Effector T-cell access to tumor tissue is a limiting step for clinical efficacy of antigen-specific T-cell-based immunotherapies. Ectopic mouse tumor models, in which a subcutaneously implanted tumor is treated with subcutaneous or intramuscular therapeutic immunization, may not be optimal for targeting effector T cells to an organ-borne tumor. We used an orthotopic renal carcinoma model to evaluate the impact of injection routes on therapeutic efficacy of a Modified Vaccinia Ankara viral vector expressing the human mucin 1 tumor-associated xeno-antigen (MVA-MUC1). We show that intravenous (i.v.) administration of MVA-MUC1 displayed enhanced efficacy when compared to subcutaneous (s.c.) injection. Therapeutic efficacy of MVA-MUC1 was further enhanced by i.v. injection of a TLR9 agonist. In all cases, infiltration of tumor-bearing kidney by CD8+ lymphocytes was associated with control of tumor growth. Biodistribution experiments indicate that, following i.v. injection, MVA-encoded antigens are quickly expressed in visceral organs and, in particular, in splenic antigen presenting cells, compared with that following s.c. injection. This appears to result in a faster generation of MUC1-specific CD8+ T cells. Lymphocytes infiltrating tumor-bearing kidneys are characterized by an effector memory phenotype and express PD-1 and Tim3 immune checkpoint molecules. Therapeutic efficacy was associated with a modification of the tumor microenvironment towards a TH1 type immune response, and recruitment of activated lymphocytes. This study supports the clinical evaluation of MVA-based immunotherapies via the intravenous route.
- Received March 21, 2014.
- Revision received July 22, 2014.
- Accepted August 15, 2014.
- Copyright © 2014, American Association for Cancer Research.