Doxorubicin and paclitaxel enhance the antitumor efficacy of vaccines directed against HER 2/neu in a murine mammary carcinoma model.
BACKGROUND
The purpose of the present study was to determine whether cytotoxic chemotherapeutic agents administered prior to immunotherapy with gene vaccines could augment the efficacy of the vaccines.


METHODS
Mice were injected in the mammary fat pad with an aggressive breast tumor cell line that expresses HER2/neu. The mice were treated 3 days later with a noncurative dose of either doxorubicin or paclitaxel, and the following day with a gene vaccine to HER2/neu. Two more doses of vaccine were given 14 days apart. Two types of gene vaccines were tested: a plasmid vaccine encoding a self-replicating RNA (replicon) of Sindbis virus (SINCP), in which the viral structural proteins were replaced by the gene for neu; and a viral replicon particle derived from an attenuated strain of Venezuelan equine encephalitis virus, containing a replicon RNA in which the Venezuelan equine encephalitis virus structural proteins were replaced by the gene for neu.


RESULTS
Neither vaccination alone nor chemotherapy alone significantly reduced the growth of the mammary carcinoma. In contrast, chemotherapy followed by vaccination reduced tumor growth by a small, but significant amount. Antigen-specific CD8+ T lymphocytes were induced by the combined treatment, indicating that the control of tumor growth was most probably due to an immunological mechanism. The results demonstrated that doxorubicin and paclitaxel, commonly used chemotherapeutic agents for the treatment of breast cancer, when used at immunomodulating doses augmented the antitumor efficacy of gene vaccines directed against HER2/neu.


CONCLUSIONS
The combination of chemotherapeutic agents plus vaccine immunotherapy may induce a tumor-specific immune response that could be beneficial for the adjuvant treatment of patients with minimal residual disease. The regimen warrants further evaluation in a clinical setting.
Eralp
Yesim
Y
Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. yeralp@yahoo.com
Wang
Xiaoyan
X
Wang
Jian-Ping
JP
Maughan
Maureen F
MF
Polo
John M
JM
Lachman
Lawrence B
LB
D000818:Animals; D000951:Antigens, Neoplasm / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology / Q000628:therapy*; D002460:Cell Line; D003131:Combined Modality Therapy / Q000379:methods / Q000639:trends; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D000939:Epitopes / Q000502:physiology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000627:therapeutic use
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D004317:Doxorubicin; D000939:Epitopes; D007371:Interferon-gamma; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA