Circulating regulatory T cells (CD4+CD25+FOXP3+) decrease in breast cancer patients after vaccination with a modified MHC class II HER2/neu (AE37) peptide

Gates, Jeremy D.; Clifton, Guy T.; Benavides, Linda C.; Sears, Alan K.; Carmichael, Mark G.; Hueman, Matthew T.; Holmes, Jarrod P.; Jama, Yusuf; Mursal, Mohamed; Zacharia, Athina; Ciano, Kathy; Khoo, Steven; Stojadinovic, Alexander; Peoples, George E.

doi:10.1016/j.vaccine.2010.09.029

Cited by 33 publications

(13 citation statements)

References 55 publications

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“…Gates et. al, demonstrated the primary CD4+ T helper cell stimulating AE37 peptide vaccine may increase the number of activated CD8+ CTLs [26]. And Perez et al demonstrated vaccination with AE37 primes not only the CD4+ T cells, but also primes CD8+ T cells and is able to induce CD8+ responses to both AE36 and AE37 in cancer patients [27].…”

Section: Discussionmentioning

confidence: 99%

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Brown

Mittendorf

Hale

et al. 2020

Breast Cancer Res Treat

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Purpose AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. Methods In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. Results 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. Conclusions This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.Keywords Immunotherapy · Vaccine · Breast cancer · HER2 · AE37 · GP2 Abbreviations CGControl group CI 95% Confidence interval CTLCytotoxic T-lymphocyte DFS Disease-free survival GM-CSF Granulocyte-macrophage colony-stimulating factor

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Section: Discussionmentioning

confidence: 99%

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Brown

Mittendorf

Hale

et al. 2020

Breast Cancer Res Treat

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“…It is the Ii-Key hybrid of the MHC class II peptide, AE36 (HER2/ neu 776–790) 86. AE37 vaccine has been found to reduce the number of Tregs in peripheral blood from breast cancer patients 99. A Phase I clinical trial showed that AE37 vaccine is safe and well tolerated with minimal toxicity in breast cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches

Ayoub¹,

Al-Shami²,

Yaghan³

2019

BCTT

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Cancer immunotherapy has evolved dramatically with improved understanding of immune microenvironment and immunosurveillance. The immunogenicity of breast cancer is rather heterogeneous. Specific subtypes of breast cancer such as estrogen receptor (ER)-negative, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown evidence of immunogenicity based on tumor–immune interactions. Several preclinical and clinical studies have explored the potential for immunotherapy to improve the clinical outcomes for different subtypes of breast cancer. This review describes the immune microenvironment of HER2-positive breast cancer and summarizes recent clinical advances of immunotherapeutic treatments in this breast cancer subtype. The review provides rationale and ongoing clinical evidence to the use of immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell immunotherapy in breast cancer. In addition, the present paper describes the most relevant clinical progress of strategies for the combination of immunotherapy with standard treatment modalities in HER2-positive breast cancer including chemotherapy, targeted therapy, and radiotherapy.

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“…Clinical research reported by Schmidt et al showed that breast globin and HLA-DRB1 ∗ 04 : 01; HLA-DRB1 ∗ 07 : 01 as prepared by Tetramer Technology can detect the specific Tregs in breast cancer patients [ 41 ]. Gates et al used HLA II molecules with HER2/neu peptide (AE37) vaccine treatment on breast cancer patients and found that the number of peripheral blood lymphocytes CD4 + CD25 + Foxp3 + Tregs decreased in the patients [ 42 ]. This suggested that breast cancer patients may have high frequencies of Tregs, which can be used as a therapeutic target for breast cancer patients with high-frequency specific Tregs.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Heterogeneity of CD4⁺CD25⁺ T Cell TCR β CDR3 Repertoires in Breast Tumor Tissues, Lung Metastatic Tissues, and Spleens from 4T1 Tumor-Bearing BALB/c Mice

Zhang

Duan

et al. 2020

Journal of Immunology Research

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To study the homogeneity and heterogeneity of CD4+CD25+ T cells receptor β-chain complementarity determining region 3 (TCR β CDR3) repertoires in breast tumor tissues, lung metastatic tissues, and spleens from 4T1 tumor-bearing BALB/c mice. We used high-throughput sequencing to analyze the characteristics and changes of CD4+CD25+ TCR β CDR3 repertoires among tumor tissues, lung metastatic tissues, and spleens. The diversity of the CD4+CD25+ TCR β CDR3 repertoires in breast tumor tissue was similar to that of lung metastatic tissues and less pronounced than that of spleen tissues. Breast tumor tissues and lung metastatic tissues had a greater number of high-frequency CDR3 sequences and intermediate-frequency CDR3 sequences than those of spleens. The proportion of unique productive CDR3 sequences in breast tumor tissues and lung metastatic tissues was significantly greater than that in the spleens. The diversity and frequency of the CDR3 repertoires remained homogeneous in breast tumors and lung metastatic tissues and showed great heterogeneity in the spleens, which suggested that the breast tissues and lung metastatic tissues have characteristics of CD4+CD25+ T cells that relate to the tumor microenvironment. However, the number and characteristics of overlapping CDR3 sequences suggested that there were some different CD4+CD25+ T cells in tumors and in the circulatory immune system. The study may be used to further explore the characteristics of the CDR3 repertoires and determine the source of the CD4+CD25+ T cells in the breast cancer microenvironment.

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Circulating regulatory T cells (CD4+CD25+FOXP3+) decrease in breast cancer patients after vaccination with a modified MHC class II HER2/neu (AE37) peptide

Cited by 33 publications

References 55 publications

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches

Analysis of the Heterogeneity of CD4⁺CD25⁺ T Cell TCR β CDR3 Repertoires in Breast Tumor Tissues, Lung Metastatic Tissues, and Spleens from 4T1 Tumor-Bearing BALB/c Mice

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Circulating regulatory T cells (CD4+CD25+FOXP3+) decrease in breast cancer patients after vaccination with a modified MHC class II HER2/neu (AE37) peptide

Cited by 33 publications

References 55 publications

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence

Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches

Analysis of the Heterogeneity of CD4+CD25+ T Cell TCR β CDR3 Repertoires in Breast Tumor Tissues, Lung Metastatic Tissues, and Spleens from 4T1 Tumor-Bearing BALB/c Mice

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Analysis of the Heterogeneity of CD4⁺CD25⁺ T Cell TCR β CDR3 Repertoires in Breast Tumor Tissues, Lung Metastatic Tissues, and Spleens from 4T1 Tumor-Bearing BALB/c Mice