Neoadjuvant therapy of breast cancer using Newcastle disease virus
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The role of Newcastle disease virus and neoadjuvant therapy was assessed in 84 cases of breast cancer T1-4N0-2M0 (2005-2008). Combined use of the virus vaccine and chemotherapy (group A), therapy with the vaccine alone (group B) and chemotherapy regimen identical with that used in group A (group C) were compared. Histological pattern of tumor and stage were identified using expression of receptors of steroid hormones, oncoproteins Her2/neu and p53 as well as proliferation activity (marker Ki-67) before and after therapy. It was shown that the efficiency and safety of Newcastle disease virus (apathogenic strain La-Sotha) met specific immuno- and neoadjuvant therapy standards.Keywords:
Newcastle Disease
Regimen
Neoadjuvant Therapy
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The aim of this study was to evaluate the efficacy and safety of recombinant human adenovirus-p53 (rhAd‑p53) combined with neoadjuvant chemotherapy in treatment of locally advanced cervical cancer (LACC). A total of 40 patients with LACC (stage IB2 to IIIA) were randomized into 2 groups (n=20 each): PVB group (cisplatin + vincristine + bleomycin, intravenously) and combined group (rhAd‑p53 gene therapy + neoadjuvant chemotherapy). Both groups underwent a course of chemotherapy; the only exception was the injection of the rhAd‑p53 solution 1x1012 VP intratumorally at an interval of three days thrice in the combined group thereafter. The tumor sizes and adverse events in both groups were observed. The expression of vascular endothelial growth factor (VEGF), protein p53 and micro‑vessel density (MVD) in tumor tissue was respectively determined by immunohistochemistry. The evaluation was performed three weeks after the completion of chemotherapy. The efficacy was 75% in the PVB group versus 95% efficacy in the combined group; the tumor size was reduced by 11.42±2.78 cm2 in PVB group versus the significant shrinkage of 15.25±4.00 cm2 in the combined group (P<0.05). The expression of VEGF, p53 and MVD was downregulated in both the PVB and combined groups, with significantly statistical differences versus the control. No additional adverse events were evidenced in the combined group. Therefore, intratumoral injection of rhAd‑p53 combined with neoadjuvant chemotherapy has advantage over conventional chemotherapy for its high efficacy, safety and synergism in the therapy for LACC.
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Breast cancer patients diagnosed with HR+/HER2- tumors face a persistent risk of distant recurrence long after completion of their treatment. Strategies to induce anti-tumor immune responses could complement standard-of-care therapies for these patients. The current study was performed to examine the feasibility, safety and immunogenicity of adding P10s-PADRE to standard-of-care chemotherapy in HR+/HER2- early-stage breast cancer patients. Twenty-five subjects were treated in a single-arm Phase Ib clinical trial. Five different immunization schedules were considered to evaluate the feasibility of eliciting an immune response. The primary immunogenicity endpoint was antibody titer. The expression of several activation markers on natural killer (NK) cells and serum concentrations of Th1/Th2 cytokines were also examined. The percentage of tumor-infiltrating lymphocytes (TILs) was determined. Antibody response was superior in schedule C where 3 weekly immunizations preceded the first dose of chemotherapy. A significant change in CD16, NKp46 and CD94 expression levels on NK cells and a rise in serum content of IFN-γ was observed after treatment. Schedule C showed an increase in TILs in residual lesions. The combination therapy is safe and immunogenic with treatment schedule C being immunologically promising. Randomized trials focused on long-term survival outcomes are needed to evaluate clinical benefits.
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HER2/neu
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Abstract PURPOSE: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. EXPERIMENTAL DESIGN: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells. RESULTS: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. CONCLUSION: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.
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Taxane
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Since treatment modalities for metastatic recurrent triple-negative breast cancer (mrTNBC) are limited, a novel treatment approach including immunotherapy is required. We have developed a novel regimen of personalized peptide vaccination (PPV), in which vaccine antigens are individually selected from a pool of different peptide candidates based on the pre-existing host immunity. Herein we conducted a phase II study of PPV for metastatic recurrent breast cancer patients to investigate the feasibility of PPV for mrTNBC.Seventy-nine patients with metastatic recurrent breast cancer who had metastases and had failed standard chemotherapy and/or hormonal therapy were enrolled. They were subgrouped as the mrTNBC group (n = 18), the luminal/human epidermal growth factor receptor 2 (HER2)-negative group (n = 41) and the HER2-positive group (n = 18), while the remaining two patients had not been investigated. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher peptide-specific immunoglobulin G (IgG) responses in pre-vaccination plasma were selected from 31 pooled peptide candidates applicable for the four HLA-IA phenotypes (HLA-A2, -A24, or -A26 types, or HLA-A3 supertypes), and were subcutaneously administered weekly for 6 weeks and bi-weekly thereafter. Measurement of peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses along with other laboratory analyses were conducted before and after vaccination.No severe adverse events associated with PPV were observed in any of the enrolled patients. Boosting of CTL and/or IgG responses was observed in most of the patients after vaccination, irrespective of the breast cancer subtypes. There were three complete response cases (1 mrTNBC and 2 luminal/HER2-negative types) and six partial response cases (1 mrTNBC and 5 luminal/HER2-negative types). The median progression-free survival time and median overall survival time of mrTNBC patients were 7.5 and 11.1 months, while those of luminal/HER2-negative patients were 12.2 and 26.5 months, and those of HER2-positive patients were 4.5 and 14.9 months, respectively.PPV could be feasible for mrTNBC patients because of the safety, immune responses, and possible clinical benefits.UMIN000001844 (Registration Date: April 5, 2009).
Surgical oncology
Triple-negative breast cancer
Triple negative
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Dialyzable leukocyte extract (DLE) is one of the immunological agents used as an adjuvant in cancer therapy; it has been associated with improved quality of life during cancer chemotherapy. Based on these previous findings and on the observed clinical benefits attributed to DLE in other types of cancer, we investigated its clinical and immunological effects as a therapy adjuvant on breast cancer patients who received only chemotherapy, as compared to patients administered bovine DLE (bDLE) as an adjuvant. This study included 43 breast cancer patients who were about to begin chemotherapy. This group was divided as follows: 25 received chemotherapy and bDLE as an adjuvant therapy, and 18 received only chemotherapy without the adjuvant. All patient clinical and immunological responses were monitored. Among patients in the group that received bDLE as adjuvant, 60% showed a complete response, 32% showed a partial response and 8% did not respond. By contrast, in the group without the adjuvant, 39% showed a complete response, 50% displayed a partial response and 11% were non-responders. In addition, bDLE treatment in combination with chemotherapy resulted in the enhancement of the Karnofsky performance scale during chemotherapy. Even though patients underwent several cycles of chemotherapy without bDLE, the lymphocyte population dropped to below the reference value. On the other hand, in patients with bDLE as adjuvant, the CD4+ and CD8+ lymphocytes and the B lymphocytes were maintained within the median range of the reference value. The number of natural killer cells also increased after chemotherapy treatment with bDLE as an adjuvant. In conclusion, bDLE treatment contributes to significant immunological recovery in patients that have undergone heavy chemotherapy, increasing the clinical response and quality of life during chemotherapy.
Adjuvant Therapy
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Objective To investigate the changes of liver function in breast cancer patients after anthracycline-based adjuvant chemotherapy, as well as activation of Hepatitis B virus (HBV). Methods The clinical data of 98 breast cancer patients after postoperative anthracycline-based adjuvant chemotherapy were analyzed, including 25 patients complicated with HBV infection. CAF or CEF scheme was used for chemotherapy. Results After chemotherapy, a higher proportion of liver damage was investigated in the HBV-infected patients. Among the 25 patients, 5 (20%) were found with activation of HBV, 12 were found with hepatic dysfunction (48%), including 2 (8%)of degree Ⅲ. No chemotherapy-related death occurred. Conclusion Breast cancer patients with HBV infection showed activation of HBV after anthracycline-based adjuvant chemotherapy, in which the hepatic dysfunction is more serious than those without HBV infection.
Hepatitis B
Liver function
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Introduction.CD8 + CTLs are important components of tumor specific cellular adaptive immunity in breast cancer. Chemotherapy can increase the response of cytotoxic lymphocytes and provide anti-tumor immunity. Therefore, chemotherapy can cause cell death and trigger tumor antigens that are processed by APC and activate CD8 + cells to destroy tumor cells. Evaluation of the immune system before treatment can predict chemotherapy response. The purpose of this study was to assess the effect of neo-adjuvant chemotherapy on serum CD8 + levels in patients with locally advanced breast cancer.Methods.Non-comparative clinical trials were conducted at Dr. Mohammad Hoesin Hospital Palembang from October 2017 to June 2018.The sample of this study was 30 breast cancer patients who met the inclusion criteria. All samples underwent FAC neo-adjuvant chemotherapy and data were analyzed with SPSS version 21. Results.The mean age of advanced breast cancer patients was 45.97 ± 10,526 years with an age range of 30-66 years. Serum CD8 + levels after chemotherapy decreased significantly compared to before chemotherapy (p = 0.000). The value of serum CD8 + before chemotherapy has a sensitivity of 42.86% and specificity of 43.48% with a cut of point of 660.7 cells / mm3.Conclusion.Neo-adjuvant chemotherapy significantly decreases serum CD8 + levels in local advanced breast cancer patients.Keyword: CD8 +, locally advanced breast cancer, immune system, neo-adjuvant chemotherapy
Breast cancer chemotherapy
Adjuvant Therapy
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Interferon alfa
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The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer.Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected.Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached.Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.
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