Clinical and Immunologic Responses of HLA-A3+ Breast Cancer Patients Vaccinated with the HER2/ neu -Derived Peptide Vaccine, E75, in a Phase I/II Clinical Trial

Patil, Ritesh; Clifton, Guy T.; Holmes, Jarrod P.; Amin, Asna; Carmichael, Mark G.; Gates, Jeremy D.; Benavides, Linda C.; Hueman, Matthew T.; Ponniah, Sathibalan; Peoples, George E.

doi:10.1016/j.jamcollsurg.2009.10.022

Cited by 45 publications

(28 citation statements)

References 35 publications

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“…A strong correlation between Granzyme B and IFN-g ELISPOT assay with cytotoxicity in 51 Cr-release assay (R 2 D 0.95) was reported by Shafer-Weaver et al 39 In the ex vivo ELISPOT assay, which has been previously reported by Patil et al, 40 PBMCs were first incubated with 50 ng/ml of IL-7 and 10 ng/ml of IL-12 in culture medium for 2 h at 37 C. After incubation, the cells were washed with HBSS (Gibco, Life Technologies) and re-suspended at 5 £ 10 5 cells per well with complete culture medium containing RPMI (Gibco, Life Technologies) supplemented with 5% heat-inactivated human AB serum (Gemini Bio-Product) and 1£ penicillin/streptomycin (Gibco, Life Technologies) in a 96-well plate. Then, 50 mg/ml of peptides (appropriately selected depending on patient's HLAtype) was added to the respective wells and the cells were incubated overnight at 37 C and followed by ELISPOT assay as described below.…”

Section: Dendritic Cell Preparation and Stimulation Of T Cellssupporting

confidence: 55%

Identification of immunogenic MAGED4B peptides for vaccine development in oral cancer immunotherapy

Lim¹,

Chun²,

Gan³

et al. 2014

Human Vaccines & Immunotherapeutics

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The ever-increasing number of tumor-associated antigens has provided a major stimulus for the development of therapeutic peptides vaccines. Tumor-associated peptides can induce high immune response rates and have been developed as vaccines for several types of solid tumors, and many are at various stages of clinical testing. MAGED4B, a melanoma antigen, is overexpressed in oral squamous cell carcinoma (OSCC) and this expression promotes proliferation and cell migration. In this study, we have identified 9 short peptides derived from MAGED4B protein that are restricted in binding to the HLA subtypes common in the Asian population (HLA-A2, A11, and A24). The peptides had good binding affinity with the MHC-Class I molecules and stimulated ex-vivo IFN-gamma and Granzyme-B production in blood samples from OSCC patients, suggesting that they are immunogenic. Further, T cells stimulated with peptide-pulsed dendritic cells showed enhanced T-cell cytotoxic activity against MAGED4B-overexpressing OSCC cell lines. In summary, we have identified MAGED4B peptides that induce anti-tumor immune responses advocating that they could be further developed as vaccine candidates for the treatment of OSCC.

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Section: Dendritic Cell Preparation and Stimulation Of T Cellssupporting

confidence: 55%

Identification of immunogenic MAGED4B peptides for vaccine development in oral cancer immunotherapy

Lim¹,

Chun²,

Gan³

et al. 2014

Human Vaccines & Immunotherapeutics

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“…18) is the best studied Her2/neu-derived peptide to date. It binds to HLA-A2 and HLA-A3 expressed in 60%-75% of the general population and is processed and presented by tumor cells (19,20). Although the exact immunodominant peptide (Her2/neu 369-377 or Her2/neu 373-382) presented by tumor cells is debated, anti-E75 CD8 þ T cells recognized these two epitopes (21).…”

Section: Introductionmentioning

confidence: 99%

A Therapeutic Her2/neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/neu–Expressing Tumor in HLA-A2 Transgenic Mice

Tran

Diniz

Dransart

et al. 2016

Clinical Cancer Research

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Purpose: E75, a peptide derived from the Her2/neu protein, is the most clinically advanced vaccine approach against breast cancer. In this study, we aimed to optimize the E75 vaccine using a delivery vector targeting dendritic cells, the B-subunit of Shiga toxin (STxB), and to assess the role of various parameters (Her2/neu expression, combination with trastuzumab) in the efficacy of this cancer vaccine in a relevant preclinical model.Experimental Design: We compared the differential ability of the free E75 peptide or the STxB-E75 vaccine to elicit CD8 þ T cells, and the impact of the vaccine on murine HLA-A2 tumors expressing low or high levels of Her2/neu. Results: STxB-E75 synergized with granulocyte macrophage colony-stimulating factors and CpG and proved to be more efficient than the free E75 peptide in the induction of multifunctional and high-avidity E75-specific anti-CD8 þ T cells resulting in a potent tumor protection in HLA-A2 transgenic mice. High expression of HER2/neu inhibited the expression of HLA-class I molecules, leading to a poor recognition of human or murine tumors by E75-specific cytotoxic CD8 þ T cells. In line with these results, STxB-E75 preferentially inhibited the growth of HLA-A2 tumors expressing low levels of Her2/neu. Coadministration of anti-Her2/neu mAb potentiated this effect.Conclusions: STxB-E75 vaccine is a potent candidate to be tested in patients with low Her2/neu-expressing tumors. It could also be indicated in patients expressing high levels of Her2/neu and low intratumoral T-cell infiltration to boost the recruitment of T cells-a key parameter in the efficacy of anti-Her2/neu mAb therapy.

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“…The vaccinated HLA-A3+ patients experienced similar toxicities to HLA-A2+ patients and developed comparable immunologic responses, as assessed by delayed-type hypersensitivity reactions. HLA-A3+ patients also had a similar 5-year DFS (92.3%) as HLA-A2+ vaccinated patients [31]. Finally, with longer follow-up, recurrences were noted several years after completion of the vaccine series, corresponding with waning immunity in some patients.…”

Section: Peptide-based Breast Cancer Vaccinesmentioning

confidence: 99%

Clinical Development of the E75 Vaccine in Breast Cancer

Clifton

Gall

Peoples³

et al. 2016

Breast Care

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E75 is an immunogenic peptide derived from the human epidermal growth factor receptor 2 (HER2) protein. A large amount of preclinical work evaluated the immunogenicity of E75, after which phase I trials investigated using E75 mixed with an immunoadjuvant as a vaccine. Those studies showed the vaccine to be safe and capable of stimulating an antigen-specific immune response. Subsequent to that, our group conducted trials evaluating E75 + granulocyte macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting. The studies enrolled node-positive and high-risk node-negative breast cancer patients, with the goal being to determine if vaccination could decrease the recurrence risk. The studies included 187 evaluable patients: 108 vaccinated ones and 79 controls. The 5-year disease-free survival for the vaccinated patients was 89.7% compared to 80.2% for the control patients, a 48% reduction in relative risk of recurrence. Based on these data, E75 + GM-CSF, now known as NeuVax™, is being evaluated in a phase III trial. In this article, we review preclinical data and results of the early-phase trials and provide an update on the ongoing phase III study. We also present additional strategies for employing the vaccine to be included as a component of combination immunotherapy as well as in the setting of ductal carcinoma in situ as an initial step towards primary prevention.

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Clinical and Immunologic Responses of HLA-A3+ Breast Cancer Patients Vaccinated with the HER2/ neu -Derived Peptide Vaccine, E75, in a Phase I/II Clinical Trial

Cited by 45 publications

References 35 publications

Identification of immunogenic MAGED4B peptides for vaccine development in oral cancer immunotherapy

Identification of immunogenic MAGED4B peptides for vaccine development in oral cancer immunotherapy

A Therapeutic Her2/neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/neu–Expressing Tumor in HLA-A2 Transgenic Mice

Clinical Development of the E75 Vaccine in Breast Cancer

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