Dendritic cell-based cancer immune therapy

Transcription

1 Dendritic cell-based cancer immune therapy Danger signals in cancer immune therapy with dendritic cells: experience and first trends from a randomized clinical trial ISCT 2014,

2 DC-CIT basic principle Manufacturing/in vitro Treatment/in vivo Tumour tissue Antigen extraction LPS/IFN-g maturation Intranodal inoculation Monocyte collection Differentiation into DC Charging DC with antigen Antigen presentation to CTL ISCT

3 Unique characteristics of AV0113 Priming tumour cell-specific cytotoxic immune responses Intranodal inoculation for optimal antigen presentation In principle applicable to any neoplastic disease ISCT

4 Unique characteristics of AV0113 Priming tumour cell-specific cytotoxic immune responses Intranodal inoculation for optimal antigen presentation In principle applicable to any neoplastic disease ISCT

5 Dendritic cell subsets Heath (Nat Immunol, 2009) Haematopoietic stem cell Monocyte Monocyte DC Plasmocytoid DC CD8 + CD4 + DN CD11b + classical dermal CD103 + langerin dermal Inflammatory Spleen Migratory Lymph nodes Langerhans cell ISCT 2014

6 Dendritic cell mode of action ISCT

7 Pre-clinical proof of concept KG Hüttner (Cancer Imm Immunother, 2005), T Felzmann (Cancer Imm Immunother, 2005) In vivo In vitro ISCT

8 Unique characteristics of AV0113 Priming tumour cell-specific cytotoxic immune responses Intranodal inoculation for optimal antigen presentation In principle applicable to any neoplastic disease ISCT

9 Migratory deficit of DC S Ul-Haq, D Wimmer, D Wall (PeterMac, Melbourne, AUS) 2 hours 18 hours 53 hours 75 hours ISCT

10 Intra-nodal application route J Buchroithner (Wagner-Jauregg Hospital, Linz, Austria) Before After ISCT

11 Unique characteristics of AV0113 Priming tumour cell-specific cytotoxic immune responses Intranodal inoculation for optimal antigen presentation In principle applicable to any neoplastic disease ISCT

12 Status of clinical development W Holter, V Witt (St. Anna, Vienna, A), F Wimpissinger (KAR, Vienna, A), P Funovics, MB Fischer (MUW, Vienna, A) The Austrian GBM-Vax consortium (Linz, Wien, Innsbruck, Graz, Feldkirch, Salzburg) Cancer Study type Patients Objectives Sarcoma Safety & feasibility 20 6/20 patients alive >10 years Kidney Safety & feasibility 13 Extended survival in 4 patients Prostate Safety & feasibility 10 Artificial antigen Brain Efficacy 78 Randomised efficacy study Providing evidence for potential universal applicability ISCT

13 Status of clinical development W Holter, V Witt (St. Anna, Vienna, A), F Wimpissinger (KAR, Vienna, A), P Funovics, MB Fischer (MUW, Vienna, A) The Austrian GBM-Vax consortium (Linz, Wien, Innsbruck, Graz, Feldkirch, Salzburg) Cancer Study type Patients Objectives Sarcoma Safety & feasibility 20 6/20 patients alive >10 years Kidney Safety & feasibility 13 Extended survival in 4 patients Prostate Safety & feasibility 10 Artificial antigen Brain Efficacy 78 Randomised efficacy study Providing evidence for potential universal applicability ISCT

14 Paediatric & young adult sarcoma, April/13 L Kager, V Witt, W Holter (St. Anna Children s Hospital, Vienna, A), P Funovics (Medical University Wien, Department of Orthopaedics) Patient Diagnosis Age Administration Outcome, April 2013 (months) TM002 Osteosarcoma 21 s.c. Lost for follow-up BG004 Osteosarcoma 17 s.c. 2,6 AE005 Osteosarcoma 8 s.c. 163,8 (Alive) SiH007 Ewing sarcoma 22 s.c. 151,6 (Alive) NH016 Ewing sarcoma 13 s.c. 138,1 (Alive) TP017 Ewing sarcoma 22 i.n. 26,5 MK019 Osteosarcoma 10 s.c. Lost LS020 Osteosarcoma 13 s.c. + i.n. 136,9 (Alive) AI031 Desmoplastic small-cell 14 i.n. 17,0 sarcoma CV033 Fibrosarcoma 12 i.n. 127,8 (Alive) DB042 Osteosarcoma 13 i.n. 14,1 DH044 Osteosarcoma 16 i.n. 80,7 RI057 Ewing sarcoma 15 i.n. 31,8 TK076 Osteosarcoma 15 i.n. 21,3 TL078 Epitheloid sarcoma 35 i.n. 103,6 (Alive) MK092 Chondrosarcoma 34 i.n. 5,6 MA119 Osteosarcoma 15 i.n. 17,7 MS129 Osteosarcoma 19 i.n. 8,9 TA143 Myxofibrosarcoma 27 i.n. Lost for follow-up SG155 Synovialsarcoma 32 i.n. 1,6 ISCT

15 Status of clinical development W Holter, V Witt (St. Anna, Vienna, A), F Wimpissinger (KAR, Vienna, A), P Funovics, MB Fischer (MUW, Vienna, A) The Austrian GBM-Vax consortium (Linz, Wien, Innsbruck, Graz, Feldkirch, Salzburg) Cancer Study type Patients Objectives Sarcoma Safety & feasibility 20 6/20 patients alive >10 years Kidney Safety & feasibility 13 Extended survival in 4 patients Prostate Safety & feasibility 10 Artificial antigen Brain Efficacy 78 Randomised efficacy study Providing evidence for potential universal applicability ISCT

16 Glioblastoma multiforme GBM The most severe form of brain cancer Frequency About 50 thousand cases annually Age At any age from childhood to elderly; 2/3 of patients younger than 70 years Treatment Surgery, irradiation, chemotherapy with Temozolomide (Temodal ) Prognosis Average 7-8 months until relapse (PFS), months until death (OS) Second line Bevacizumab (Avastin ), palliative surgery Conclusion Patients need access to novel treatment paradigms like DC cancer vaccine Meeting an unmet medical need! ISCT

17 The Austrian GBM-Vax consortium Wagner-Jauregg Blood Bank Red Cross Linz MedUni Wien KFJ/KAR Donauspital Blood Bank MedUni LKH Feldkirch MedUni Innsbruck Blood Bank MedUni Salzburg Landesklinikum Blood Bank SALK MedUni Graz Blood Bank MedUni ISCT

18 GBM-Vax treatment schedule ISCT

19 Objectives Primary objective Secondary objectives To evaluate efficacy of the dendritic cell cancer immune therapy AV0113 in patients with GBM after at least 70% surgical resection who are treated with standard chemo-therapy with radiotherapy and Temozolomide that is switched to Bevacizumab upon disease recurrence. Progression free survival measured as percentage of non-progressive patients at 12 months post initiation of treatment. Progression free survival measured as percentage of non-progressive patients at 18 and 24 months post initiation of treatment. Overall survival at 12, 18 and 24 months post initiation of treatment. Quality of life using ECOG (Eastern Cooperative Oncology Group) performance status (for study patients years). ISCT

20 PFS is a poor surrogate parameter in CIT PW Kantoff (NEJM, 2010), PW Kantoff (JCO, 2010), JH Sampson (JCO, 2010), FS Hodi (NEJM, 2010) DC PSA/GM-CSF (Prostate) Peptide EGFRvIII (Brain) Poxvirus PSA (Prostate) Ipilimumab (Melanoma) Dendreon Celldex Bavaria Nordic BMS Treat Control Treat Control Treat Control Treat Control Patient number Historic Overall survival n.a PFS n.a Primary objective OS PFS PFS OS Secondary objective PFS OS OS PFS A paradigm shift in the treatment of neoplastic diseases. ISCT

21 Inclusion/exclusion criteria Inclusion criteria Exclusion criteria Female & male, years, qualifying for standard treatment. Glioblastoma Multiforme WHO stages IV-VI, proven by histology. At least 70% reduction of tumour mass defined by MRI. Supra-tentorial tumours. At least ECOG 3. At least 12 weeks by assessment of the attending physician. No written informed consent. Insufficient amount of tumour tissue Anti-neoplastic chemo- or radiotherapy within 4 weeks prior to study. Pregnancy or lactation, unable or unwilling to perform safe birth control. ISCT

22 Number of patients 56 planned Original study design 76 amended For recruiting 56 evaluable patients 105 total recruitment 18 not randomised Withdrawing consent, GBM not confirmed, etc 78 randomised 9 safety & feasibility 36 treatment 42 control 2 paediatric 7 elderly ISCT 2014

23 GBM-Vax 12 months survival trend, January 2014 The Austrian GBM-Vax trial consortium (Linz, Wien, Innsbruck, Graz, Feldkirch, Salzburg) Percentage surviving patients & AV0113 7/25 (28%) Control 13/30 (43%) & AV0113 3/19 16% deaths Control 9/20 45% deaths All patients Only patients receiving 2 nd line Bevacizumab Days ISCT 2014

24 PFS, May 2013 The Austrian GBM-Vax trial consortium (Linz, Wien, Innsbruck, Graz, Feldkirch, Salzburg) ISCT 2014

25 Pseudo-progression hypothesis ISCT 2014

26 AV0113 regulatory status Granted Q4/2012 Q2/2013 Q4/2013 Q1/2014 Q1/2014 Planned Q3/2014 EMA orphan drug designation FDA orphan drug designation Austria compassionate use programme FDA pre-ind meeting & IND EMA pre-submission meeting scientific advice & protocol assistance EMA & FDA (conditional) marketing authorisation ISCT

27 Take home message Surgery Radiotherapy Chemotherapy Immune therapy Cancer immune therapy is here to stay! ISCT

28 Thank you for taking the time!