Addition of anti-estrogen therapy to anti-HER2 dendritic cell vaccination improves regional nodal immune response and pathologic complete response rate in patients with ER^pos/HER2^posearly breast cancer

Abstract

HER2-directed therapies are less effective in patients with ER compared to ER breast cancer, possibly reflecting bidirectional activation between HER2 and estrogen signaling pathways. We investigated dual blockade using anti-HER2 vaccination and anti-estrogen therapy in HER2/ER early breast cancer patients. In pre-clinical studies of HER2 breast cancer cell lines, ER cells were partially resistant to CD4 Th1 cytokine-induced metabolic suppression compared with ER cells. The addition of anti-estrogen treatment significantly enhanced cytokine sensitivity in ER, but not ER, cell lines. In two pooled phase-I clinical trials, patients with HER2 early breast cancer were treated with neoadjuvant anti-HER2 dendritic cell vaccination; HER2/ER patients were treated with or without concurrent anti-estrogen therapy. The anti-HER2 Th1 immune response measured in the peripheral blood significantly increased following vaccination, but was similar across the three treatment groups (ER vaccination alone, ER vaccination alone, ER vaccination + anti-estrogen therapy). In the sentinel lymph nodes, however, the anti-HER2 Th1 immune response was significantly higher in ER patients treated with combination anti-HER2 vaccination plus anti-estrogen therapy compared to those treated with anti-HER2 vaccination alone. Similar rates of pathologic complete response (pCR) were observed in vaccinated ER patients and vaccinated ER patients treated with concurrent anti-estrogen therapy (31.4% vs. 28.6%); both were significantly higher than the pCR rate in vaccinated ER patients who did not receive anti-estrogen therapy (4.0%, = 0.03). Since pCR portends long-term favorable outcomes, these results support additional clinical investigations using HER2-directed vaccines in combination with anti-estrogen treatments for ER/HER2 DCIS and invasive breast cancer.

Th1 cytokines in conjunction with pharmacological Akt inhibition potentiate apoptosis of breast cancer cells in vitro and suppress tumor growth in vivo

“…This observation prompted a new clinical trial where a brief course of anti-estrogen therapy was supplied to ER pos DCIS subjects concurrent with vaccination. In this second trial, pCRs of ER pos subjects increased from 5% to about 30% such that their rates were now no longer statistically different from their ER neg counterparts [9]. This study showed that combining vaccination with small molecule drugs capable of inhibiting signaling pathways associated with maintenance of an oncogenic phenotype could dramatically enhance clinical response rates.…”

Tribody [(HER2)2xCD16] Is More Effective Than Trastuzumab in Enhancing γδ T Cell and Natural Killer Cell Cytotoxicity Against HER2-Expressing Cancer Cells

“…Datta et al reported that a preserved anti-HER2 Th1 response was associated with pCR to neoadjuvant trastzumab application combined with chemotherapy ( 70 ). In addition, the anti-HER2 DC vaccination was combined with anti-estrogen therapy which improved regional nodal immune response and pCR rate in patients with estrogen receptor + /HER2 + early breast cancer ( 71 ).…”

Clinical development of immunotherapies for HER2+ breast cancer: a review of HER2-directed monoclonal antibodies and beyond

“…Interestingly, Czerniecki et al showed anti-HER2 CD4 + Th1 immunity to be a relevant component of HER2 + therapy, as loss of CD4 + Th1 responses correlated with poor prognosis and treatment responses 15 . The administration of a class II HER2 peptide-pulsed Type I polarized DC1 vaccine was shown to induce a strong anti-HER2 CD4 + Th1 response, with a pathologic complete response rate (pCR) among HER2 + ductal carcinoma in situ (DCIS) patients [69][70][71] .…”