/c undifferentiated colon adenocarcinoma cell line. 34 CT26.CL25 is a clone of CT26.WT that has been transduced with the E. coli -gal (both cell lines kindly provided by NP Restifo, NCI, Bethesda, MD, USA). 34 E22 cells, a clone of the mouse thymoma EL4 (H- 2 b ) cell line transduced with the gal gene, was used as a negative control in the CTL assay (E22 was provided by Y Paterson, University of Pennsylvania, Philadelphia, PA, USA). 34 The SVBalb (H-2 d ) fibroblast cell line was used as in vitro stimulator cells in the CTL assay; this cell line is syngeneic to BALB/c mice (provided by L Gooding, Emory University, Atlanta, GA, USA). 35 CT26.WT and SVBalb were grown in complete RPMI media (10% fetal bovine serum, 2 mm l-glutamine, 100 g/ml streptomycin, and 100 U/ml penicillin). CT26.CL25 and E22 were grown in complete RPMI containing 400 g/ml G418 (Life Technologies, Gaithersburg, MD, USA). Generation of dendritic cells in vitro from bone marrow Primary DC were obtained from mouse bone marrow precursors as previously described. 20,36 Briefly, lymphocyte- and erythrocyte-depleted murine bone marrow cells harvested from femurs and tibias were plated in complete RPMI media supplemented with recombinant murine GM-CSF (100 U/ml; Sigma, St Louis, MO, USA) and recombinant murine interleukin 4 (20 ng/ml; Genzyme, Farmington, MA, USA). On days 2 and 4, nonadherent granulocytes were gently removed and fresh medium was added. On day 6, loosely adherent proliferating DC aggregates were dislodged and replated. On day 8 of culture, released, mature, nonadherent cells with the typical morphological features of DC were used for the immunization of mice. The quality of the DC preparations were characterized by cell surface marker analysis, typical morphology and their ability to activate naive allogeneic T cells in vitro in a mixed leukocyte reaction assay, as previously reported. 20,36 Immunization with ex vivo adenovirus vector-transduced DC The replication-deficient Ad vectors used in this study are E1a, partially E1b, and partially E3 vectors based on human Ad5. 37,38 The construction of these Ad vectors have been described previously, including vectors expressing no transgene (AdNull) and the E. coli gal gene (Ad gal). 39 All Ad vectors were propagated in 293 cells, purified by two rounds of CsCl density centrifugation, dialyzed and stored at 70 C as previously described. 37,38 The titer of viral stock was determined by plaque-forming assay using 293 cells. All vector preparations were demonstrated to be free of replicationcompetent adenovirus. 40 DC used for immunization were infected with Ad gal or AdNull for 2 h at a multiplicity of infection (MOI) of 100. Twenty-four hours later, the Ad gal-infected DC (referred to as DC-Ad gal ) were observed to have gal expression in 90% of cells as quantified by flow cytometry as previously reported. 20 In contrast, no gal expression was observed in the AdNull-infected DC (referred to as DC-AdNull ). BALB/c mice were immun-

6 ized once by subcutaneous injection of modified DC suspended in 100 l Hank s balanced saline solution (HBSS) in the left lower quadrant of the ventral abdominal wall. Detection of antigen-specific CTL To determine the extent of persistence of the model antigen ( gal)-specific CTL response long after DC immunization, the spleens were removed from these mice and the splenocytes were pooled and cocultured ( /ml) with irradiated (5000 rad) syngeneic SVBalb cells ( /ml) pulsed with the synthetic gal peptide (1 m) in a six-well plate (5 ml per well). After 5 days of coculture, the in vitro restimulated viable splenocytes were assayed in a 51 Cr-release assay for specific cell lysis against a variety of target cells, including syngeneic cell lines CT26.WT, gal-expressing CT26.CL25, and gal peptidepulsed CT26.WT, as well as a major histocompatibility complex (MHC)-mismatched, gal-expressing E22 (H-2 b ) cell line. The gal peptide used in the CTL studies is the nanomer TPHPARIGL (residues ) that is naturally presented by the H-2 L d molecule. 41 The peptide was synthesized (Biosynthesis, Lewisville, TX, USA) to a purity 99% as determined by high pressure liquid chromatography and amino acid analysis. The 51 Cr-release assay was performed as previously described. 20,42,43 Protection against lethal i.v. tumor challenge after DC immunization BALB/c mice were immunized subcutaneously with DC-Ad al in 100 l HBSS. Control animals received either no DC or DC infected with AdNull. Two weeks later, naive and immunized mice were challenged with 10 5 syngeneic CT26.CL25 murine colon carcinoma cells injected intravenously through the jugular vein. The mice were then followed for survival. In addition, to evaluate if the antitumor immunity was gal-specific, another group of mice immunized with DC-Ad gal was challenged with CT26.WT tumor cells that did not express gal and followed for survival. Suppression of pre-established lung metastases by DC immunization To evaluate if pre-existing lung metastases could be suppressed following immunization with gal-expressing DC, BALB/c mice were first injected with CT26.CL25 tumor cells intravenously to generate multiple lung metastases. Three days later, tumor-bearing mice were either left untreated, or treated with subcutaneous injections of DC-AdNull or DC-Ad gal. The mice were then followed for survival. To evaluate if the treatment effect was gal-specific, a group of mice with preestablished CT26.WT tumors that did not express gal was treated with DC-Ad gal and followed for survival. Secondary subcutaneous tumor challenge in long-term survivor mice To determine the extent of persistence of antitumor immunity in mice, the mice that survived the initial i.v. tumor challenge for a long time ( 300 days) were given a second subcutaneous tumor challenge. To generate subcutaneous tumors, CT26.CL25 or CT26.WT tumor cells (10 5 cells in 100 l HBSS) were implanted in the lower flanks of BALB/c mice. The mice were followed for tumor growth by measuring tumor size in two dimen- Persistent antitumor immunity induced by genetically modified DC sions using calipers and the product was calculated (product = width length). 44 Animals were killed when the tumor diameter exceeded 15 mm, when there was tumor ulceration or when there were other signs of animal distress. Adoptive CTL transfer for tumor prevention To determine whether the gal-specific CTL induced by DC-Ad gal immunization were responsible in vivo for the protection of mice from tumor challenge or regression of pre-established lung tumors, gal-specific CTL were generated from DC-immunized mice as described above. CTL ( ) were infused i.v. into naive mice. One day later, these mice were challenged either subcutaneously or intravenously with 10 5 CT26.CL25 or CT26.WT and then followed for tumor size (subcutaneous challenge) or survival (intravenous challenge). Statistical analysis All animal experiments utilized a minimum of four animals and were repeated at least twice with similar results. Quantitative results are expressed as mean ± standard error of the mean. Statistical analysis was performed using the unpaired two-tailed Student s t test, with the exception of the survival data which were analyzed using the log-rank test. 45 Acknowledgements We thank N Mohamed in helping to prepare this manuscript. These studies were supported, in part, by the National Cancer Institute R01 CA75192; Will Rogers Memorial Fund, Los Angeles, CA; and GenVec, Inc., Rockville, MD. References 1 Pardoll DM. Cancer vaccines. Immunol Today 1993; 14: Houghton AN. Cancer antigens: immune recognition of self and altered self. J Exp Med 1994; 180: Boon T, van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J Exp Med 1996; 183: Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991; 9: Grabbe S, Beissert S, Schwarz T, Granstein RD. Dendritic cells as initiators of tumor immune responses: a possible strategy for tumor immunotherapy? Immunol Today 1995; 16: Young JW, Inaba K. Dendritic cells as adjuvants for class I major histocompatibility complex-restricted antitumor immunity. J Exp Med 1996; 183: Schuler G, Steinman RM. Dendritic cells as adjuvants for immune-mediated resistance to tumors. J Exp Med 1997; 186: Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392: Crystal RG. Transfer of genes to humans: early lessons and obstacles to success. Science 1995; 270: Verma IM, Somia N. Gene therapy promises, problems and prospects. Nature 1997; 389: Mayordomo JI et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nature Med 1995; 1: Boczkowski D, Nair SK, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 1996; 184: Celluzzi CM et al. Peptide-pulsed dendritic cells induce antigenspecific, CTL-mediated protective tumor immunity. J Exp Med 1996; 183:

7 2086 Persistent antitumor immunity induced by genetically modified DC 14 Hsu FJ et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nature Med 1996; 2: Porgador A, Snyder D, Gilboa E. Induction of antitumor immunity using bone marrow-generated dendritic cells. J Immunol 1996; 156: Zitvogel L et al. Therapy of murine tumors with tumor peptidepulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med 1996; 183: Nestle FO et al. Vaccination of melanoma patients with peptideor tumor lysate-pulsed dendritic cells. Nature Med 1998; 4: Henderson RA et al. Human dendritic cells genetically engineered to express high levels of the human epithelial tumor antigen mucin (MUC-1). Cancer Res 1996; 56: Reeves ME et al. Retroviral transduction of human dendritic cells with a tumor-associated antigen gene. Cancer Res 1996; 56: Song W et al. Dendritic cells genetically modified with an adenovirus vector encoding the cdna for a model antigen induce protective and therapeutic antitumor immunity. J Exp Med 1997; 186: Brossart P et al. Virus-mediated delivery of antigenic epitopes into dendritic cells as a means to induce CTL. J Immunol 1997; 158: Ribas A et al. Genetic immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine dendritic cells. Cancer Res 1997; 57: Specht JM et al. Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases. J Exp Med 1997; 186: Wan Y et al. Dendritic cells transduced with an adenoviral vector encoding a model tumor-associated antigen for tumor vaccination. Hum Gene Ther 1997; 8: Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTL. Nature 1998; 392: Celluzzi CM, Falo LD Jr. Physical interaction between dendritic cells and tumor cells results in an immunogen that induces protective and therapeutic tumor rejection. J Immunol 1998; 160: Uyttenhove C, Maryanski J, Boon T. Escape of mouse mastocytoma P815 after nearly complete rejection is due to antigen-loss variants rather than immunosuppression. J Exp Med 1983; 157: Lurquin C et al. Structure of the gene of tum transplantation antigen P91A: the mutated exon encodes a peptide recognized with L d by cytolytic T cells. Cell 1989; 58: Lehmann F et al. Differences in the antigens recognized by cytolytic T cells on two successive metastases of a melanoma patient are consistent with immune selection. Eur J Immunol 1995; 25: Maeurer MJ et al. Tumor escape from immune recognition. Lethal recurrent melanoma in a patient associated with downregulation of the peptide transporter protein TAP-1 and loss of expression of the immunodominant MART-1/Melan-A antigen. J Clin Invest 1996; 98: Bevan MJ. Antigen presentation to cytotoxic T lymphocytes in vivo. J Exp Med 1995; 182: Germain RN. MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994; 76: Huang AY et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 1994; 264: Wang M et al. Active immunotherapy of cancer with a nonreplicating recombinant fowlpox virus encoding a model tumorassociated antigen. J Immunol 1995; 154: Rawle FC et al. Specificity of the mouse cytotoxic T lymphocyte response to adenovirus 5. E1a is immunodominant in H-2b, but not in H-2d or H-2k mice. J Immunol 1991; 146: Inaba K et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 1992; 176: Rosenfeld MA et al. Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo. Science 1991; 252: Rosenfeld MA et al. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 1992; 68: Hersh J, Crystal RG, Bewig B. Modulation of gene expression after replication-deficient, recombinant adenovirus-mediated gene transfer by the product of a second adenovirus vector. Gene Therapy 1995; 2: Crystal RG et al. Administration of an adenovirus containing the human CFTR cdna to the respiratory tract of individuals with cystic fibrosis. Nat Genet 1994; 8: Gavin MA et al. Alkali hydrolysis of recombinant proteins allows for the rapid identification of class I MHC-restricted CTL epitopes. J Immunol 1993; 151: Mack CA et al. Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum Gene Ther 1997; 8: Song W, Kong H-L, Traktman P, Crystal RG. Cytotoxic T lymphocyte responses to proteins encoded by heterologous transgenes transferred in vivo by adenoviral vectors. Hum Gene Ther 1997; 8: Kong HL et al. Regional suppression of tumor growth by in vivo transfer of a cdna encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. Hum Gene Ther 1998; 9: Peto R et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 1977; 35: 1 39.

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