Safety and long-term maintenance of anti-HER2 immunity following booster inoculations of the E75 breast cancer vaccine.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2529-2529
Author(s):  
Raetasha Sheavette Dabney ◽  
Diane F Hale ◽  
Timothy J Vreeland ◽  
Guy T. Clifton ◽  
Alan K. Sears ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Vaccine ◽  
Peptide Vaccine ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Recurrence Rates ◽  
Specific Immunity

2529 Background: We have completed accrual and are in the follow up portion of phase I/II clinical trials evaluating the E75 HER2 peptide vaccine. E75 has been proven safe, capable of stimulating HER2 immunity, and effective in decreasing breast cancer recurrence rates. During the conduct of this trial, it was noted that E75-specific immunity waned after the Primary Vaccine Series (PVS) which corresponded with late recurrences. To maintain long-term immunity, a voluntary booster program was started. Here we present analysis of the booster inoculations. Methods: The trial enrolled node-positive or high-risk, node-negative breast cancer patients (pts) with tumors expressing any level of HER2 (IHC 1-3+). HLA-A2/A3+ pts comprised the vaccine group (VG), HLA-A2/A3- pts were followed as the control group (CG). The VG received 4-6 monthly inoculations of E75+GM-CSF. Volunteer booster program pts (BG) received inoculations every 6 months after the PVS. Pts were monitored for toxicities, in vivo responses by local reactions (LR) and DTH, and in vitro responses measured by enumeration of E75 specific cytotoxic T lymphocytes. Results: 53 pts received at least 1 booster, 34 received 2, 24 three, 20 four, 12 five, and 8 at least 6. 24% of pts had no local toxicity, 73% Grade 1 (G1), 3% G2. 74% had no systemic toxicity, 35% G1, 1% G2. LRs increased significantly from the initial vaccine (R1) during PVS to each booster (B) (R1: 59.5±3.1 v B1: 89.2±3.3, p<0.001; v B2: 95.15±5, p<0.001; v B3: 86.63±5.5, p<0.001; v B4: 83.26±4.6, p=<0.001; v B5: 80.67±6.7, p=0.006; v B6: 78.75±9.4, p=0.04). Dimer values increased from the end of PVS to each post-booster value (pre B1:1.29±0.25 v post B1: 1.46±0.38; post B2: 1.41±0.4; post B3: 1.84±0.35; post B4: 2.23±0.4; post B5:1.94±0.31; post B6: 2.73±0.09, p=0.02). At median 60 months, the recurrence rate for BG was 3.8% vs 18.9% in the CG (p=0.01). Conclusions: Booster inoculations are well-tolerated and appear to assist in the maintenance of long term peptide-specific immunity. Boosted pts have improved recurrence rates. Based on the success of this program, we have incorporated the practice of booster inoculations in our current cancer vaccine trials.

Biomarker correlation to clinical response in phase I/II trials of the adjuvant breast cancer vaccine neuvax (nelipepimut-S or E75).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3126-TPS3126
Author(s):  
John S. Berry ◽  
Alfred F Trappey ◽  
Alan K. Sears ◽  
Timothy J Vreeland ◽  
Guy T. Clifton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Peptide Vaccine ◽  
Clonal Expansion ◽  
Mean Difference ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Clinical Recurrence ◽  
The Mean

TPS3126 Background: We completed phase I/II clinical trials with NeuVax (nelipepimut-S), a HLA-A2/A3-restricted, HER2-derived peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrence in breast cancer patients rendered disease-free with standard-of-care therapy. Here, we examine the relationship between in vitro immunologic response (IR) and clinical recurrence (CR) after 5-year follow-up. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node-negative patients (pts) with tumors expressing any level of HER2 (IHC 1+,2+,or 3+). HLA-A2/A3+ pts were enrolled in the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as an untreated control group (CG). The VG was given 4-6 monthly intradermal inoculations of nelipepimut-S+GMCSF (immunoadjuvant) during the primary vaccine series (PVS). In vitro IR was assessed for E75-specific, cytotoxic T lymphocyte clonal expansion by HLA-A2:IgG dimer assay and expressed as mean dimer index (mdi) at baseline, after PVS (R6), and six months after the PVS. HER2 under-expression was defined as an IHC 1/2, and a FISH < 2.2. VG and CG pts were followed for CR over 60 months. P-values were calculated using the Fisher’s exact test. Results: Of the 195 pts enrolled, 8 withdrew, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. R6 dimer assays were available for 86 pts in the VG. The mean R6 dimer in the VG is 0.63 mdi+.08. Of the 30 pts with an R6 dimer above the mean, only one recurred, compared to eight of the 56 below the mean (p=.09). The difference between baseline and maximum mdi was available in 56 HER2 under-expressing VG pts. Of the 26 pts above the mean difference (1.08 mdi +.17), one recurred, compared to six CR in the 30 pts below the mean (p=.06). There were no CR in pts with HER2 under expression with a mean difference ranked in the top third. Conclusions: In prospective, completed phase I/II trials of NeuVax (nelipepimut-S), patients who exhibit robust in vitro IR have lower recurrence rates. This finding suggests that nelipepimut-specific CTL clonal expansion is a valid biomarker for CR in pts treated with NeuVax. Clinical trial information: NCT00841399.

Results of the First Phase I Clinical Trial of the Novel Ii-Key Hybrid Preventive HER-2/neu Peptide (AE37) Vaccine

2008 ◽  
Vol 26 (20) ◽  
pp. 3426-3433 ◽  
Author(s):  
Jarrod P. Holmes ◽  
Linda C. Benavides ◽  
Jeremy D. Gates ◽  
Mark G. Carmichael ◽  
Matthew T. Hueman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Peptide Vaccine ◽  
Delayed Type Hypersensitivity ◽  
Breast Cancer Patients ◽  
Gm Csf ◽  
Her 2 ◽  
Dose Reductions

Purpose HER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4+ T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four–amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients. Patients and Methods The dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 μg, 500 μg, 1,000 μg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 μg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [3H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790). Results All 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 μg; GM-CSF, 250 μg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36. Conclusion The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu–specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.

Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

2021 ◽  
pp. 1-10
Author(s):  
Yu Wang ◽  
Han Zhao ◽  
Ping Zhao ◽  
Xingang Wang
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Poor Prognosis ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

scholarly journals A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

Oncogene ◽  
2021 ◽  
Author(s):  
Pengpeng Zhu ◽  
Fang He ◽  
Yixuan Hou ◽  
Gang Tu ◽  
Qiao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
Rapid Expansion ◽  
Breast Cancer Patients ◽  
Coding Region ◽  
Signaling Axis

AbstractThe hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, the underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding RNA (lncRNA) KB-1980E6.3, which is aberrantly upregulated in clinical breast cancer tissues and closely correlated with poor prognosis of breast cancer patients. The enhanced lncRNA KB-1980E6.3 facilitates breast cancer stem cells (BCSCs) self-renewal and tumorigenesis under hypoxic microenvironment both in vitro and in vivo. Mechanistically, lncRNA KB-1980E6.3 recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form a lncRNA KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained the stability of c-Myc mRNA through increasing binding of IGF2BP1 with m6A-modified c-Myc coding region instability determinant (CRD) mRNA. In conclusion, we confirm that lncRNA KB-1980E6.3 maintains the stemness of BCSCs through lncRNA KB-1980E6.3/IGF2BP1/c-Myc axis and suggest that disrupting this axis might provide a new therapeutic target for refractory hypoxic tumors.

scholarly journals Time-Programmed Delivery of Sorafenib and Anti-CD47 Antibody via a Double-Layer-Gel Matrix for Postsurgical Treatment of Breast Cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Liping Huang ◽  
Yiyi Zhang ◽  
Yanan Li ◽  
Fanling Meng ◽  
Hongyu Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Near Infrared ◽  
Immune Escape ◽  
Regulatory Protein ◽  
In Vivo Studies ◽  
Breast Cancer Patients ◽  
Thermally Responsive ◽  
Immunosuppressive Microenvironment

AbstractThe highly immunosuppressive microenvironment after surgery has a crucial impact on the recurrence and metastasis in breast cancer patients. Programmable delivery of immunotherapy-involving combinations through a single drug delivery system is highly promising, yet greatly challenging, to reverse postoperative immunosuppression. Here, an injectable hierarchical gel matrix, composed of dual lipid gel (DLG) layers with different soybean phosphatidylcholine/glycerol dioleate mass ratios, was developed to achieve the time-programmed sequential delivery of combined cancer immunotherapy. The outer layer of the DLG matrix was thermally responsive and loaded with sorafenib-adsorbed graphene oxide (GO) nanoparticles. GO under manually controlled near-infrared irradiation generated mild heat and provoked the release of sorafenib first to reeducate tumor-associated macrophages (TAMs) and promote an immunogenic tumor microenvironment. The inner layer, loaded with anti-CD47 antibody (aCD47), could maintain the gel state for a much longer time, enabling the sustained release of aCD47 afterward to block the CD47-signal regulatory protein α (SIRPα) pathway for a long-term antitumor effect. In vivo studies on 4T1 tumor-bearing mouse model demonstrated that the DLG-based strategy efficiently prevented tumor recurrence and metastasis by locally reversing the immunosuppression and synergistically blocking the CD47-dependent immune escape, thereby boosting the systemic immune responses.

scholarly journals Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽  
2021 ◽  
Author(s):  
Francesco Pantano ◽  
Martine Croset ◽  
Keltouma Driouch ◽  
Natalia Bednarz-Knoll ◽  
Michele Iuliani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Osteolytic Lesions ◽  
Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

scholarly journals CircBCBM1 Promotes Breast Cancer Brain Metastasis via miR-125a/BRD4 Axis

2020 ◽  
Author(s):  
Bo Fu ◽  
Wei Liu ◽  
Peng Li ◽  
Li Pan ◽  
Ke Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Breast Cancer Patients ◽  
Breast Cancer Brain Metastasis ◽  
Tumorigenesis And Progression ◽  
And Migration

Abstract Background: Accumulating evidence indicates that circular RNAs (circRNAs) play critical roles in tumorigenesis and progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown.Methods: In this reserch, we validated the expression and characterization of circBCBM1 through RT-qPCR, Sanger sequencing, RNase R assay and fluorescence in situ hybridization (FISH). Functional experiments were performed to determine the effect of circBCBM1 on growth and metastasis of 231-BR cells both in vitro and in vivo. The regulatory mechanisms among circBCBM1, miR-125a (has-miR-125a-5p), and BRD4 (bromodomain containing 4) were investigated by RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter assay and western blot. Results: Our findings demonstrated that circBCBM1 is a stable and cytoplasmic circRNA. Functionally, silencing of circBCBM1 led to decreased proliferation and migration of 231-BR cells whereas elevated circBCBM1 expression showed reverse effects in vitro. These findings were confirmed in vivo in mouse models, as knockdown of circBCBM1 significantly decreased growth and brain metastases of 231-BR cells. Mechanistically, circBCBM1 functions as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 expression and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, the overexpression of circBCBM1 in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients.Conclusions: These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis, which sheds light on the pathogenic mechanism of circBCBM1 and provides translational evidence that circBCBM1 may serve as a novel diagnostic or prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.

scholarly journals Blockade of CDK7 Reverses Endocrine Therapy Resistance in Breast Cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 2974 ◽  
Author(s):  
Yasmin M. Attia ◽  
Samia A. Shouman ◽  
Salama A. Salama ◽  
Cristina Ivan ◽  
Abdelrahman M. Elsayed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Volume ◽  
Apoptotic Cell ◽  
Therapy Resistance ◽  
Tamoxifen Treatment ◽  
Clinical Samples ◽  
Breast Cancer Cell Lines ◽  
Breast Cancer Patients

Cyclin-dependent kinase (CDK)-7 inhibitors are emerging as promising drugs for the treatment of different types of cancer that show chemotherapy resistance. Evaluation of the effects of CDK7 inhibitor, THZ1, alone and combined with tamoxifen is of paramount importance. Thus, in the current work, we assessed the effects of THZ1 and/or tamoxifen in two estrogen receptor-positive (ER+) breast cancer cell lines (MCF7) and its tamoxifen resistant counterpart (LCC2) in vitro and in xenograft mouse models of breast cancer. Furthermore, we evaluated the expression of CDK7 in clinical samples from breast cancer patients. Cell viability, apoptosis, and genes involved in cell cycle regulation and tamoxifen resistance were determined. Tumor volume and weight, proliferation marker (Ki67), angiogenic marker (CD31), and apoptotic markers were assayed. Bioinformatic data indicated CDK7 expression was associated with negative prognosis, enhanced pro-oncogenic pathways, and decreased response to tamoxifen. Treatment with THZ1 enhanced tamoxifen-induced cytotoxicity, while it inhibited genes involved in tumor progression in MCF-7 and LCC2 cells. In vivo, THZ1 boosted the effect of tamoxifen on tumor weight and tumor volume, reduced Ki67 and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy.

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