The Impact of HER2/<i>neu</i>Expression Level on Response to the E75 Vaccine: From U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02

Benavides, Linda C.; Gates, Jeremy D.; Carmichael, Mark G.; Patel, R. J.; Holmes, Jarrod P.; Hueman, Matthew T.; Mittendorf, Elizabeth A.; Craig, Dianna; Stojadinovic, Alexander; Ponniah, Sathibalan; Peoples, George E.

doi:10.1158/1078-0432.ccr-08-1126

Cited by 108 publications

(69 citation statements)

References 39 publications

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“…Particularly, the maintenance of HER2-specific CD4 C immunity in HER2 neg -IBC patients may, in part, explain their improved clinical outcomes after vaccination with HER2 peptides aimed at activating CD8 C T-cells. 25 It is somewhat surprising that HD/BDs maintained a readily identifiable population of circulating anti-HER2 Th1 cells. Since HER2 is normally a membrane constituent in branching breast ductal cells during pregnancy and lactation, 26 it is plausible that pre-existing CD4 C T-cell responses in HD/BDs are generated as a result of HER2-epitope presentation by antigen-presenting cells (APC) within the breast.…”

Section: Discussionmentioning

confidence: 99%

Progressive loss of anti-HER2 CD4⁺ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

et al. 2015

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Genomic profiling has identified several molecular oncodrivers in breast tumorigenesis. A thorough understanding of endogenous immune responses to these oncodrivers may provide insights into immune interventions for breast cancer (BC). We investigated systemic anti-HER2/neu CD4 C T-helper type-1 (Th1) responses in HER2-driven breast tumorigenesis. A highly significant stepwise Th1 response loss extending from healthy donors (HD), through HER2 pos -DCIS, and ultimately to early stage HER2 pos -invasive BC patients was detected by IFNg ELISPOT. The anti-HER2 Th1 deficit was not attributable to host-level T-cell anergy, loss of immune competence, or increase in immunosuppressive phenotypes (T reg /MDSCs), but rather associated with a functional shift in IFNg:IL-10-producing phenotypes. HER2 high , but not HER2 low , BC cells expressing IFNg/TNF-a receptors were susceptible to Th1 cytokine-mediated apoptosis in vitro, which could be significantly rescued by neutralizing IFNg and TNF-a, suggesting that abrogation of HER2-specific Th1 may reflect a mechanism of immune evasion in HER2-driven tumorigenesis. While largely unaffected by cytotoxic or HER2-targeted (trastuzumab) therapies, depressed Th1 responses in HER2 pos -BC patients were significantly restored following HER2-pulsed dendritic cell (DC) vaccinations, suggesting that this Th1 defect is not "fixed" and can be corrected by immunologic interventions. Importantly, preserved anti-HER2 Th1 responses were associated with pathologic complete response to neoadjuvant trastuzumab/chemotherapy, while depressed responses were observed in patients incurring locoregional/systemic recurrence following trastuzumab/chemotherapy. Monitoring anti-HER2 Th1 reactivity following HER2-directed therapies may identify vulnerable subgroups at risk of clinicopathologic failure. In such patients, combinations of existing HER2-targeted therapies with strategies to boost anti-HER2 CD4 C Th1 immunity may decrease the risk of recurrence and thus warrant further investigation.

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Section: Discussionmentioning

confidence: 99%

Progressive loss of anti-HER2 CD4⁺ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

et al. 2015

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“…These results provide a proof of concept for the potential benefit of using a combination of immunotherapeutic strategies. Finally, Benavides et al [72] have recently demonstrated that in a subset of high expressor patients (IHC 3 ? ), who received trastuzumab before vaccination, such therapeutic combination was safe and immunologically beneficial.…”

Section: E75 Peptidementioning

confidence: 99%

“…Benavides et al [72] have studied the impact of HER2 expression level on the response to the E75 vaccine. They demonstrated that most patients responded immunologically and seemed to benefit from vaccination independently from the level of HER2 expression of their cancer.…”

Section: E75 Peptidementioning

confidence: 99%

“…However, the low expressors (specifically, IHC 1? patients) had more robust immune responses and thus might derive the greatest clinical benefit from vaccination with E75 [72].…”

Section: E75 Peptidementioning

confidence: 99%

“…It is in this context that a vaccine strategy may be useful as it could favor long-term immune surveillance, thus avoiding or delaying the onset of recurrence. Recently, Benavides et al [72] have demonstrated that in a subset of patients with strongly HER2-positive cancers (IHC: 3? ), the combination of trastuzumab followed by vaccination with the E75 peptide seemed safe and immunologically beneficial.…”

Section: Combination With Trastuzumabmentioning

confidence: 99%

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Anti-HER2 vaccines: new prospects for breast cancer therapy

Ladjemi

Jacot

Chardès

et al. 2010

Cancer Immunol Immunother

118

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Each year, breast cancer accounts for more than 400,000 new cancer cases and more than 130,000 cancer deaths in Europe. Prognosis of nonmetastatic breast cancer patients is directly related to the extent of the disease, mainly nodal spreading and tumor size, and to the molecular profile, particularly HER2 over-expression. In patients with HER2-over-expressing tumors, different studies have shown cellular and/or humoral immune responses against HER2 associated with a lower tumor development at early stages of the disease. These findings have led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-over-expressing tumor growth. Taken together with the clinical efficiency of trastuzumab-based anti-HER2 passive immunotherapy, these observations allowed to envisage various vaccine strategies against HER2. The induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be either composed of tumoral allogenic cells or autologous cells, or specific to HER2. It can be delivered by dendritic cells or in a DNA, peptidic or proteic form. Another area of research concerns the use of antiidiotypic antibodies mimicking HER2.

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Clinical trial results of the HER‐2/neu (E75) vaccine to prevent breast cancer recurrence in high‐risk patients

Mittendorf

Clifton

Holmes

et al. 2011

Cancer

Self Cite

161

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BACKGROUND The authors conducted exploratory phase 1–2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3–restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS). METHODS These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3+) expressing tumors. HLA-A2/A3+ patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. RESULTS Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred. CONCLUSIONS The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.

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The Impact of HER2/neuExpression Level on Response to the E75 Vaccine: From U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02

Cited by 108 publications

References 39 publications

Progressive loss of anti-HER2 CD4⁺ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

Progressive loss of anti-HER2 CD4⁺ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

Anti-HER2 vaccines: new prospects for breast cancer therapy

Clinical trial results of the HER‐2/neu (E75) vaccine to prevent breast cancer recurrence in high‐risk patients

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The Impact of HER2/neuExpression Level on Response to the E75 Vaccine: From U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02

Cited by 108 publications

References 39 publications

Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

Anti-HER2 vaccines: new prospects for breast cancer therapy

Clinical trial results of the HER‐2/neu (E75) vaccine to prevent breast cancer recurrence in high‐risk patients

Contact Info

Product

Resources

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Progressive loss of anti-HER2 CD4⁺ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

Progressive loss of anti-HER2 CD4⁺ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration