Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial

Abstract

BackgroundAdjuvant trastuzumab (Herceptin) treatment of breast cancer patients significantly improves their clinical outcome. Vaccination is an attractive alternative approach to provide HER-2/neu (Her2)-specific antibodies and may in addition concomitantly stimulate Her2-reactive T-cells. Here we report the first administration of a Her2-plasmid DNA (pDNA) vaccine in humans.Patients and MethodsThe vaccine, encoding a full-length signaling-deficient version of the oncogene Her2, was administered together with low doses of GM-CSF and IL-2 to patients with metastatic Her2-expressing breast carcinoma who were also treated with trastuzumab. Six of eight enrolled patients completed all three vaccine cycles. In the remaining two patients treatment was discontinued after one vaccine cycle due to rapid tumor progression or disease-related complications. The primary objective was the evaluation of safety and tolerability of the vaccine regimen. As a secondary objective, treatment-induced Her2-specific immunity was monitored by measuring antibody production as well as T-cell proliferation and cytokine production in response to Her2-derived antigens.ResultsNo clinical manifestations of acute toxicity, autoimmunity or cardiotoxicity were observed after administration of Her2-pDNA in combination with GM-CSF, IL-2 and trastuzumab. No specific T-cell proliferation following in vitro stimulation of freshly isolated PBMC with recombinant human Her2 protein was induced by the vaccination. Immediately after all three cycles of vaccination no or even decreased CD4+ T-cell responses towards Her2-derived peptide epitopes were observed, but a significant increase of MHC class II restricted T-cell responses to Her2 was detected at long term follow-up. Since concurrent trastuzumab therapy was permitted, λ-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab. Her2-pDNA vaccination induced and boosted Her2-specific antibodies that could be detected for several years after the last vaccine administration in a subgroup of patients.ConclusionThis pilot clinical trial demonstrates that Her2-pDNA vaccination in conjunction with GM-CSF and IL-2 administration is safe, well tolerated and can induce long-lasting cellular and humoral immune responses against Her2 in patients with advanced breast cancer.Trial registrationThe trial registration number at the Swedish Medical Products Agency for this trial is Dnr151:785/2001.

Antibody-Dependent Natural Killer Cell–Mediated Cytotoxicity Engendered by a Kinase-Inactive Human HER2 Adenovirus-Based Vaccination Mediates Resistance to Breast Tumors

“…This has spurred efforts to actively induce a protective immunity against HER2-expressing tumors with vaccines based on peptides, plasmid DNA (pDNA), or recombinant proteins tested in models of spontaneous or transplantable mammary carcinomas (6)(7)(8)(9). HER2 tumor vaccines have now also reached the clinic with several phase I and II studies based on different approaches (10)(11)(12)(13)(14)(15). These studies show that HER2 can be immunogenic and also suggest an improved clinical outcome as the result of the vaccination (16,17).…”

Eleutheroside E inhibits doxorubicin-induced inflammation and apoptosis in rat cardiomyocytes by modulating activation of NF-κB pathway

“…It has been shown to contribute to the accumulation of IL-6 and GCSF as well as cardiotoxicity induced by DOX. [16][17][18].…”

Harnessing DNA-induced immune responses for improving cancer vaccines

“…patient situation. For patients enrolled in most clinical trials the tumor has had ample time to establish itself 83,112 leading to the above-described immune-suppressive environment. Concurrent with this immune-suppressive environment the patient typically has undergone "classical" therapies including chemotherapy or iM, intramuscular; iD, intradermal; iL, intralesional; iC, intracutaneous; eP, electroporation; N.D., not described; PMeD, particle-mediated epidermal delivery; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; PAP, prostatic acid phosphatase.…”