dendritic cell-based cancer immune therapy - c.ymcdn.comc.ymcdn.com/sites/ · dendritic cell-based...

Dendritic cell-based cancer immune therapyDanger signals in cancer immune therapy with dendritic cells: experience and first trends from a randomized clinical trial

ISCT 2014, April 2014

ISCT 2014 April 2014

DC-CIT basic principle

2

Monocyte collection Differentiation into DC Charging DC with antigen Antigen presentation to CTL

Treatment/in vivoManufacturing/in vitro

Tumour tissue Antigen extraction LPS/IFN-gmaturation Intranodal inoculation


Unique characteristics of AV0113

3

Priming tumour cell-specific cytotoxic immune responses

Intranodal inoculation for optimal antigen presentation

In principle applicable to any neoplastic disease



4





Dendritic cell subsets

Haematopoietic stem cell

Monocyte

Monocyte DC Plasmocytoid DC CD8+ CD4+ DNCD11b+

classical dermalCD103+

langerin dermal Langerhans cell

Inflammatory Spleen Migratory

Lymph nodes

Heath (Nat Immunol, 2009)


Dendritic cell mode of action

6


Pre-clinical proof of concept

7

In vivo In vitro

KG Hüttner (Cancer Imm Immunother, 2005), T Felzmann (Cancer Imm Immunother, 2005)



8





Migratory deficit of DC

9

2 hours 18 hours 53 hours 75 hours

S Ul-Haq, D Wimmer, D Wall (PeterMac, Melbourne, AUS)


Intra-nodal application route

10

J Buchroithner (Wagner-Jauregg Hospital, Linz, Austria)

Before After



11





Status of clinical development

12

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

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)

Providing evidence for potential universal applicability



13









Paediatric & young adult sarcoma, April/13

14

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 sarcoma

14 i.n. 17,0

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

L Kager, V Witt, W Holter (St. Anna Children’s Hospital, Vienna, A), P Funovics (Medical University Wien, Department of Orthopaedics)



15









Glioblastoma multiforme

16

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), 14-15 months until death (OS)

Second line Bevacizumab (Avastin®), palliative surgery

Conclusion Patients need access to novel treatment paradigms like DC cancer vaccine

www.cureglioma.info

Meeting an unmet medical need!


The Austrian GBM-Vax consortium

17

MedUni WienKFJ/KARDonauspitalBlood Bank MedUni

Wagner-JaureggBlood Bank Red Cross Linz

LKHFeldkirch

MedUni GrazBlood Bank MedUni

MedUni InnsbruckBlood Bank MedUni

Salzburg Landesklinikum Blood Bank SALK


GBM-Vax treatment schedule

18


Objectives

19

Primary objective 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.

Secondary objectives

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 18-70 years).


PFS is a poor surrogate parameter in CIT

20

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 341 171 65 Historic 82 40 403 136

Overall survival 26 22 26 n.a. 25 16 10 6

PFS 3.7 3.6 14.2 n.a. 3.8 3.7 2.8 2.8

Primary objective OS PFS PFS OS

Secondary objective PFS OS OS PFS

PW Kantoff (NEJM, 2010), PW Kantoff (JCO, 2010), JH Sampson (JCO, 2010), FS Hodi (NEJM, 2010)

A paradigm shift in the treatment of neoplastic diseases.


Inclusion/exclusion criteria

21

Inclusion criteria Female & male, 18-70 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.

Exclusion criteria No written informed consent.Insufficient amount of tumour tissueAnti-neoplastic chemo- or radiotherapy within 4 weeks prior to study.Pregnancy or lactation, unable or unwilling to perform safe birth control.


36 treatment

42 control

78 randomised

105 total recruitment

56 plannedOriginal study design

Number of patients

76 amendedFor recruiting 56 “evaluable” patients

18 not randomisedWithdrawing consent, GBM not confirmed, etc

2 paediatric

7 elderly

9 safety & feasibility


GBM-Vax 12 months survival trend, January 2014The Austrian GBM-Vax trial consortium (Linz, Wien, Innsbruck, Graz, Feldkirch, Salzburg)

Only patients receiving 2nd line BevacizumabAll patients

& AV0113 Control

3/1916% deaths

9/2045% deaths

7/25(28%)

13/30(43%)

& AV0113 Control

Perc

enta

ge s

urv

ivin

g p

atie

nts

Days


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


Pseudo-progression hypothesis


AV0113 regulatory status

26

Granted Q4/2012Q2/2013Q4/2013

EMA orphan drug designationFDA orphan drug designationAustria compassionate use programme

Q1/2014Q1/2014

FDA pre-IND meeting & INDEMA pre-submission meeting scientific advice & protocol assistance

Planned Q3/2014 EMA & FDA (conditional) marketing authorisation


Take home message

27

Cancer immune therapy is here to stay!

Surgery Radiotherapy Chemotherapy Immune therapy

Thank you for taking the time!

dendritic cell-based cancer immune therapy - c.ymcdn.comc.ymcdn.com/sites/ · dendritic cell-based...

Documents