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 IFNγ 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 IFNγ 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.
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 IFNγ 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 IFNγ 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.
Authors: Redas Trepiakas; Annika Berntsen; Sine Reker Hadrup; Jon Bjørn; Poul F Geertsen; Per Thor Straten; Mads H Andersen; Anders E Pedersen; Amir Soleimani; Torben Lorentzen; Julia S Johansen; Inge Marie Svane Journal: Cytotherapy Date: 2010-10 Impact factor: 5.414
Authors: Roy S Herbst; Jean-Charles Soria; Marcin Kowanetz; Gregg D Fine; Omid Hamid; Michael S Gordon; Jeffery A Sosman; David F McDermott; John D Powderly; Scott N Gettinger; Holbrook E K Kohrt; Leora Horn; Donald P Lawrence; Sandra Rost; Maya Leabman; Yuanyuan Xiao; Ahmad Mokatrin; Hartmut Koeppen; Priti S Hegde; Ira Mellman; Daniel S Chen; F Stephen Hodi Journal: Nature Date: 2014-11-27 Impact factor: 49.962
Authors: Genevieve M Weir; Olga Hrytsenko; Marianne M Stanford; Neil L Berinstein; Mohan Karkada; Robert S Liwski; Marc Mansour Journal: Oncoimmunology Date: 2014-11-14 Impact factor: 8.110
Authors: Elena García-Martínez; Melody Smith; Aitziber Buqué; Fernando Aranda; Francisco Ayala de la Peña; Alejandra Ivars; Manuel Sanchez Cánovas; Ma Angeles Vicente Conesa; Jitka Fucikova; Radek Spisek; Laurence Zitvogel; Guido Kroemer; Lorenzo Galluzzi Journal: Oncoimmunology Date: 2018-02-15 Impact factor: 8.110
Authors: Ellyn Hughes; Martin Scurr; Emma Campbell; Emma Jones; Andrew Godkin; Awen Gallimore Journal: Immunology Date: 2018-03-09 Impact factor: 7.397