Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms.
The most widely used approach to cancer immunotherapy is vaccines. Unfortunately, the need for multiple administrations of antigens often limits the use of one of the most effective vaccine approaches, immunogene therapy using viral vectors, because neutralizing antibodies are rapidly produced. We hypothesized that after viral immunogene therapy "primed" an initial strong antitumor immune response, subsequent "boosts" could be provided by sequential courses of chemotherapy. Three adenoviral (Ad)-based immunogene therapy regimens were administered to animals with large malignant mesothelioma and lung cancer tumors followed by three weekly administrations of a drug regimen commonly used to treat these tumors (Cisplatin/Gemcitabine). Immunogene therapy followed by chemotherapy resulted in markedly increased antitumor efficacy associated with increased numbers of antigen-specific, activated CD8(+) T-cells systemically and within the tumors. Possible mechanisms included: (i) decreases in immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), T-regulatory cells (T-regs), and B-cells, (ii) stimulation of memory cells by intratumoral antigen release leading to efficient cross-priming, (iii) alteration of the tumor microenvironment with production of "danger signals" and immunostimulatory cytokines, and (iv) augmented trafficking of T-cells into the tumors. This approach is currently being tested in a clinical trial and could be applied to other trials of viral immunogene therapy.
Fridlender
Zvi G
ZG
Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Fridlender@hadassah.org.il
Sun
Jing
J
Singhal
Sunil
S
Kapoor
Veena
V
Cheng
Guanjun
G
Suzuki
Eiji
E
Albelda
Steven M
SM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use; D018925:Chemokines / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D045142:Cross-Priming; D016207:Cytokines / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D007372:Interferons / Q000008:administration & dosage / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008570:Memory, Short-Term; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000008:administration & dosage / Q000235:genetics*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D000093542:Gemcitabine
D019496:Cancer Vaccines; D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D003841:Deoxycytidine; D007372:Interferons; D013937:Thymidine Kinase; D002945:Cisplatin; D000093542:Gemcitabine