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


METHODS
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).


CONCLUSIONS
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.
Cesson
Valérie
V
Department of Biochemistry, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Stirnemann
Kathrin
K
Robert
Bruno
B
Luescher
Immanuel
I
Filleron
Thomas
T
Corradin
Giampietro
G
Mach
Jean-Pierre
JP
Donda
Alena
A
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000276:immunology; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D006023:Glycoproteins / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D007114:Immunization / Q000379:methods; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use; D007140:Immunoglobulin Fab Fragments / Q000096:biosynthesis / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D009980:Influenza A virus / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014758:Viral Core Proteins / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000912:Antibodies, Neoplasm; D000954:Antigens, Surface; D000956:Antigens, Viral; D002272:Carcinoembryonic Antigen; D006023:Glycoproteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D014758:Viral Core Proteins; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; C102366:nucleoprotein (366-374), influenza virus