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Safety and Immunogenicity of a DNA Vaccine Encoding Carcinoembryonic Antigen and Hepatitis B Surface Antigen in Colorectal Carcinoma Patients1

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Safety and Immunogenicity of a DNA Vaccine Encoding Carcinoembryonic Antigen and Hepatitis B Surface Antigen in Colorectal Carcinoma Patients1 2782 Vol. 8, 2782–2787, September 2002 Clinical Cancer Research Advances in Brief Safety and Immunogenicity of a DNA Vaccine Encoding Carcinoembryonic Antigen and Hepatitis B Surface Antigen in Colorectal Carcinoma Patients1 Robert M. Conry, David T. Curiel, Introduction Theresa V. Strong, Susan E. Moore, Between 1990 and 1993, the administration of “naked” Karen O. Allen, Daunte L. Barlow, plasmid DNA encoding a specific protein antigen was shown to Denise R. Shaw, and Albert F. LoBuglio2 induce expression of the protein in mouse myocytes, elicit antibodies against the protein, and protect against influenza Department of Medicine, Division of Hematology/Oncology challenge via cytolytic T-cell responses against the expressed [R. M. C., T. V. S., S. E. M., K. O. A., D. L. B., D. R. S., A. F. L.] and the Gene Therapy Center [D. T. C.], University of Alabama at protein (1–3). Hundreds of publications since have reported the Birmingham, Comprehensive Cancer Center, Birmingham, Alabama efficacy of DNA vaccines in small and large animal models of 35294-3300 infectious diseases and cancer (4, 5). DNA vaccination provides the following advantages over protein vaccines: (a) greater chemical stability; (b) relative ease Abstract of purification and characterization; (c) inherent adjuvant effects Despite an abundance of preclinical data, relatively of unmethylated CpG dinucleotide motifs; (d) direct entry of little is known regarding the efficacy of DNA vaccination in antigen into intracellular MHC class I processing pathways humans. Here, we present results from a dose-escalation facilitating CTL induction; and (e) intracellular antigen synthe- clinical trial of a dual expression plasmid encoding carcino- sis with posttranslational modification producing native tertiary embryonic antigen (CEA) and hepatitis B surface antigen antigen structure. Similarly, DNA vaccination provides advan- (HBsAg) in 17 patients with metastatic colorectal carcinoma. tages compared with recombinant viral vaccines as follows: (a) CEA was selected as a prototypic tumor-associated self- relative ease of construction, production and quality control; (b) antigen, and the HBsAg cDNA was included as a positive less risk of insertional mutagenesis; (c) absence of vector- control for immune response to the DNA vaccine without specific immune responses that limit the efficacy of booster relying upon breaking tolerance to a self-antigen. Groups of immunizations; and (d) absence of risk related to recombina- 3 patients received escalating single i.m. doses of the DNA tional events leading to pathogenic viruses. vaccine at 0.1, 0.3, and 1.0 mg. Subsequent groups of 3 Despite an abundance of preclinical data, relatively little is patients received three repetitive 0.3- or 1.0-mg doses at known regarding the efficacy of DNA vaccination in humans. 3-week intervals. A final group of 2 patients received three Early clinical trials of DNA vaccines against infectious patho- repetitive 2.0 mg doses at 3-week intervals. Toxicity was gens have provided mixed results. Trials conducted in HIV- limited to transient grade 1 injection site tenderness, fatigue, infected individuals have been difficult to interpret because of and creatine kinase elevations, each affecting a minority of preexisting immunity (6–8). A subsequent Phase I trial of a patients in a non-dose-related manner. Repetitive dosing of DNA vaccine encoding HIV antigens in 39 healthy volunteers the DNA vaccine induced HBsAg antibodies in 6 of 8 patients, induced antigen-specific lymphoproliferative responses but no with protective antibody levels achieved in four of these pa- antibody responses and only rare CTL responses (9). In the tients. CEA-specific antibody responses were not observed, but largest DNA vaccine trial reported to date, 219 healthy volun- 4 of 17 patients developed lymphoproliferative responses to teers were randomized to receive a plasmid encoding influenza CEA after vaccination. No objective clinical responses to the hemagglutinin or placebo (10). Virus-neutralizing and hemag- DNA vaccine were observed among this population of patients glutination-inhibiting antibodies developed in only a minority of with widely metastatic colorectal carcinoma. Nevertheless, this subjects. More encouraging results have emerged from the ini- pilot trial has provided encouraging human immune response tial clinical trial of a DNA vaccine encoding a malarial antigen, data in support of this vaccine technology. the Plasmodium falciparum circumsporozoite protein (11). Per- sons receiving vaccines unequivocally developed antigen- specific, CD8-positive CTLs restricted by multiple HLA alleles, providing a foundation for further human trials of this poten- Received 4/24/00; revised 5/23/02; accepted 5/31/02. tially revolutionary vaccine technology. The costs of publication of this article were defrayed in part by the In this report, we present results from a dose-escalation payment of page charges. This article must therefore be hereby marked clinical trial of a dual-expression plasmid encoding CEA3 and advertisement in accordance with 18 U.S.C. Section 1734 solely to HBsAg in 17 patients with metastatic colorectal carcinoma. indicate this fact. 1 Supported in part by NIH/National Cancer Institute Grant CA 68256. 2 To whom requests for reprints should be addressed, at University of Alabama at Birmingham, Comprehensive Cancer Center, 1530 3rd Avenue South, Wallace Tumor Institute, Room 237, Birmingham, AL 3 The abbreviations used are: CEA, carcinoembryonic antigen; HBsAg, 35294-3300. Phone: (205) 934-5807; Fax: (205) 975-7428; E-mail: hepatitis B surface antigen; PHA, phytohemagglutinin; S.R., stimulation [email protected]. ratio; rV-CEA, recombinant vaccinia virus encoding CEA. Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2002 American Association for Cancer Research. Clinical Cancer Research 2783 CEA was selected as a prototypic tumor-associated self-antigen, (21). Patients had an Eastern Cooperative Oncology Group and HBsAg cDNA was included as a positive control for im- performance status of 0–2 and no serological evidence of anti- mune response to the DNA vaccine uncomplicated by immu- body to HBsAg or active hepatitis B infection. Therapy was nological tolerance to a self-antigen. CEA is a Mr 180,000 initiated at least 4 weeks after prior chemotherapy or radiother- membrane-anchored glycoprotein expressed on the great major- apy. All patients gave informed consent. ity of colorectal, gastric, and pancreatic carcinomas as well as Each DNA vaccine dose consisted of bilateral i.m. injec- ϳ50% of breast cancers and 70% of non-small cell lung cancers tions using a volume of 1–2 ml into each deltoid muscle. Groups (12). CEA is also expressed, to a limited extent, in normal of 3 patients received escalating single doses of pCEA/HBsAg colonic mucosa and fetal digestive organs. at 0.1, 0.3, and 1.0 mg total dose. Subsequently, groups of three Our group has demonstrated that i.m. administration of patients received three repetitive 0.3 or 1.0-mg doses at 3-week plasmid DNA encoding human CEA induces CEA-specific hu- intervals. A final group of two patients received three repetitive moral and cellular immune responses in mice and nonhuman 2.0 mg doses at 3-week intervals. All patients underwent 9 primates as well as protection of mice against challenge with weeks of clinical and immunological monitoring after their first syngeneic colon carcinoma cells expressing human CEA (13– DNA vaccine dose. Patients were examined 1 and 3 weeks after 15). However, it is important to emphasize that human CEA is each immunization to assess the degree of inflammation at the a foreign antigen in both mice and nonhuman primates, whereas inoculation site, regional adenopathy, or other signs of toxicity. humans should be immunologically tolerant to CEA because of A complete blood count, serum chemistries, and C-reactive its expression in fetal and normal adult tissues. protein level were obtained before each immunization as well as The goals of the present study were 3-fold: (a) to examine 7 and 28 days after each immunization. Serum CEA levels were the safety of single and repetitive administration of the DNA obtained at 3-week intervals, and anti-double-stranded DNA vaccine over a range of 0.1–2.0 mg/dose; (b) to examine the antibody titers were checked before immunization and during efficacy of DNA vaccination in humans based upon immune the off-study evaluation on day 64. All patients were evaluated response to the HBsAg control antigen; (c) to evaluate any for evidence of objective antitumor response 9 weeks after the CEA-specific immune responses or antitumor effects induced primary immunization. by the vaccine. Lymphoproliferative Assay. Fresh peripheral blood mononuclear cells obtained by Ficoll density gradient centrifu- gation were resuspended in complete medium consisting of Materials and Methods RPMI 1640 supplemented with 10% pooled normal human AB DNA Vaccine. We obtained the cDNA encoding full- serum, 2 mML-glutamine, 50 ␮M 2-mercaptoethanol, and anti- length human CEA from J. Kanter, National Cancer Institute biotics. Cells were added at 1.5 ϫ 105 per well to 96-well, (16) and cDNA for the small and middle (S2.S) proteins of flat-bottomed plates. Stimulated cells were incubated in quad- HBsAg from Robert Whalen (Centre National de la Recherche ruplicate wells with baculovirus-derived recombinant human Scientifique, Paris, France; Refs. 17, 18). These two cDNAs CEA (MicroGeneSys, Meriden, CT) over a range
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