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.
BACKGROUND
Adjuvant 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.


METHODS
The 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.


RESULTS
No 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, lambda-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.


CONCLUSIONS
This 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.
Norell
Håkan
H
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Poschke
Isabel
I
Charo
Jehad
J
Wei
Wei Z
WZ
Erskine
Courtney
C
Piechocki
Marie P
MP
Knutson
Keith L
KL
Bergh
Jonas
J
Lidbrink
Elisabet
E
Kiessling
Rolf
R
D000328:Adult; D000368:Aged; D000912:Antibodies, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D007376:Interleukin-2 / Q000627:therapeutic use*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000276:immunology; D010865:Pilot Projects; D010957:Plasmids / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination
D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D004247:DNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human