1 Adoptive T-cell therapy Translation of clinical efficacy in melanoma to pancreatic cancer Rienk Offringa K.H. Bauer foundation endowed professor Div. Molecular Oncology of Gastrointestinal Tumors, DKFZ Div. Pancreas Cancer Research, Uniklinikum Heidelberg
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Adoptive T-cell therapy - NCT · Adoptive T-cell therapy ... Matthias Schlesner ... Niels Halama Dirk Jäger Jessica Hassel Alexander Enk BioNTech Ugur Sahin Marta Faryna Martin Loewer
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1
Adoptive T-cell therapy
Translation of clinical efficacy in melanoma
to pancreatic cancer
Rienk Offringa
K.H. Bauer foundation endowed professor
Div. Molecular Oncology of Gastrointestinal Tumors, DKFZ
Div. Pancreas Cancer Research, Uniklinikum Heidelberg
2
‘Tumor-observing’ T-cell response in human
melanoma
T-cell
OFF ON
Dominance of
inhibitory signals
Tumor Infiltrating Lymphocytes (TILs)
3
Mobilization anti-tumor T-cell response
Go!
T-cell
OFF ON
Tumor Infiltrating Lymphocytes (TILs) Block
inhibitory signals
Cancer vaccines
Pre-requisites:
• Time (> 3 months)
• Immune system in good shape
• 1st (2nd?) line treatment
4 Adoptive T-cell therapy for
advanced, metastatic melanoma
ex vivo expansion
re-infusion tumor biopsy
TIL
TIL
Dudley/Rosenberg
OR rate: ~50%
Durable CR: ~20%
Advanced melanoma
> 300 patients
Also in European centers (but not yet in Germany)
TIL isolation
TIL = tumor-infiltrating lymphocyte
5
Proof of concept for TIL therapy in Heidelberg
ex vivo expansion
re-infusion tumor biopsy
TIL
TIL
TIL isolation
TIL = tumor-infiltrating lymphocyte
Clinical trial
• Metastatic melanoma (n=8)
• Progression after initial response to
checkpoint inhibitors (CTLA-4; PD-1)
• TIL-infusion & PD-1 blockade
Primary endpoint:
• Clinical response (RECIST)
Secondary endpoints:
• Toxicity
• Longevity TIL response (TCR deep seq.)
• Molec. tumor imaging
Further biomarkers:
• Antigen-specificity TIL response
• Tumor-antigen expression
A. Enk, D. Jäger, R. Offringa
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Proof of concept for TIL therapy in Heidelberg
ex vivo expansion
re-infusion tumor biopsy
TIL
TIL
TIL isolation
TIL = tumor-infiltrating lymphocyte
Objectives:
• Offer TIL therapy to melanoma patients
in Heidelberg/Germany
• Combine with other approaches
(checkpoint blockade, vaccines, other)
• Prelude to studies with engineered T-
cells (TCR, CAR)
• Prelude to T-cell therapy in other
cancers
7
4 4
UK: 5th
USA: 4th
Pancreatic cancer-related death: 4th
(Germany 2012)
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GER
UK
USA
Incidence*
11.5
9.6
10.9
Death*
11.1
9.0
10.9
Lifetime risk
~ 1.4%
* yearly cases/100.000
Pancreatic cancer
Incidence and death rates almost equal
9
Trends in 5-year survival rates (U.K.)
GER: 7%
USA: 6% age-standardized rates
Overall survival rates barely improved in 40 years (unmet medical need)
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Pancreas cancer management to date
• Surgery only effective treatment option
• Fraction of eligible patients: 20-30%
• Devastating recurrence rate
• Chemotherapy: adjuvant treatment & palliative care
Markus Büchler
Oettle JAMA 2007 70% recurrence
in 2 years!
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T-cell therapy for countering recurrence
Oettle JAMA 2007 70% recurrence
in 2 years!
Isolate TILs from operated patients freeze
2. TIL therapy as adjuvant treatment
(4 wks needed for preparing TILs)
1. TIL therapy at tumor recurrence
(palliative setting)
12 Pancreatic cancer has been branded
poorly immunogenic
• Highly malignant
• No spontaneous regressions
• Very few T-cells
• T-cells cannot be isolated and cultured
Don Quichote Is immunotherapy of pancreatic cancer überhaupt a valid concept?
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T-cell infiltrate found in majority of PDA samples
450 CD3+/mm2
280 CD3+/mm2
48 CD3+/mm2
Low (<100) Medium (100-300) High (>300)
~20% ~ 20% ~ 60%
CD3+ T-cells
14 Ex vivo expansion of Tumor-Infiltrating Lymphocytes
the melanoma TIL protocol
tumor
activated T cells
cluster of
proliferating T cells
Minced tumor bits
in 24 well format
with high-dose IL-2
Rapid expansion on
allogeneic feeders,
anti-CD3 and IL-2
Large number of
activated T cells
2 w
eek
s
2 w
eek
s
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A lot of experiments
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Mel008 TOP50 tumor
blood tumor tumor unique0
1
2
3
4
10
20
rela
tive
fre
qu
en
cy (b
eta
-se
q)
36/50
blood tumor tumor unique0.0
0.2
0.4
0.6
0.8
1.01.01.52.02.53.0
Tumor
enriched
Tumor
unique
Tumor
enriched
Tumor
unique
Pancreatic cancer Melanoma
Poschke, Hassel, Volkmar, Sahin & Offringa
TC
R-b
eta
re
lative
fre
que
ncy (
%)
TCR-seq: evidence for tumor-reactive TIL clones
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IHC: Tertiary Lymphoid Structures (TLS)
CD3 CD20
CD208 (DC-Lamp+ DC) CD21 (follicular DC)
• TLS in approx. 50% of PDA biopsies
• Definition: B and T cell areas with
appropriate DC subsets; HEV
• Associated with good prognosis in
lung, breast and colorectal cancer
Poschke, Halama, Bergmann & Offringa
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All TCR+ T-cells (CD3)
V-beta 2+ T-cells
Poschke, Halama, Bergmann & Offringa
Tertiary
Lymphoid
Structures
Evidence for clonal expansion in TLS
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Planning 2015-2016
Perform TIL study in melanoma
• GMP test runs
• Trial
Pre-clinical proof of concept for tumor-reactivity TILs in pancreatic cancer