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Active Antiviral T-Lymphocyte Response Can Be Redirected against Tumor Cells by Antitumor Antibody x MHC/Viral Peptide Conjugates

Authors' Affiliations: ¹ Department of Biochemistry and ² Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; ³ Institut National de la Sante et de la Recherche Medicale, EMI 0227, Centre de Recherche en Cancérologie de Montpellier; ⁴ Université de Montpellier I, ⁵ CRLC Val d'Aurelle-Paul Lamarque, and ⁶ Biostatistiques, Montpellier, France

Requests for reprints: Alena Donda, Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland. Phone: 41-21-692-57-47; Fax: 41-21-692-57-05; E-mail: alena.donda{at}unil.ch.

Purpose: To redirect an ongoing antiviral T-cell response against tumor cells in vivo, we evaluated conjugates consisting of antitumor antibody fragments coupled to class I MHC molecules loaded with immunodominant viral peptides.

Experimental Design: First, lymphochoriomeningitis virus (LCMV)–infected C57BL/6 mice were s.c. grafted on the right flank with carcinoembryonic antigen (CEA)–transfected MC38 colon carcinoma cells precoated with anti-CEA x H-2D^b/GP33 LCMV peptide conjugate and on the left flank with the same cells precoated with control anti-CEA F(ab')₂ fragments. Second, influenza virus–infected mice were injected i.v., to induce lung metastases, with HER2-transfected B16F10 cells, coated with either anti-HER2 x H-2D^b/NP366 influenza peptide conjugates, or anti-HER2 F(ab')₂ fragments alone, or intact anti-HER2 monoclonal antibody. Third, systemic injections of anti-CEA x H-2D^b conjugates with covalently cross-linked GP33 peptides were tested for the growth inhibition of MC38-CEA⁺ cells, s.c. grafted in LCMV-infected mice.

Results: In the LCMV-infected mice, five of the six grafts with conjugate-precoated MC38-CEA⁺ cells did not develop into tumors, whereas all grafts with F(ab')₂-precoated MC38-CEA⁺ cells did so (P = 0.0022). In influenza virus–infected mice, the group injected with cells precoated with specific conjugate had seven times less lung metastases than control groups (P = 0.0022 and P = 0.013). Most importantly, systemic injection in LCMV-infected mice of anti-CEA x H-2D^b/cross-linked GP33 conjugates completely abolished tumor growth in four of five mice, whereas the same tumor grew in all five control mice (P = 0.016).

Conclusion: The results show that a physiologic T-cell antiviral response in immunocompetent mice can be redirected against tumor cells by the use of antitumor antibody x MHC/viral peptide conjugates.