Abstract
IntroductionThe 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.MethodsMice 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.ResultsNeither 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.ConclusionsThe 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.
Highlights
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
The antitumor effect of DOX followed by vaccination with SINCP-neu Using the race model, we investigated the efficacy of chemotherapy followed by vaccination to inhibit tumor growth
The group of 10 mice treated with DOX and SINCP-neu had a significant delay in tumor progression compared with the mice treated with DOX and SINCP-βgal (P < 0.0001)
Summary
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. Cancer treatment options directed at specific molecular targets, such as HER2/neu in breast cancer and c-kit in chronic myeloid leukemia and gastrointestinal stromal sarcomas, have proven effective [1,2,3,4]. Immunotherapy could offer potential therapeutic benefit to patients with HER2/neu+ tumors by impairing the downstream molecular signaling pathways, leading to CTL = cytotoxic T lymphocytes; DOX = doxorubicin; FITC = fluorescein isothiocyanate; HA = hemagglutinin; IFN = interferon; IL = interleukin; PTX =. Traztuzumab has produced remarkable results, providing substantial support for an immunotherapeutic approach to cancer [10]
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