CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems.
Xenogeneic DNA vaccination can elicit tumor immunity through T cell and antibody-dependent effector mechanisms. Blockade of CTLA-4 engagement with B7 expressed on APCs has been shown to enhance T cell-dependent immunity. We investigated whether CTLA-4 blockade could increase T-cell responses and tumor immunity elicited by DNA vaccines. CTLA-4 blockade enhanced B16 tumor rejection in mice immunized against the melanoma differentiation antigens tyrosinase-related protein 2 and gp100, and this effect was stronger when anti-CTLA-4 was administered with booster vaccinations. CTLA-4 blockade also increased the T-cell responses to prostate-specific membrane antigen (PSMA) when given with the second or third vaccination. Based on these pre-clinical studies, we suggest that anti-CTLA-4 should be tested with xenogeneic DNA vaccines against cancer and that special attention should be given to sequence and schedule of administration.
Gregor
Polly D
PD
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. gregorp@mskcc.org
Wolchok
Jedd D
JD
Ferrone
Cristina R
CR
Buchinshky
Heidi
H
Guevara-Patiño
Jose A
JA
Perales
Miguel-Angel
MA
Mortazavi
Fariborz
F
Bacich
Dean
D
Heston
Warren
W
Latouche
Jean-Baptiste
JB
Sadelain
Michel
M
Allison
James P
JP
Scher
Howard I
HI
Houghton
Alan N
AN
D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000494:pharmacology*; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007115:Immunization Schedule; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology*; D010957:Plasmids / Q000276:immunology; D011467:Prostate / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse; D007166:Immunosuppressive Agents; D019444:Vaccines, DNA