Faculty Opinions recommendation of Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer.

Purpose Allogeneic T lymphocytes can induce regression of metastatic breast cancer through an immune-mediated graft-versus-tumor (GVT) effect in murine models. To determine if a clinical GVT effect exists against metastatic breast cancer, allogeneic lymphocytes were used as adoptive cellular therapy after a reduced-intensity chemotherapy conditioning regimen and allogeneic hematopoietic stem-cell transplantation (HSCT) from human leukocyte antigen–matched siblings. Patients and Methods Sixteen patients with metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes, hormonal agents, and trastuzumab, received allogeneic HSCT. The reduced-intensity transplant conditioning regimen consisted of cyclophosphamide and fludarabine. To distinguish an immunological GVT effect from any antitumor effect of cytotoxic chemotherapy in the transplant-conditioning regimen, allogeneic T lymphocytes were removed from the stem-cell graft and were subsequently administered late postallogeneic HSCT. Allogeneic lymphocytes containing 1 × 106, 5 × 106, and 10 × 106 CD3+ cells/kg were infused on days +42, +70, and +98 post–allogeneic HSCT, respectively. Results Objective tumor regressions occurred after day +28 post–allogeneic HSCT in six patients and were attributed to allogeneic lymphocyte infusions. Two of these responding patients had disease progression post–allogeneic HSCT before subsequent tumor regression. Tumor regressions occurred concomitantly with the establishment of complete donor T-lymphoid engraftment, were associated with the development of graft-versus-host disease (GVHD), and were abrogated by subsequent systemic immunosuppression for GVHD. Conclusion Allogeneic lymphocytes can induce regression of advanced metastatic breast cancer. These results indicate that an immunological GVT effect from allogeneic lymphocytes exists against metastatic breast cancer and provide rationale for further development of allogeneic cellular therapy for this largely incurable disease.

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High-dose combination alkylating agent chemotherapy with autologous bone marrow support for metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1986.4.11.1592 ◽

1986 ◽

Vol 4 (11) ◽

pp. 1592-1597 ◽

Cited By ~ 78

Author(s):

J P Eder ◽

K Antman ◽

W Peters ◽

W D Henner ◽

A Elias ◽

...

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Metastatic Breast Cancer ◽

Alkylating Agent ◽

Tumor Regression ◽

Metastatic Breast ◽

Autologous Bone Marrow ◽

High Dose ◽

Prior Chemotherapy ◽

Dose Combination

Seventeen patients with metastatic breast cancer were treated with a high-dose combination chemotherapy regimen and autologous bone marrow support. Thirteen patients had prior combination chemotherapy. Fifteen patients were treated with a phase II regimen of cyclophosphamide (5.625 g/m2), cisplatin (165 mg/m2), and BCNU (600 mg/m2). Bone marrow harvest and reconstitution were uncomplicated. All patients became profoundly myelosuppressed. Fourteen of 16 evaluable patients (88%) responded, including six complete responses (CRs) (38%). The median time to tumor progression was 5 months. The median survival was 8 months. CRs occurred more frequently in patients with no prior chemotherapy for metastatic disease, inflammatory breast cancer; and patients treated within 3 months of first recurrence. The rate of tumor regression was rapid, with a median of 11 days to partial response (PR) and 12 days to CR. Those patients achieving a PR by day 7 had a greater likelihood (P = .03) of attaining a CR than those patients whose PR occurred later. Three deaths (18%) occurred, all in women with inflammatory breast cancer treated with prior chemotherapy. High-dose combined alkylating agent therapy produced high PR and CR rates in metastatic breast cancer patients, most of whom had failed prior chemotherapy. The rate of tumor regression was rapid. Current efforts are directed at developing a regimen using drugs specifically active in breast cancer, with an intent of combining an effective high-dose regimen with additional modalities of therapy in the treatment of breast cancer.

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Effects of Combinatorial Ubiquitinated Protein-Based Nanovaccine and STING Agonist in Mice With Drug-Resistant and Metastatic Breast Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.707298 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fang Huang ◽

Ning Pan ◽

Yiting Wei ◽

Jinjin Zhao ◽

Mohanad Aldarouish ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

T Cell ◽

Tumor Regression ◽

Therapeutic Vaccine ◽

Metastatic Breast ◽

Cancer Cell Line ◽

Tumor Infiltrating Lymphocytes ◽

Cell Receptor ◽

Drug Resistant

We previously reported that enriched ubiquitinated proteins (UPs) from tumor cells have the potential to be used as immunotherapy vaccine against cancer. Here we enriched UPs from epirubicin (EPB)-induced multi-drug-resistant cancer stem-like breast cancer cell line (4T1/EPB) and tested the efficacy of α-Al2O3-UPs-4T1/EPB (short for UPs-4T1/EPB) as therapeutic vaccine alone and in combination with the stimulator of interferon genes (STING) agonist in mice with drug-resistant and metastatic breast cancer. Vaccination with UPs-4T1/EPB exerted profound anti-tumor effects through augmented specific CD8+ T cell responses and amplified T cell receptor diversity of tumor-infiltrating lymphocytes (TILs). Importantly, the combination with STING agonist further facilitated the migration of mature CD8α+ dendritic cells to the lymph nodes and the infiltration of TILs within tumors, resulting in primary tumor regression and pulmonary metastasis eradication in mice. Moreover, the cured mice were completely resistant against a subsequent rechallenge with the same tumor. Our study indicates that this novel combinatorial immunotherapy with UPs-4T1/EPB vaccine and STING agonist is effective in mice with drug-resistant and metastatic breast cancer.

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Comparison of circulating CA15-3 and carcinoembryonic antigen levels in patients with breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1986.4.10.1542 ◽

1986 ◽

Vol 4 (10) ◽

pp. 1542-1550 ◽

Cited By ~ 208

Author(s):

D F Hayes ◽

V R Zurawski ◽

D W Kufe

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Bone Metastases ◽

Carcinoembryonic Antigen ◽

Tumor Regression ◽

Hepatic Metastases ◽

Metastatic Breast ◽

Breast Diseases ◽

Evaluation And Monitoring ◽

Sensitive Marker

An immunoradiometric assay (IRMA) has been used to determine circulating levels of the breast cancer-associated antigen, CA15-3. Of 1,050 normal control subjects, serum from 99 (9.4%) had CA15-3 antigen levels greater than 22 U/mL, while that from 58 (5.5%) and 14 (1.3%) had levels greater than 25 U/mL and 30 U/mL, respectively. In contrast, 115 of 158 patients (73%) with metastatic breast cancer had CA15-3 levels greater than 22 U/mL. Thirteen of 26 patients (50%) with only local metastases, 27 of 34 (79%) of those with only bone metastases, and 20 of 24 (83%) with hepatic metastases had CA15-3 levels greater than 22 U/mL. Furthermore, nine of 31 patients (29%) with primary breast cancer had CA15-3 levels greater than 22 U/mL. CA15-3 and carcinoembryonic antigen (CEA) levels were compared for the same patient population. Significantly more patients with metastatic breast cancer had elevated CA15-3 levels than had elevated CEA levels (P less than .001). Furthermore, the CA15-3 IRMA was more sensitive than the CEA assay in patients with only bone metastases, as well as those with only local metastases. Significantly more patients with primary carcinoma of the breast also had elevated CA15-3 than had elevated CEA levels (P less than .02). CA15-3 levels were greater than 22 U/mL in patients with nonmalignant conditions, including five of 25 patients (20%) with benign breast diseases, and 23 of 52 patients (44%) with benign liver diseases. Furthermore, CA15-3 levels were also greater than 22 U/mL in 24 of 54 patients (44%) with gastrointestinal (GI) malignancies, 12 of 17 patients (71%) with bronchogenic carcinoma, and 29 of 44 patients (66%) with epithelial ovarian carcinoma. Serial CA15-3 levels correlated with clinical disease course. Nineteen of 21 patients (91%) with tumor progression had at least a 25% increase in CA15-3 levels. Conversely, seven of nine patients (78%) with tumor regression had at least a 50% decrease in CA15-3 levels. Among 27 patients with stable disease, 16 (59%) had levels that did not vary by more than +/- 25% of the original CA15-3 levels. These results indicate that the CA15-3 antigen is a sensitive marker for the evaluation and monitoring of patients with breast cancer.

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Targeted tumor-derived cellular immunotherapy in advanced breast cancer patients induces initial immune responses and tumor regression.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.6 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 6-6

Author(s):

Vivekananda Sunkari ◽

William Williams ◽

George Peoples ◽

Sanne Graeve ◽

Charles Wiseman ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Metastatic Breast Cancer ◽

Phase I ◽

Advanced Breast Cancer ◽

Tumor Regression ◽

Metastatic Breast ◽

Advanced Breast ◽

Delayed Type Hypersensitivity ◽

Sera Samples

6 Background: SV-BR-1-GM is a GM-CSF secreting breast cancer cell line which also expresses HLA class I & II antigens. In a previous clinical trial, a partial response of widely metastatic breast cancer was seen in a patient who allele-matched SV-BR-1-GM at HLA-DRB3. Here we report regression of metastatic breast cancer and efficacy analysis with immunologic correlates in subjects of a Phase I/IIa trial of SV-BR-1-GM in patients with advanced breast cancer. Methods: 24 patients with recurrent and/or metastatic breast cancer refractory to standard therapies have been dosed with SV-BR-1-GM in a Phase I/IIa trial. Patients who have undergone at least one cycle of SV-BR-1-GM therapy were analyzed. Patients first received low-dose cyclophosphamide, then intradermal injection of SV-BR-1-GM (20-40x106 cells/four sites) with interferon-α injected into inoculation sites (10,000 IU/site) ~2 & 4 days subsequently. Immunologic responses were measured by delayed type hypersensitivity (DTH) after inoculation and IgG titers of antibodies against SV-BR-1 were measured in sera samples collected prior to and after the first dose of SV-BR-1-GM by flow cytometry. Results: 24 patients have been inoculated with SV-BR-1-GM cells with no unexpected adverse events. None of the patients exhibited immediate hypersensitivity to SV-BR-1. DTH response was recorded in 18 subjects till date, of these, 61% exhibited DTH to cell inoculations. The patient with the most marked DTH response, 01-002, also had a clinical response with regression of multiple lung metastases. Two other patients had evidence of tumor regression (tumor regression is matched SV-BR-1-GM at least at one HLA allele). Sera samples from 6 patients were evaluated and found to contain anti-SV-BR-1 antibodies. Conclusions: SV-BR-1-GM in this regimen appears to be safe and well-tolerated. Initial analysis of SV-BR-1-GM showed significant DTH and antibody responses. HLA matching improves the response rate and is being evaluated as a predictor of response. Clinical trial information: NCT03066947.

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