Download Evelien Smits, UZ Antwepen

BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
Hallmarks of cancer
(Hanahan and Weinberg, Cell 2000)
Basics in immunotherapy
Prof. dr. Evelien Smits
14 January 2017
[email protected]
Hanahan and Weinberg, 2000
Concept of immune evasion
Extra hallmark of cancer
(Hanahan and Weinberg, Cell 2011)
Evading destruction mediated by the immune system:
immune evasion
Finn O. J. Ann Oncol. 2012 Sep; 23(Suppl 8): viii6–viii9.
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
Concept of immune evasion
Kiss of death…
Finn O. J. Ann Oncol. 2012 Sep; 23(Suppl 8): viii6–viii9.
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Antitumor immune response
Shotton D M , and Attaran A PNAS 1998;95:15571‐15576
©1998 by National Academy of Sciences
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Degli‐Esposti and Smyth, Nat Rev Immunol 2005
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
Gastric cancer
Cancer diagnostics: Immunoscore
Mlecnik B et al, Immunity 2016
• Intratumoral infiltration of cytotoxic T cells, memory T cells,
NK cells and DC: better survival
• Abundant immune cell type: tumor-associated macrophages,
suppressing T cell responses
associated with poor prognosis
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Cancer immunotherapy
• Using the immune system to control or to eliminate cancer
• Cancer breakthrough of the year 2013
(editors of Science; Couzin-Frankel, Science 2013)
• Different ways:
1. Injection of immune effector molecules (e.g. antibodies)
2. Injection of immune effector cells
(e.g. activated T cells or natural killer cells)
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Inducing the immune response in the patient (vaccination)
Mlecnik B et al, Immunity 2016
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
Classification of immunotherapy
Main categories of GI immunotherapy
Research ongoing in Antwerp
- Immune checkpoint blockade
• Anti-CTLA-4: ipilimumab, tremelimumab
• Anti-PD-1: nivolumab, pembrolizumab
• Anti-PD-L1: durvalumab, avelumab
- Adoptive cell transfer
• T cells
• NK cells
• CIK cells: cytokine-induced killer cells, ie mixture of activated T cells/NK cells
- Vaccination
• Peptides
• Dendritic cells (DC)
• Tumor cells (autologous or allogeneic)
- Oncolytic viruses
Galluzzi et al, Oncotarget 2014 12
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‘Three signal’ theory of CD8+ T cell activation
Immune checkpoint blockers
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
Signals for T cell activation
• Signal 2
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E. Smits – Tumor Immunology
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Marcq E et al, Cancer Treatment Reviews 2015
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PD-1/PD-L1 blocking antibodies
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
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© A. Marabelle
© A. Marabelle
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Response to immune checkpoint blockade associated with:
• High mutational burden
• Presence of immunogenic neo-epitopes
• Number of tumor-infiltrating T cells
• PD-L1 expression in the tumor tissue
• MSI-status
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© A. Marabelle
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
In general – immune checkpoint blockers
• Amazing responses in several cancer types
• However:
- Many cancer types are resistant
- Significant percentage of patients do not respond
• How to overcome resistance?
© A. Marabelle
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Signals for T cell activation
• Signal 2
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Jacobs et al, J Immunol Res 2015
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
Combination strategies
Anti‐CTLA‐4 + anti‐PD‐1/PD‐L1
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Releasing two different brakes
Combining them (nivo+ipi) has priven to be more effective
than either alone in melanoma
Significant toxicity: 30% of patients has to stop treatment early
Association between treatment‐related adverse events and clinical benefit
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Combination strategies
Chemotherapy inducing immunogenic cell death + checkpoint inhibitors
Oxaliplatin, anthracyclins: chemotherapeutics causing
immunogenic tumor cell death, leading to activation of the antitumor immune response
Targeted therapy + checkpoint inhibitors
Bendell et al, ESMO 2016, Phase Ib, 23 pat. metastatic CRC
MEK inhibition (cobimetinib) + anti‐PD‐L1
4 pat. >30% tumor shrinkage; 5 pat. stable disease 30
© A. Marabelle
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BGDO Annual Meeting 2107
How to use immunotherapy & locoregional treatments?
Basics in immunotherapy –
Evelien Smits, UZ Antwepen
Challenges
Future directions in cancer immunotherapy
1. Immune-mediated toxicity
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Identification of novel targets
2. Financial toxicity
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Testing combination therapies (beyond doublet combin.)
We might not need to treat for long.
3. Overcoming resistance
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Combining different immunotherapeutic strategies
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Combining immunotherapy with other therapeutic
strategies
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Identification of predictive biomarkers
and markers to monitor treatment response
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Immune profiling, immune checkpoints and novel combination therapies
at the Center for Oncological Research, University of Antwerp
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