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, 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, and where are we going? Camillo Porta

From 2000 to date, I-O has evolved Immu n ot h er apy in t h e Cl inical Set t ing: What is Th is? 1 2 3 4 5 6 7 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... What remained: Antitumor vaccines Monoclonal antibodies The new BIG thing: Immune checkpoint inhibitors

1. Rini BI, et al. Lancet Oncol 2016;17:1599-1611. However, vaccines in mrcc failed

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? Vaccine require co-treatment for T cells to withstand immune-suppressive microenvironment 1. Van der Burg SH, et al. Nat Rev Cancer 2016;16:219-33.

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.

1. De la Puente P, et al. Clin Cancer Res 2013;19:3330-8. or endothelial progenitor cells

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

No informations at all on 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 * * 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.

In mrcc, PD-L1 expression is prognostic, not predictive 1. Iacovelli R, et al. Target Oncol 2016;11:143-8.

1. Motzer RJ, et al New Engl J Med. 2015;373:1803-13. Checkmate 025 confirmed this

although Checkmate 214 didn t PD-L1 <1% (n = 562) PD-L1 1% (n = 214) Median PFS, months (95% CI) Median PFS, months (95% CI) 1. 0 0. 9 NIVO + IPI 11.0 (8.1 14.9) SUN 10.4 (7.5 13.8) 1. 0 0. 9 NIVO + IPI 22.8 (9.4 NE) SUN 5.9 (4.4 7.1) 0. 8 0. 8 0. 7 0. 7 0. 6 0. 6 0. 5 0. 5 0. 4 0. 4 0. 3 0. 3 0. 2 0. 2 0. 1 0. 1 0. 0 0. 0 0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30 1. Escudier B, et al. ESMO 2017; 2. Motzer RJ, et al New Engl J Med. 2018 (Accepted).

CORE 4 CORE 3 AQUA scores CORE 2 CORE 1 PD-L1 expression is definitely not an ideal biomarker 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 Cytokeratin DAPI PD-L1 P = 0.0017 Cytokeratin DAPI PD-L1 50 40 Cytokeratin DAPI PD-L1 30 20 Cytokeratin DAPI PD-L1 10 Metastatic Primary PD-L1 expression (red) in 4 sites within the same primary RCC tumour 1. Jilaveanu LB, et al. J Cancer 2014;5:166 172. PD-L1 expression significantly different in metastatic and primary specimens from patients with mrcc

The paradox of I-O in GU malignancies Renal cell carcinoma Prostate cancer Urothelial cancers Testicular cancers Clinical use Yes No Presence of potentially immunogenic antigens Low High

If not PD-L1 or tissue antigens, what? Tumor microenvironment 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) Blood 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 Other Gene signatures Gut microbiota Modified from Rivoltini L.

Zehir A, et al. Nat Med 2017;23:703-13. Mutational burden and neoantigens?

T cell infiltrate features of tumor microenvironment 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.

1. Benci JL, et al. Cell 2016;167:1540-1554. Gene signatures?

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

Thank You for Your kind attention!!! T c.porta@smatteo.pv.it