Iris Bigalke ISCT Europe 2015 Regional Meeting

Transcription

1 Vaccination with a new generation of tumorspecific mrna loaded dendritic cells prolong progression free survival in patients with different types of malignancies Iris Bigalke ISCT Europe 2015 Regional Meeting

2 DC vaccine studies Stage IV melanoma/ prostate cancer Id vs in Pediatric cancers Stage IV Melanoma: in + IL-2 prostate cancer: Id + aldara Stage III melanoma Temodal Transfection of mdc Irradiation and intratumoral idc NHL Glioblastoma Amplified neurosphere mrna + htert/survivin mrna Stage IV melanoma +Temodal +Transfection of idc +T cell expansion Prostate cancer Autologous mrna +htert/survivin mrna Amplified ovarian cancer stem cell mrna htert/survivin Acute myeloid leukaemia/ Glioblastoma Fast DC Munich collaboration Autologous mrna and /or htert/survivin mrna Department of Cellular Therapy

3 Main conclusions in early studies: RNA/DC-vaccine production is feasible RNA/DC-vaccine is well tolerated Immune responses in ~50% of patients Immune responses observed after 3 6 months Intradermal injection intranodal injection Department of Cellular Therapy

4 Antigen-tailored dendritic cell (DC) vaccines: optimal delivery of 3 signals for T cell activation CCR7 Signal 1 MHC-Peptid TCR Zytokine Signal 2 Costimulation CD28 B7- Family (CD80, CD86); CD40 CD40L IL-12 IL-4 IL-10 Signal 3 Th1: IL-2, IFN,TNF Th2: IL-4,IL-5, IL-13

5 Production of mrna loaded autologous dendritic cells Leukapheresis PBMC Elutriation Monocytes fresh or frozen Gas-Permeable Teflon Bags Differentiation Day 0 GM-CSF IL-4 Maturation Day 2-3 GM-CSF IL-4 IL-1β TNFα IFNγ PGE 2 R hours Electroporation Mature DCs mrna: 2-3 antigens Recovery Freezing DC-vaccine A. Zobywalski GMP production and analysis in the cleanroom facility of the Department of Cellular Therapy at the Oslo University Hospital

6 Patient CU020: Phenotype mdcs mdcs htert mdcs survivin CD 274 CD 14 CD 80 CD 83 CD 86 CCR 7 HLA-DR CD 40 Monocytes Immature Dendritic Cells Mature Dendritic Cells

7 Functionality Signal 3: Culture medium with DCs Layer with CD40L- Mouse Fibroblasts or soluble CD40L in culture medium 786pg IL-12p70 IL HD CU012 CU020 CU024 CU028 CU031 CU040 Controls

8 Study flow chart mdct Further therapy depending on clinical/immunological response CT CT CT Week Vaccines 4 vaccines DTH Booster vaccines every 4th week Frequent blood sampling for immune response assessment

9 Treatment of a patient with NSCLC with mrna htert transfected DCs 61 year old patient, Radiosurgery of the 2 brain metastases with Cyberknife Cycles 4+5 chemotherapy Cisplatin/Gemcitabine Obstruction of bronchus Irradiation of primary tumor (60Gy) Cortisone therapy New brain metastasis Radio surgery with Cyberknife Cyberknife treatment of a lung metastasis in 2014 and a brain metastasis in 2015 Cycles 1-3 chemotherapy Cisplatin/Pemetrexed DC-vaccination /2011 Diagnosis Non small cell lung cancer Tumor stage IV T2N2M1 b (lung and brain) Stable Disease Stable Disease

10 AML patients not eligible for BM transplantation treated with mrna WT-1 and PRAME transfected DCs Age at diagnosis Gender Time of diagnosis Start DC vaccination WT-1 in BM at time of diagnosis Status ObservationtTime since start of vaccination (months) Observation time total (months) CU f 09/ / CR CU m 08/ / Relapse 08/ Allotransplantation 09/2015 CU f 05/ / CR CU f 07/ / CR 5 14 CU f 10/ / CR started 9/

11 Events CU year old patient, AML diagnosed in 9/2013 Not eligible for BM transplantation due to severe side effects to chemotherapy Start of vaccination with DCs loaded with WT-1 and PRAME mrna at the beginning of May WT-1 Start of vaccination BM CD8 WT-1 CD8 PRAME CU030 CD8 CD8 htert CD8 survivin Baseline w5 w9 w13 w45 w53 w61 w69

12 Events CU year old patient, male AML diagnosed in 8/2013 Not eligible for BM transplantation Start of vaccination with DCs loaded with WT-1 and PRAME mrna at the end of August 2014 WT-1 CU031 CD Start of vaccination BM WT-1 PRAME Baseline w5 w13 w18 w22 w29 w33 w37 w41

13 Vaccination with TC mrna transfected DCs in Glioblastomas DC-GSC (7 pat): median PFS = 534 days Standard 11 pat): median PFS = 223 days Vik-Mo et al Radio/C Surgery hemo Leukapheresis DC vaccination Department of Cellular Therapy

14 Glioblastoma patients treated with DCs loaded with autologous tumor mrna and mrna htert and survivin Age at diagnosis Gender OP Vaccine 1 Last Boost Status Observation Time from surgery OS CU f May-13 Jul-13 Apr-15 alive 840 days ongoing CU027* 64 f Sep-13 Dec-13 Aug-15 Pseudorelapse, OP 09/ days ongoing CU028* 69 m Sep-13 Jan-14 Jan-14 Pseudorelapse 04/2014 and 08/2014, 2x OP CU m Jan-13 Jan-14 Jun-14 Decision to stop DC vaccination by patient CU m Oct-14 Feb-15 Jul-15 Progression/pseudorelapse (?) in 07/2015, chemo- and cortisone therapy CU m Nov-14 Jan-15 Aug-15 Pseudorelapse 06/2015, cortisone therapy 570 days 570 days 330 days 330 days 330 days ongoing 300 days ongoing No autologous tumor RNA was available

15 Main conclusions from these productions and patients RNA/DC-vaccine production with our new generation DCs is feasible for patients with different types of cancer RNA/DC-vaccine of our new generation DCs is well tolerated DTH responses appear earlier and are more prominent than observed with the standard DCprotocol, indicating specific immune responses Specific CD8 responses could be detected Phase I/II study to treat AML patients has just started in Oslo Randomized studyto treat Glioblastoma patients in preparation Department of Cellular Therapy

16 RESEARCH GROUPS Dept. of Cellular Therapy DC-Projects Gunnar Kvalheim Iris Bigalke Kirsti Hønnåshagen Marianne Lundby Guri Solum Lisbeth Skoge Grete Andreassen Dagny Merete S. Knudtzon Lene Mowinckel Jens Andreas L. Jørgensen Lena Tjeldhorn Else Marit Inderberg Suso Stein Sæbøe-Larssen Anne-Merete Tryggestad Kristina Anderson Leukapheresis-Team QC-Lab Dept. of Clinical Cancer Research Steinar Aamdal Paal Brunsvig Study coordinators/nurses Helmholtz Center Munich Dolores J. Schendel (now Medigene AG) Julitta Kasten AML-Trial Munich University Hospital Munich, Med. III Marion Subklewe AML-Trial Oslo Yngvar Fløisand Glioblastoma Trial Oslo Iver Langmoen Einar Vik-Mo Prostate-Cancer Trial Oslo Svein Dueland