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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.

Norell H, Poschke I, Charo J, Wei WZ, Erskine C, Piechocki MP, Knutson KL, Bergh J, Lidbrink E, Kiessling R - J Transl Med (2010)

Bottom Line: 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.Since concurrent trastuzumab therapy was permitted, lambda-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

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.

Patients and 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.

Conclusion: 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.

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Her2-pDNA vaccination generates Her2-specific humoral immunity. A-B. Mean binding activity derived from A. Her2-specific or B. tetanus toxoid Ig λ-subclass specific ELISAs. Bars show the mean (± s.e.m.) binding activity of patients evaluable at all time points (patient #3, 4, 8, pre, post and late). C. Binding activity in the serum of all patients at all available individual time points (pre- and post-immunization as well as long-term follow up at 22-41 months following the last immunization).
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Figure 3: Her2-pDNA vaccination generates Her2-specific humoral immunity. A-B. Mean binding activity derived from A. Her2-specific or B. tetanus toxoid Ig λ-subclass specific ELISAs. Bars show the mean (± s.e.m.) binding activity of patients evaluable at all time points (patient #3, 4, 8, pre, post and late). C. Binding activity in the serum of all patients at all available individual time points (pre- and post-immunization as well as long-term follow up at 22-41 months following the last immunization).

Mentions: Pre- and post-vaccination sera from all patients were analyzed for the presence of anti-Her2 antibodies. Since most patients received concurrent trastuzumab treatment during the Her2-pDNA vaccinations, λ-subclass specific ELISAs were performed. The specific detection of λ-subclass anti-Her2 antibodies allowed measurement of endogenous antibody production without detection of trastuzumab, an IgG1κ antibody present at high serum concentrations during therapeutic administration [37]. Comparison of pre- and post-Her2-pDNA vaccine responses in patients evaluable at all time points showed a trend towards higher mean binding activity of post- versus pre-vaccination sera against Her2 (Figure 3A). Notably, the Her2-specific binding activity in the responding patients reached levels comparable to those of the TT-specific antibodies following TT vaccine administered as a control before the Her2-pDNA vaccination schedule (Figure 3B, C). One of eight (12.5%) patients enrolled in the study had a pre-existing antibody response against Her2, as defined by a binding activity >2. The majority of evaluable patients (3/5) showed an increased Her2-specific binding activity after completion of three vaccination cycles (Figure 3C).


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.

Norell H, Poschke I, Charo J, Wei WZ, Erskine C, Piechocki MP, Knutson KL, Bergh J, Lidbrink E, Kiessling R - J Transl Med (2010)

Her2-pDNA vaccination generates Her2-specific humoral immunity. A-B. Mean binding activity derived from A. Her2-specific or B. tetanus toxoid Ig λ-subclass specific ELISAs. Bars show the mean (± s.e.m.) binding activity of patients evaluable at all time points (patient #3, 4, 8, pre, post and late). C. Binding activity in the serum of all patients at all available individual time points (pre- and post-immunization as well as long-term follow up at 22-41 months following the last immunization).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2903523&req=5

Figure 3: Her2-pDNA vaccination generates Her2-specific humoral immunity. A-B. Mean binding activity derived from A. Her2-specific or B. tetanus toxoid Ig λ-subclass specific ELISAs. Bars show the mean (± s.e.m.) binding activity of patients evaluable at all time points (patient #3, 4, 8, pre, post and late). C. Binding activity in the serum of all patients at all available individual time points (pre- and post-immunization as well as long-term follow up at 22-41 months following the last immunization).
Mentions: Pre- and post-vaccination sera from all patients were analyzed for the presence of anti-Her2 antibodies. Since most patients received concurrent trastuzumab treatment during the Her2-pDNA vaccinations, λ-subclass specific ELISAs were performed. The specific detection of λ-subclass anti-Her2 antibodies allowed measurement of endogenous antibody production without detection of trastuzumab, an IgG1κ antibody present at high serum concentrations during therapeutic administration [37]. Comparison of pre- and post-Her2-pDNA vaccine responses in patients evaluable at all time points showed a trend towards higher mean binding activity of post- versus pre-vaccination sera against Her2 (Figure 3A). Notably, the Her2-specific binding activity in the responding patients reached levels comparable to those of the TT-specific antibodies following TT vaccine administered as a control before the Her2-pDNA vaccination schedule (Figure 3B, C). One of eight (12.5%) patients enrolled in the study had a pre-existing antibody response against Her2, as defined by a binding activity >2. The majority of evaluable patients (3/5) showed an increased Her2-specific binding activity after completion of three vaccination cycles (Figure 3C).

Bottom Line: 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.Since concurrent trastuzumab therapy was permitted, lambda-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT

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.

Patients and 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus