Abstract 774: Preliminary experiment of α-gal epitopes immune-based therapy against pancreatic cancer using tumor cell lysates

Abstract

Abstract Potential targets for the immunotherapy of pancreatic cancer are antigens such as MUC1 and mutant ras. But, vaccinating against a single antigen has disadvantages, because it is unknown which of the identified antigens have the potential to induce an effective anti-tumor immune response. Immunity against a single antigen may be ineffective in tumors with heterogeneous cell population and carries the risk of inducing tumor-associated antigen (TAA) escape variants. The use of tumor cell lysate circumvents these disadvantages. Unfortunately, TAAs fail to stimulate immune response against cancer cells, because immunity toward TAAs in cancer patients is weak and the presentation of TAAs to the immune system seems to be poor. Human natural Ab, Anti-Gal, which is an IgG known to be present in large amounts in normal subjects and cancer patients, comprising ∼1% of serum circulating IgG. Anti-Gal specifically binds to α-gal epitopes (Galα1, 3Galβ1, 4GlcNAc-R), synthesized by α1, 3 galactosyltransferase (α1,3GT) on cell surface glycolipids and glycoproteins. This study addresses the effectiveness of elicitation of both Ab production and T cell responses against pancreatic cancer by the tumor lysate vaccination, expressing α-gal epitopes. A human pancreatic cancer cell line, PANC1, which expresses MUC1 was employed and transfected with α1,3GT gene (α-gal PANC1). Cell lysates were created by injection of either 2 × 106 parental PANC1 or α-gal PANC1 into NOD/SCID mice, respectively. The mice were sacrificed and tumors were enucleated for preparing cell lysates. α1,3GT KO mice were immunized with pig tissue to generate anti-Gal in their sera like human. These mice were vaccinated intraperitoneally by either 10 mg of parental (control group) or α-gal PANC1 cell lysate (α-gal group). Cell lysate of parental PANC1 lacked of α-gal epitopes and it of α-gal PANC1 expressed ∼40 × 106 of these epitopes per 1mg of lysate. MUC1 expression in both cell lysates was observed at similar level. Production of anti-PANC1 Ab in α-gal group was 16∼64-fold higher than that of control group. Anti-MUC1 Ab production in α-gal group was also increased in comparison with that in control group (16-fold higher). Expansion of anti-MUC1 B cells in α-gal group was significantly higher [number of spots at 1 × 106 splenocytes: α-gal vs. control; 305.3 ± 44.0 vs. 136.7 ± 93.2 (p<0.007)]. Expansion of specific T-cell response to MUC1 peptide in α-gal group was significantly higher [number of IFN-γ spots at 1 × 106 splenocytes: α-gal vs. control; 626.7 ± 118.6 vs. 181.7 ± 27.5 (p<0.0031)]. We conclude that vaccination with cell lysate expressing α-gal epitopes may result in elicitation of immune response toward tumor antigens, including MUC1 and thus to mount an immune response that may lead to cure pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 774. doi:10.1158/1538-7445.AM2011-774