Active antiviral T-lymphocyte response can be redirected against tumor cells by antitumor antibody x MHC/viral peptide conjugates

Abstract

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 α H-2Db/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 α H-2Db/NP366 influenza peptide conjugates, or anti-HER2 F(ab′)2 fragments alone, or intact anti-HER2 monoclonal antibody. Third, systemic injections of anti-CEA α 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 α H-2D h/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 α MHC/viral peptide conjugates. © 2006 American Association for Cancer Research.