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MRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma.

ABSTRACT: INTRODUCTION:Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safety of vaccination with DCs transfected with mRNA in combination with mCy in patients with metastatic malignant melanoma (MM). In addition, clinical and immunological effect of the treatment was evaluated. EXPERIMENTAL DESIGN:Twenty-two patients were enrolled and treated with six cycles of cyclophosphamide 50 mg orally bi-daily for a week every second week (day 1-7). During the six cycles patients received at least 5 × 106 autologous DCs administered by intradermal (i.d.) injection in the week without chemotherapy. Patients were evaluated 12 and 27 weeks and every 3rd mo thereafter with CT scans according to RECIST 1.0. Blood samples for immune monitoring were collected at baseline, at the time of 4th and 6th vaccines. Immune monitoring consisted of IFN? ELISpot assay, proliferation assay, and flow cytometry for enumeration of immune cell subsets. RESULTS:Toxicity was manageable. Eighteen patients were evaluable after six cycles. Of these, nine patients had progressive disease as best response and nine patients achieved stable disease. In three patients minor tumor regression was observed. By IFN? ELISpot and proliferation assay immune responses were seen in 6/17 and 4/17 patients, respectively; however, no correlation with clinical response was found. The percentage of Tregs was unchanged during treatment. CONCLUSION:Treatment with autologous DCs transfected with mRNA in combination with mCy was feasible and safe. Importantly, mCy did not alter the percentage of Tregs in our patient cohort. There was an indication of clinical benefit; however, more knowledge is needed in order for DCs to be exploited as a therapeutic option.

SUBMITTER: Borch TH

PROVIDER: S-EPMC5048758 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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mRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma.

Borch Troels Holz TH Engell-Noerregaard Lotte L Zeeberg Iversen Trine T Ellebaek Eva E Met Özcan Ö Met Özcan Ö Hansen Morten M Andersen Mads Hald MH Thor Straten Per P Svane Inge Marie IM

Oncoimmunology 20160708 9

<h4>Introduction</h4>Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safet ...[more]

PMID: 27757300

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Project description:PurposeTo assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC).MethodsThirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers.ResultsAdequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).ConclusionsThe LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.

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MRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma.

Publications

mRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma.

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