Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model

TY - JOUR

T1 - Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model

AU - Sørensen, Maria Rathmann

AU - Holst, Peter J

AU - Steffensen, Maria Abildgaard

AU - Christensen, Jan P

AU - Thomsen, Allan Randrup

N1 - Copyright © 2010 Elsevier Ltd. All rights reserved.

PY - 2010/9/24

Y1 - 2010/9/24

N2 - Therapeutic vaccination with replication deficient adenovirus expressing a viral antigen linked to invariant chain was recently found to markedly delay the growth of B16.F10 melanomas expressing the same antigen; however, complete regression of the tumors was never observed. Here we show that the delay in tumor growth can be converted to complete regression and long-term survival in 30-40% of the mice by a booster vaccination plus combinational treatment with agonistic anti-CD40 monoclonal antibodies (mAb) and anti-CTLA-4 mAb. Regarding the mechanism underlying the improved clinical effect, analysis of the tumor-specific response revealed a significantly prolonged tumor-specific CD8 T cell response in spleens of the mice receiving the combinational treatment compared with mice receiving either treatment individually. Matching this, CD8 T cell depletion completely prevented tumor control.These results indicate that even with a strong tumor vaccine candidate, combinatorial treatment may be required to obtain clinically relevant results.

AB - Therapeutic vaccination with replication deficient adenovirus expressing a viral antigen linked to invariant chain was recently found to markedly delay the growth of B16.F10 melanomas expressing the same antigen; however, complete regression of the tumors was never observed. Here we show that the delay in tumor growth can be converted to complete regression and long-term survival in 30-40% of the mice by a booster vaccination plus combinational treatment with agonistic anti-CD40 monoclonal antibodies (mAb) and anti-CTLA-4 mAb. Regarding the mechanism underlying the improved clinical effect, analysis of the tumor-specific response revealed a significantly prolonged tumor-specific CD8 T cell response in spleens of the mice receiving the combinational treatment compared with mice receiving either treatment individually. Matching this, CD8 T cell depletion completely prevented tumor control.These results indicate that even with a strong tumor vaccine candidate, combinatorial treatment may be required to obtain clinically relevant results.

KW - Adenoviridae

KW - Animals

KW - Antibodies, Monoclonal

KW - Antigens, CD

KW - Antigens, CD40

KW - Antigens, Differentiation, B-Lymphocyte

KW - CD8-Positive T-Lymphocytes

KW - Cancer Vaccines

KW - Female

KW - Histocompatibility Antigens Class II

KW - Immunization, Secondary

KW - Lymphocyte Depletion

KW - Melanoma, Experimental

KW - Mice

KW - Mice, Inbred C57BL

KW - Spleen

U2 - 10.1016/j.vaccine.2010.07.066

DO - 10.1016/j.vaccine.2010.07.066

M3 - Journal article

C2 - 20682365

SN - 0264-410X

VL - 28

SP - 6757

EP - 6764

JO - Vaccine

JF - Vaccine

IS - 41

ER -