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Keynote Lecture: Immunotherapy in GU cancer:
where are we, and where are we going?
Camillo Porta S.C. di Oncologia Medica
Università degli Studi di Pavia & I.R.C.C.S. Fondazione Policlinico
San Matteo di Pavia
Keynote Lecture:Immunotherapy in GU cancer:
where are we, andwhere are we going?
Camillo PortaS.C. di Oncologia Medica
Università degli Studi di Pavia &I.R.C.C.S. Fondazione Policlinico
San Matteo di Pavia
Immu n ot h er apy i n t h e Cl i n i ca l
Set t i n g: Wh at i s Th i s?
BCG
Thymic extracts and/or hormones
Drugs endowed also with immunomodulatory properties,
e.g., Levamisole, Cimetidine, etc…
True Biological Response Modifiers, i.e., cytokines such as
Interferons, Interleukins, etc…
Complex procedures such as Mini-Allo Transplantation,
antitumor Vaccination, etc…
Monoclonal Abs, e.g., anti-CD20, anti-Her2neu, ...
The next thing ...
1
2
3
4
5
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7
From 2000 to date, I-O has evolved …
What remained:
Antitumor vaccines
Monoclonal antibodies
The new BIG thing:
Immune checkpoint inhibitors
However, vaccines in mRCC failed …
1. Rini BI, et al. Lancet Oncol 2016;17:1599-1611.
And all failed, indeed ….
http://files.shareholder.com/downloads/AMDA-TSH5S/6059512445x0x929144/05D33EFC-D368-4DBD-9F37-BEF386BA6D9D/ARGS_News_2017_2_22_General_Releases.pdf
… despite all the attempts to demonstrate the contrary
Figlin R, et al. ESMO 2017.
Why vaccines against established tumors did not work?
1. Van der Burg SH, et al. Nat Rev Cancer 2016;16:219-33.
Vaccine require co-treatment for T cells to withstand immune-suppressive microenvironment
Microenvironment: a double-faced Janus
1. Noonan DM, et al. Cancer Metastasis Rev 2008;27:31-40.
We are missing the role of a number of cells …
E.g., macrophages …
Antitumor response, inflammation (‘hot’ tumors)
Tumor-promoting activity; anti-inflammtory response (‘cold’ tumors)
Chen Y, Zhang X. Exp Hematol Oncol 2017;6:23.
… or eosinophils
1. Moroni M, et al. Haematologica 2000;85:298-303; 2. Porta C, et al. Br J Hematol 1998;100:607-9; 3. Moroni M, et al. Ann NY Acad Sci 1997;832:295-303; 4. Hude I, et al. Br J Hematol 2017; Apr 25. doi: 10.1111/bjh.14705. [Epub ahead of print]; 5. Heppt MV, et al. Eur J Cancer 2017;82:56-65.
… or endothelial progenitor cells
1. De la Puente P, et al. Clin Cancer Res 2013;19:3330-8.
EPCs and tumor angiogensis: an elegant proof of concept
1. Peters B, et al. Nat Med 2005;11:261-2; 2. Lodola F et al. PLoS One 2012;7:e42541; 3. Porta C, et al. manuscript submitted.
Immune checkpoint inhibitors today: the tip of the iceberg …
No informations at all on …
… the kinetics of activation of the different stimulatory and inhibitory checkpoints
… the differential role of different anticancer agents (including VRGFR-TKIs) on the immune system (any priming effect?)
… in order to design rational trials of sequential therapies
*
* *
No informations at all on …
1. Verzoni E, et al. ESMO 2017.
What we do really badly need to have …
1. Golovastova M, et al. Curr Urol Rep 2017;18:3 DOI 10.1007/s11934-017-0655-1.
1. Iacovelli R, et al. Target Oncol 2016;11:143-8.
In mRCC, PD-L1 expression is prognostic, not predictive
1. Motzer RJ, et al New Engl J Med. 2015;373:1803-13.
Checkmate 025 confirmed this …
1. Escudier B, et al. ESMO 2017; 2. Motzer RJ, et al New Engl J Med. 2018 (Accepted).
… although Checkmate 214 didn’t
PD-L1 <1% (n = 562) PD-L1 ≥1% (n = 214)
Median PFS, months (95% CI)
NIVO + IPI 22.8 (9.4–NE)
SUN 5.9 (4.4–7.1)
Median PFS, months (95% CI)
NIVO + IPI 11.0 (8.1–14.9)
SUN 10.4 (7.5–13.8)
0 . 8
0 . 9
1 . 0
0 . 4
0 . 5
0 . 6
0 . 7
0 9 6 3 2 1 1 8 1 5 1 2 3 0 2 7 2 4
0 . 1
0 . 0
0 . 2
0 . 3
0 . 8
0 . 9
1 . 0
0 . 4
0 . 5
0 . 6
0 . 7
0 9 6 3 2 1 1 8 1 5 1 2 3 0 2 7 2 4
0 . 1
0 . 0
0 . 2
0 . 3
• PD-L1 expression can vary between different sites within the primary tumour
• There is only a weak correlation between PD-L1 expression in the primary tumour and the metastases
1. Jilaveanu LB, et al. J Cancer 2014;5:166‒172.
PD-L1 expression (red) in 4 sites within the same primary RCC tumour
Cytokeratin
Cytokeratin
Cytokeratin
DAPI
DAPI
DAPI
PD-L1
PD-L1
PD-L1
Cytokeratin DAPI PD-L1
CO
RE
1
CO
RE
2
CO
RE
3
CO
RE
4
PD-L1 expression significantly different in metastatic and primary specimens from patients
with mRCC
Metastatic Primary
10
20
30
40
50
AQ
UA
sco
res
P = 0.0017
PD-L1 expression is definitely not an ideal biomarker …
Renal cell carcinoma
Urothelial cancers
Prostate cancer
Testicular cancers
Yes No
Clinical use
Low High
Presence of potentially immunogenic antigens
The paradox of I-O in GU malignancies
If not PD-L1 or tissue antigens, what?
PDL-1 expression by tumor and/or stroma and/or infiltrating cells Amount of tumor neoantigens • mutational burden • deletions/insertions • copy number loss CD8+PD-1+ T cell infiltrate Myeloid immunosuppressive infiltrate (EMT)
Tumor microenvironment
Neoantigens and Mutational Status on circulating DNA Myeloid cell alterations Phenotypic and functional profiling of peripheral T cells Soluble factors (cytokines, chemokines soluble PD-1/PD-L1, etc …) Plasma extracellular vesicles
Blood Other
Gene signatures Gut microbiota
Modified from Rivoltini L.
Zehir A, et al. Nat Med 2017;23:703-13.
Mutational burden and neoantigens?
Immune-inflammed Frequent response
Immune-excluded possible response
Immune-desert quite rare/no response
Immune suppressive
stroma
Immune suppressive
stroma
High tumor immunogenicity
(high neoantigen load) Low immune suppression
High PD-1/PDL-1 expression
tumor immunogenicity? immune suppression?
IC expression?
Low tumor immunogenicity?
High immune suppression? Low IC expression?
1. Chen DS & Mellman I. Nature 2017; 541:321-330.
T cell infiltrate features of tumor microenvironment
Gene signatures?
1. Benci JL, et al. Cell 2016;167:1540-1554.
Microbiota?
1. Routy B, et al. Science 2018;359:91-7; 2. Derosa L, et al. Ann Oncol 2018 (submitted).
Finally, there is always the dark side of the moon …
What’s ahead of us in I-O …
