Phase II Trial of Adjuvant Immunotherapy with Autologous Tumor-derived Gp96 Vaccination in Patients with Gastric Cancer.
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ABSTRACT:
SUBMITTER: Zhang K
PROVIDER: S-EPMC5556646 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Our previous phase I/IIA study showed that autologous dendritic cells (DCs) pulsed with tumor-associated antigens are well tolerated in patients with hepatocellular carcinoma (HCC). In this randomized, multicenter, open-label, phase II trial, we investigated the efficacy and safety of this DC-based adjuvant immunotherapy with 156 patients, who treated for HCC with no evidence of residual tumor after standard treatment modalities. Patients were randomly assigned to immunotherapy (n = 77; injection of 3 × 107 DC cells, six times over 14 weeks) or control (n = 79; no treatment). The primary end point was recurrence-free survival (RFS), and the secondary endpoints were immune response and safety. The RFS between the immunotherapy and control groups was not significantly different (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.60-1.56; p = 0.90). However, post-hoc subgroup analyses revealed that DC immunotherapy significantly reduced the risk of tumor recurrence of non-radiofrequency ablation (non-RFA) group patients (n = 83, HR, 0.49; 95% CI, 0.26-0.94; p = 0.03), whereas unexpectedly increased the risk of recurrence in RFA group (n = 61, p = 0.01). Tumor-specific immune responses were significantly enhanced (both p < 0.01) in the immunotherapy group. Baseline serum interleukin (IL)-15 was statistically correlated with RFS prolongation (HR, 0.16; 95% CI, 0.03-1.58; p = 0.001) within the immunotherapy groups. Overall adverse events were more frequent in the immunotherapy group (p < 0.001) but were mainly mild to moderate in severity. In conclusion, adjuvant immunotherapy with DC vaccine reduces the risk of tumor recurrence in HCC patients who underwent standard treatment modalities other than RFA. Baseline IL-15 might be a candidate biomarker for DC-based HCC immunotherapy.
| S-EPMC5543846 | biostudies-literature
Project description:Abstract In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age < 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS > 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development. Clinicaltrials.gov NCT03400917.
| S-EPMC8598812 | biostudies-literature
Project description:INTRODUCTION:Surgery is one of the treatments of choice for patients with a single metastasis from melanoma but is rarely curative. Such patients could potentially benefit from consolidation immunotherapy. Vaccination with dendritic cells (DCs) loaded with tumour antigens elicits a tumour-specific immune response. In our experience, patients who developed delayed type hypersensitivity (DTH) after DC vaccination showed a median overall survival (OS) of 22.9 monthsvs4.8 months for DTH-negative cases. A phase II randomised trial showed an advantage OS of a DC vaccine over a tumour cell-based vaccine (2-year OS 72% vs31%, respectively). Given that there is no standard therapy after surgical resection of single metastases, we planned a study to compare vaccination with DCs pulsed with autologous tumour lysate versus follow-up. METHODS AND ANALYSIS:This is a randomised phase II trial in patients with resected stage III/IV melanoma. Assuming a median relapse-free survival (RFS) of 7.0 months for the standard group and 11.7 months for the experimental arm (HR 0.60), with a two-sided tailed alpha of 0.10, 60 patients per arm must be recruited. An interim futility analysis will be performed at 18 months. The DC vaccine, produced in accordance with Good Manufacturing Practice guidelines, consists of autologous DCs loaded with autologous tumour lysate and injected intradermally near lymph nodes. Vaccine doses will be administered every 4 weeks for six vaccinations and will be followed by 3 million unit /day of interleukin-2 for 5 days. Tumour restaging, blood sampling for immunological biomarkers and DTH testing will be performed every 12 weeks. ETHICS AND DISSEMINATION:The protocol, informed consent and accompanying material given to patients were submitted by the investigator to the Ethics Committee for review. The local Ethics Committee and the Italian Medicines Agency approved the protocol (EudraCT code no.2014-005123-27). Results will be published in a peer-reviewed international scientific journal. TRIAL REGISTRATION NUMBER:2014-005123-27.
| S-EPMC6078243 | biostudies-literature
Project description:BACKGROUND: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome. PATIENTS AND METHODS: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 x 1014 molecules) or peptides (10 versus 100 mug/ml) were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression. RESULTS: The GMP process allowed to harvest about 5 x 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood. CONCLUSION: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.
| S-EPMC554765 | biostudies-literature
Project description:BackgroundPrognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypothesized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients' survival.MethodsWe conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were finally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan-Meier method. Immune response were assessed in blood samples obtained before each vaccines.ResultsThirty-two consecutive patients were screened, one of which was a screening failure due to insufficient resection. Median age was 61 years (range 42-70). Karnofsky performance score (KPS) was 90-100 in 29%, 80 in 35.5% and 60-70 in 35.5% of cases. MGMT (O6-methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse effects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7-16) and median OS was 23.4 months (95% CI 16-33.1). Increase in post-vaccination tumor specific immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correlation between immune response and survival was found.ConclusionsOur results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival benefit of this therapeutic approach. Trial registration This phase-II trial was registered as EudraCT: 2009-009879-35 and ClinicalTrials.gov Identifier: NCT01006044 retrospectively registered.
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Project description:Background:Survival after resection of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) still remains poor. Apatinib, a vascular endothelial cell growth factor receptor 2 inhibitor, has been shown to be safe and effective in patients with advanced HCC, so in the present study its efficacy and safety in the adjuvant setting was explored. Methods:In this single-center, open-label phase II trial, the patients received apatinib (500 mg/day) until they experienced disease recurrence or intolerable toxicity. The primary endpoint was recurrence-free survival (RFS); the secondary endpoints included overall survival (OS) and safety. Results:From a total of 49 patients who were screened between August 2017 and December 2018, 30 study participants received apatinib. According to the Liver Cancer Study Group of Japan classification of PVTT, there were 7, 11, and 12 participants with Vp1, Vp2, and Vp3, respectively. The median duration of treatment was 4.8 months [interquartile range (IQR): 2.0-8.8], and the median dose of apatinib was 339.7 mg/day (IQR: 267.7-500 mg/day). The median follow-up was 14.3 months (IQR: 12.3-19.3). The median RFS was 7.6 months [95% confidence interval (CI): 5.7-9.5 months]. The 1-year RFS rate and the 1-year OS rate were 36.1% and 93.3%, respectively. A total of 29 (96.7%) patients experienced adverse events, and 14 (46.7%) had grade 3 or 4 adverse events. No treatment-related deaths occurred. Conclusions:Apatinib was well tolerated in patients after resection of HCC with PVTT. The median RFS in this group was improved compared with that previously reported. Trial registration:No.: NCT03261791 (ClinicalTrials.gov).
| S-EPMC7661881 | biostudies-literature
Project description:Lessons learnedAdjuvant treatment with zoledronic acid did not decrease the recurrence rate of giant cell tumor of bone (GCTB) in this study. The efficacy could not be determined because of the small sample size.GCTB recurrences, even in the denosumab era, are still an issue; therefore, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid.BackgroundBisphosphonates are assumed to inhibit giant cell tumor of bone (GCTB)-associated osteoclast activity and have an apoptotic effect on the neoplastic mononuclear cell population. The primary objective of this study was to determine the 2-year recurrence rate of high-risk GCTB after adjuvant zoledronic acid versus standard care.MethodsIn this multicenter randomized open-label phase II trial, patients with high-risk GCTB were included (December 2008 to October 2013). Recruitment was stopped because of low accrual after the introduction of denosumab. In the intervention group, patients received adjuvant zoledronic acid (4 mg) intravenously at 1, 2, 3, 6, 9, and 12 months after surgery.ResultsFourteen patients were included (intervention n = 8, controls n = 6). Median follow-up was long: 93.5 months (range, 48-111). Overall 2-year recurrence rate was 38% (3/8) in the intervention versus 17% (1/6) in the control group (p = .58). All recurrences were seen within the first 15 months after surgery.ConclusionAdjuvant treatment with zoledronic acid did not decrease the recurrence rate of GCTB in this study. The efficacy could not be determined because of the small sample size. Because recurrences, even in the denosumab era, are still an issue, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid.
| S-EPMC6656477 | biostudies-literature
Project description:BACKGROUND:Despite improved survival following checkpoint inhibitors, there is still a potential role for anti-cancer therapeutic vaccines. Because of biological heterogeneity and neoantigens resulting from each patient's mutanome, autologous tumor may be the best source of tumor-associated antigens (TAA) for vaccines. Ex vivo loading of autologous dendritic cells with TAA may be associated with superior clinical outcome compared to injecting irradiated autologous tumor cells. We conducted a randomized phase II trial to compare autologous tumor cell vaccines (TCV) and autologous dendritic cell vaccines (DCV) loaded with autologous TAA. METHODS:Short-term autologous tumor cell lines were established from metastatic tumor. Vaccines were admixed with 500 micrograms of GM-CSF and injected weekly for 3 weeks, then at weeks 8, 12,16, 20, and 24. The primary endpoint was overall survival. Secondary objectives were identification of adverse events, and results of delayed type hypersensitivity (DTH) reactions to intradermal tumor cell injections. RESULTS:Forty-two patients were randomized. All were followed from randomization until death or for five years; none were lost to follow-up. DCV was associated with longer survival: median 43.4 versus 20.5 months (95% CI, 18.6 to >?60 versus 9.3 to 32.3 months) and a 70% reduction in the risk of death (hazard ratio?=?0.304, p?=?0.0053, 95% CI, 0.131 to 0.702). Tumor DTH reactions were neither prognostic nor predictive. The most common treatment-related adverse events were mild to moderate local injection site reactions and flu-like symptoms; but grade 2 treatment-related adverse events were more frequent with TCV. Serum marker analyses at week-0 and week-4 showed that serum markers were similar at baseline in each arm, but differed after vaccination. CONCLUSIONS:This is the only human clinical trial comparing DCV and TCV as platforms for autologous TAA presentation. DCV was associated with minimal toxicity and long-term survival in patients with metastatic melanoma. DTH to autologous tumor cells was neither prognostic for survival nor predictive of benefit for either vaccine. TRIAL REGISTRATION:Clinical trials.gov NCT00948480 retrospectively registered 28 July 2009.
| S-EPMC5840808 | biostudies-literature
Project description:Immunotherapy is an innovative treatment approach that stimulates a patient's immune system to fight cancer. It demonstrates characteristics distinct from conventional chemotherapy and stands to revolutionize cancer treatment. We propose a Bayesian phase I/II dosefinding design that incorporates the unique features of immunotherapy by simultaneously considering three outcomes: immune response, toxicity and efficacy. The objective is to identify the biologically optimal dose, defined as the dose with the highest desirability in the risk-benefit tradeoff. An Emax model is utilized to describe the marginal distribution of the immune response. Conditional on the immune response, we jointly model toxicity and efficacy using a latent variable approach. Using the accumulating data, we adaptively randomize patients to experimental doses based on the continuously updated model estimates. A simulation study shows that our proposed design has good operating characteristics in terms of selecting the target dose and allocating patients to the target dose.
| S-EPMC6860919 | biostudies-literature
Project description:BackgroundAutologous dendritic cell (DC) vaccines can induce tumor-specific T cells, but their effect can be counteracted by immunosuppressive mechanisms. Cisplatin has shown immunomodulatory effects in vivo which may enhance efficacy of DC vaccination.MethodsThis is a prospective, randomized, open-label phase 2 study (NCT02285413) including stage III and IV melanoma patients receiving 3 biweekly vaccinations of gp100 and tyrosinase mRNA-loaded monocyte-derived DCs with or without cisplatin. Primary objectives were to study immunogenicity and feasibility, and secondary objectives were to assess toxicity and survival.ResultsTwenty-two stage III and 32 stage IV melanoma patients were analyzed. Antigen-specific CD8+ T cells were found in 44% versus 67% and functional T cell responses in 28% versus 19% of skin-test infiltrating lymphocytes in patients receiving DC vaccination with and without cisplatin, respectively. Four patients stopped cisplatin because of toxicity and continued DC monotherapy. No therapy-related grade 3 or 4 adverse events occurred due to DC monotherapy. During combination therapy, one therapy-related grade 3 adverse event, decompensated heart failure due to fluid overload, occurred. The clinical outcome parameters did not clearly suggest significant differences.ConclusionsCombination of DC vaccination and cisplatin in melanoma patients is feasible and safe, but does not seem to result in more tumor-specific T cell responses or improved clinical outcome, when compared to DC vaccination monotherapy.
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