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Enhancement of anti-murine colon cancer immunity by fusion of a SARS fragment to a low-immunogenic carcinoembryonic antigen.

ABSTRACT: BACKGROUND:It is widely understood that tumor cells express tumor-associated antigens (TAAs), of which many are usually in low immunogenicity; for example, carcinoembryonic antigen (CEA) is specifically expressed on human colon cancer cells and is viewed as a low-immunogenic TAA. How to activate host immunity against specific TAAs and to suppress tumor growth therefore becomes important in cancer therapy development. RESULTS:To enhance the immune efficiency of CEA in mice that received, we fused a partial CEA gene with exogenous SARS-CoV fragments. Oral vaccination of an attenuated Salmonella typhimurium strain transformed with plasmids encoding CEA-SARS-CoV fusion gene into BALB/c mice elicited significant increases in TNF-? and IL-10 in the serum. In addition, a smaller tumor volume was observed in CT26/CEA-bearing mice who received CEA-SARS-CoV gene therapy in comparison with those administered CEA alone. CONCLUSION:The administration of fusing CEA-SARS-CoV fragments may provide a promising strategy for strengthening the anti-tumor efficacy against low-immunogenic endogenous tumor antigens.

SUBMITTER: Lin CS

PROVIDER: S-EPMC3298716 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Enhancement of anti-murine colon cancer immunity by fusion of a SARS fragment to a low-immunogenic carcinoembryonic antigen.

Lin Chen-Si CS Kao Shih-Han SH Chen Yu-Cheng YC Li Chi-Han CH Hsieh Yuan-Ting YT Yang Shang-Chih SC Wu Chang-Jer CJ Lee Ru-Ping RP Liao Kuang-Wen KW

Biological procedures online 20120203

<h4>Background</h4>It is widely understood that tumor cells express tumor-associated antigens (TAAs), of which many are usually in low immunogenicity; for example, carcinoembryonic antigen (CEA) is specifically expressed on human colon cancer cells and is viewed as a low-immunogenic TAA. How to activate host immunity against specific TAAs and to suppress tumor growth therefore becomes important in cancer therapy development.<h4>Results</h4>To enhance the immune efficiency of CEA in mice that rec ...[more]

PMID: 22304896

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Project description:ImportanceGuidelines recommend measuring preoperative carcinoembryonic antigen (CEA) in patients with colon cancer. Although persistently elevated CEA after surgery has been associated with increased risk for metastatic disease, prognostic significance of elevated preoperative CEA that normalized after resection is unknown.ObjectiveTo investigate whether patients with elevated preoperative CEA that normalizes after colon cancer resection have a higher risk of recurrence than patients with normal preoperative CEA.Design, setting, and participantsThis retrospective cohort analysis was conducted at a comprehensive cancer center. Consecutive patients with colon cancer who underwent curative resection for stage I to III colon adenocarcinoma at the center from January 2007 to December 2014 were identified.ExposuresPatients were grouped into 3 cohorts: normal preoperative CEA, elevated preoperative but normalized postoperative CEA, and elevated preoperative and postoperative CEA.Main outcomes and measuresThree-year recurrence-free survival (RFS) and hazard function curves over time were analyzed.ResultsA total of 1027 patients (461 [50.4%] male; median [IQR] age, 64 [53-75] years) were identified. Patients with normal preoperative CEA had 7.4% higher 3-year RFS (n = 715 [89.7%]) than the combined cohorts with elevated preoperative CEA (n = 312 [82.3%]) (P = .01) but had RFS similar to that of patients with normalized postoperative CEA (n = 142 [87.9%]) (P = .86). Patients with elevated postoperative CEA had 14.9% lower RFS (n = 57 [74.5%]) than the combined cohorts with normal postoperative CEA (n = 857 [89.4%]) (P = .001). The hazard function of recurrence for elevated postoperative CEA peaked earlier than for the other cohorts. Multivariate analyses confirmed that elevated postoperative CEA (hazard ratio [HR], 2.0; 95% CI, 1.1-3.5), but not normalized postoperative CEA (HR, 0.77; 95% CI, 0.45-1.30), was independently associated with shorter RFS.Conclusions and relevanceElevated preoperative CEA that normalizes after resection is not an indicator of poor prognosis. Routine measurement of postoperative, rather than preoperative, CEA is warranted. Patients with elevated postoperative CEA are at increased risk for recurrence, especially within the first 12 months after surgery.

Project description:Pretargeted radioimmunotherapy (PRIT) with the β-emitting radionuclide 177Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using α-emitting radionuclides such as 213Bi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of 213Bi and 177Lu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of 213Bi-IMP288 were compared with those of 177Lu-IMP288. Tumor targeting of 213Bi-IMP288 and 177Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect of 213Bi-IMP288 (6, 12, or 17 MBq) and 177Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of 213Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those of 177Lu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of 213Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g). 213Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of 213Bi-IMP288 was comparable to that of 177Lu-IMP288. Mice treated with a single dose of 213Bi-IMP288 or 177Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq 213Bi-IMP288, 12 MBq 213Bi-IMP288, and 60 MBq 177Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBq 213Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq 213Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: To our knowledge, this study shows for the first time that PRIT with TF2 and 213Bi-IMP288 is feasible and at least as effective as 177Lu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity.

Dataset Information

Enhancement of anti-murine colon cancer immunity by fusion of a SARS fragment to a low-immunogenic carcinoembryonic antigen.

Publications

Enhancement of anti-murine colon cancer immunity by fusion of a SARS fragment to a low-immunogenic carcinoembryonic antigen.

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