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Immmunotherapy
Latest immune therapy approaches:
BITE, CAR-T and checkpoint inhibitors
PD Dr. med. Ulf Petrausch
Medizinische Onkologie, FMH
Klinische Immunologie & Allergologie, FMH
Allgemeine Innere Medizin, FMH
T-cell-Receptors
1.000.000.000.000.000 (1015)
Nature Reviews Immunology 4, 123-132 (February 2004)
Stars in our galaxy
100.000.000.000 (1011)
Tolerance
1015
2.5x107
Elimination of
self-reactive T cells
Nikolich-Zugich et al., Nature Reviews Immunology 4, 123-132 (February 2004)
The use of T cells to fight cancer
Schreiber et al., Science. 2011 Mar 25;331(6024):1565-70.
NO T cells to fight cancer
>50%
Schreiber et al., Science. 2011 Mar 25;331(6024):1565-70.
T cells No T cellsImmunomodulation:
- Checkpoint-Inhibitors
- IDO Inhibitors
- Agonistic antibodies
- TIL transfer
- Cytokines
T cell generation/recruitment
- BITE
- Genetically modified T cells
- Oncolytic viruses
T cells No T cellsImmunomodulation:
- Checkpoint-Inhibitors
- IDO Inhibitors
- Agonistic antibodies
- TIL transfer
- Cytokines
T cell generation/recruitment
- BITE
- Genetically modified T cells
- Oncolytic viruses
Nivolumab6
History of Checkpoint Inhibitors: Key Milestones
Melanoma
NSCLC
RCC
APPROVALS BY CANCER TYPE
Bladder cancer
R/M SCCHN
Classical Hodgkin’s lymphoma
2011 2014 20152013 20162012
Pembrolizumab (PD-L1+)1
Ipilimumab2
Pembrolizumab1
Nivolumab1
Nivolumab3
Nivolumab4
Pembrolizumab2
Nivolumab + ipilimumab1
Nivolumab1
Nivolumab + ipilimumab2
Nivolumab2
Nivolumab (SQ)1
First checkpoint inhibitor (ipilimumab)1
Nivolumab (NSQ)1
Nivolumab (NSQ)2
Pembrolizumab (PD-L1+)2,5
Pembrolizumab1Atezolizumab1
Nivolumab1
Nivolumab (SQ)2
1. U.S. Food and Drug Administration. http://www.fda.gov. Accessed July 9, 2016. 2. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/003820/WC500209310.pdf. Accessed July 9, 2016. 3. Human anti-human pd-1 monoclonal antibody "OPDIVO®
intravenous infusion 20 mg/100/mg" receives manufacturing and marketing approval in Japan for the treatment of unresectable melanoma. [press release] public [email protected]; July 4, 2014. 4. ONO Pharmaceutical Co., LTD. [press release]. March 23, 2015. 5. Merck [press release]. June 27, 2016. http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda-pembrolizumab-approved-european-commission-patients-a. Accessed August 8, 2016. 6. ONO Pharmaceutical Co., LTD. [press release]. December 17, 2015.
9
Melanoma: THE example
10
N Engl J Med 2017; 377:1345-1356 N Engl J Med 2010; 363:711-723
Melanoma
11Schadendorf et al, annual presentation at ECCO/ESMO 2013, abstract # 24LBA
• Langzeitdaten Ipilimumab von 1.861 Melanompatienten
(8 Ph. II-, 2 Ph. III-, 2 Ph. IV-Studien)
Patienten unter Progressionsrisiko
Ipilimumab 1.861 839 370 254 192 170 120 26 15 5 0
Wahrs
ch
ein
lichkeit G
esa
mtü
berle
ben
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Monate
0 12 24 36 48 60 72 84 96 108 120
Medianes OS, Monate (95% KI): 11,4 (10,7–12,1)
3-Jahres OS-Rate, % (95% KI): 22 (20–24)
Ipilimumab
Zensiert
Lung Cancer: THE most frequent one
Lung Cancer
Liver Cancer: The Challenge for the Future
14
Hepatitis B:
•WHO Western Pacific Region: 6.2% of population (115 million people)
•WHO African Region: 6.1% of population (60 million people)
•WHO Eastern Mediterranean Region: 3.3% of population (21 million people)
•WHO South-East Asia Region: 2% of population (39 million people)
•WHO European Region: 1.6% of population (15 million people)
•WHO Region of the Americas: 0.7% of population (7 million people)
Hepatitis C:
•WHO Eastern Mediterranean Region: 2.3% of population (15 million people)
•WHO European Region: 1.5% of population (14 million people)
•WHO African Region: 1% of population (11 million people)
•WHO Region of the Americas: 1% of population (7 million people)
•WHO Western Pacific Region: 1% of population (14 million people)
•WHO South-East Asia Region: 0.5% of population (10 million people)
Liver Cancer
15
Liver Cancer
Liver Cancer
Liver Cancer
Liver Cancer
Local strategies to engage the immune system
Liver Cancer
T cells No T cellsImmunomodulation:
- Checkpoint-Inhibitors
- IDO Inhibitors
- Agonistic antibodies
- TIL transfer
- Cytokines
T cell generation/recruitment
- BITE
- Genetically modified T cells
- Oncolytic viruses
1.000.000.000.000.000
25.000.000+1
Adoptive T-cell transfer
modifiziert von Jacobson and Ritz J, Blood 2011
1.000.000.000.000.000
+anti-CD19
CD19 positive ALL
CD19-specific T cells
Grupp et al., N Engl J Med 2013; 368:1509-1518
Leukemia: CD19-specific T cells
Klinische Anwendungen:
Lymphoma
Lymphoma
BITE (Blinatumomab)
ALL & Lymphoma
Summary
• Checkpoint-Inhibitors are immune-modulators: pre-existing anti-tumor T
cells are necessary
• The immune system as therapeutic partner opens new ways to fight
cancer
• Checkpoint-Inhibitors become (are) mainstays of therapeutic
approaches
• Checkpoint-Inhibitors so far have not lead to cure!
• Checkpoint-Inhibitors will be integrated into combination therapies
• Large proportion of patients have no immune system capable to
recognize and destroy cancer
• CAR T cells are one option:
• CAR T anti-CD19 low-hanging fruit, since we can life without B cells
• CAR T anti-other surface proteins: dangerous! Will take long time to
develop
• CAR T in ALL bridge to allo-transplant
• BITE another option
Swiss Tumor Immunology Institute
• Network for physicians and
patients
• Focus on the use of
immunotherapy and its
challenges
• Registry for quality control
• Supported by industry and
private donations
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