Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients

Mittendorf, Elizabeth A.; Clifton, Guy T.; Holmes, Jarrod P.; Schneble, Erika J; Echo, David Van; Ponniah, Sathibalan; Peoples, George E.

doi:10.1093/annonc/mdu211

Cited by 203 publications

(159 citation statements)

References 16 publications

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“…To support this possible extrapolation, we could show in a preclinical HLA-A2-hHer2/neu tumor model, that the efficacy of STxB-E75 was significantly higher than that of nonvectorized E75 peptide in its capacity to inhibit tumor growth and to improve overall survival. In previous clinical trials, GM-CSF was used in combination with E75 peptide (36). We found that the addition of CpG to GM-CSF greatly improved the magnitude of the anti-E75 CD8 þ T cells induced by STxB-E75, while this effect was less pronounced for the E75 peptide vaccine, similar to what has previously been reported for other peptide vaccines (38).…”

Section: Discussionsupporting

confidence: 85%

“…Her2/neu expression levels in tumor cells affects the antitumor protective efficacy of the STxB-E75 vaccine Preclinical results have pointed out the role of Her2/neu expression in the downregulation of HLA class I molecules, and preliminary clinical results suggest that the E75 vaccine is less potent in breast cancer patients whose tumors express high levels of Her2/neu (23,36). On the basis of these evidences, we therefore assessed the ability of anti-E75 CD8 þ T cells generated by the STxB-E75 immunization to recognize tumor cell lines expressing variable levels of Her2/neu.…”

Section: Persistence Of Anti-e75-specific Cd8 þ T Cells Elicited By Tmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 85%

Section: Persistence Of Anti-e75-specific Cd8 þ T Cells Elicited By Tmentioning

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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“…Another peptide based vaccine used E75 derived from the HER2 protein (nelipepimut-S) along with GMCSF as an adjuvant for treatment of breast cancer. This vaccine showed a high efficacy with almost 90% disease free survival compared with a control group [27]. A trial using a vaccine targeting a hTERT, Vx-001, in patients with advanced non-small cell lung carcinoma also showed promise with a TERT specific immunological response mounted; correlated to a better prognosis and higher progression free survival [28].…”

Section: Discussionmentioning

confidence: 99%

Cancer Vaccines: Bench to Bedside

Tuli

Maniyar

Bednarczyk

et al. 2016

IJTS

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The immune system has immense potential in cancer therapy as it is individualized, precision driven and robust, however, it is associated with challenges of its own that include immune evasion, development of tolerance and a sustained tumor rejection response. Recent FDA approval of several checkpoint inhibitors, anti-CTLA4, anti-PD-1, has re-invigorated cancer immunology by demonstrating that tolerance to cancer can be broken to induce a sustained immune response in patients. Active immunization with multivalent tumor associated antigens (TAA), however, is still a challenge. We have developed two specific distinct methods to generate multivalent antigens capable of tumor regression in prostate cancer and melanoma. In prostate cancer, we have generated specific multivalent peptide mimetics using phage display synthetic peptide libraries capable of metastatic tumor regression in an animal model. In melanoma, we have used a vaccinia virus based antigen retrieval technology to generate a multivalent antigenic vaccine. The antigenic repertoire is well defined. A protocol for the melanoma vaccine is FDA approved for clinical Science, Vol. 2016, 33-60. doi: 10.13052/ijts2246-8765.2016.003 c 2016 34 N. Tuli et al. trials. We envision defining the humoral and cellular immune response to combine our active vaccine strategy with other treatment modalities including approved checkpoint inhibitors anti-CTLA4 and anti-PD-1. We believe our vaccine candidates are a new generation of immune-therapeutics that can prolong cancer free survival and prevent secondary recurrences. Our studies have challenged the existing paradigms to re-define cancer immunotherapy that bridges the gap between humoral and cellular immunity by combining active immune response with negative checkpoint inhibitors thus activating pre-existing dormant immune response. International Journal of Translational

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“…Vaccination was well tolerated and associated with a disease-free survival rate of 89.7%, even though many individual received suboptimal vaccine doses (80.2% among non-vaccinated patients, 94.6% among optimally dosed patients). 134 A randomized, Phase III clinical trial has been initiated to confirm these results in a large patient cohort (NCT01479244, see above). To the best of our knowledge, the results of NCT00655161, NCT00854789, NCT01639885 and NCT01673217 have not been released yet (source http://www.clinicaltrials.gov).…”

Section: Gm-csf-adjuvanted Standalone Interventions In Subjects Bearimentioning

confidence: 99%

Trial Watch: Peptide-based anticancer vaccines

et al. 2015

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Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients

Abstract: NCT00841399, NCT00584789.

Cited by 203 publications

References 16 publications

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

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

Cancer Vaccines: Bench to Bedside

Trial Watch: Peptide-based anticancer vaccines

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