Immunotherapie: algemene principes

Immunotherapie: algemene principes Prof. dr. Evelien Smits Tumorimmunologie, UAntwerpen 14 Oktober 2017, IKG evelien.smits@uza.be

Concept of immune evasion Finn O. J. Ann Oncol. 2012 Sep; 23(Suppl 8): viii6 viii9. 1

Concept of immune evasion Finn O. J. Ann Oncol. 2012 Sep; 23(Suppl 8): viii6 viii9. 2

Shotton D M, and Attaran A PNAS 1998;95:15571-15576 1998 by National Academy of Sciences 3

Antitumor immune response Degli-Esposti and Smyth, Nat Rev Immunol 2005 4

Gastric cancer Intratumoral infiltration of cytotoxic T cells, memory T cells, NK cells and DC: better survival Most abundant immune cells: tumor-associated macrophages, suppressing T cell responses associated with poor prognosis 5

Cancer diagnostics: Immunoscore Mlecnik B, Immunity 2016 6

Cancer immunotherapy Using the immune system to control or to eliminate cancer Scientific 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) 3. Inducing the immune response in the patient (vaccination) 9

Classification of immunotherapy Research ongoing in Antwerp Galluzzi et al, Oncotarget 2014 10

1. Immune checkpoint blockers 2. Cell therapy 11

1. Immune checkpoint blockers 12

Three signal theory of CD8+ T cell activation 13

Signal 1 : Tumor antigens Tumor cells as transformed cells express novel proteins (e.g. AML1-ETO) or overexpress normal proteins (e.g. WT1) So called tumor antigens Best antigens to be targeted in cancer vaccination strategies: Highly expressed by all tumor cells in all cancer patients with no expression on normal cells 14

Signals for T cell activation Signal 2 15

E. Smits Tumor Immunology 16

Ipilimumab Approved in March 2011 by the US Food and Drug Administration for melanoma; in Nov 2012 in EU for second line treatment of metastatic melanoma Significant survival advantage Immunological adverse effects due to immune activation 17

PD-1/PD-L1 blocking antibodies 18

Marcq E et al, Cancer Treatment Reviews 2015 19

PD-1 / PD-L1 BLOCKING ANTIBODIES Drug of the year 2013 (Robert et al, Eur J Immun 2013) Less grade 3-4 toxicity than ipilimumab Nivolumab - Opdivo (PD-1 blocking Ab): approved by FDA for melanoma, lung cancer, renal carcinoma, bladder cancer, Hodgkin lymphoma, head and neck cancer, hepatocellular carcinoma Pembrolizumab - Keytruda (PD-1 blocking antibody): approved by FDA for advanced melanoma, lung cancer, Hodgkin lymphoma, head and neck cancer, tumors with DNA mismatch repair deficiencies, gastric cancer 20

PD-1 / PD-L1 BLOCKING ANTIBODIES Atezolizumab - Tecentriq (PD-L1 blocking Ab): bladder cancer, lung cancer Durvalumab - Imfinzi (PD-L1 blocking Ab): bladder cancer Avelumab Bavencio (PD-L1 blocking Ab): Merkel cell carcinoma, bladder cancer 21

22 Adapted from A. Marabelle

EMA-approved 23

A. Marabelle 24

A. Marabelle 25

Predictive value of infiltrating lymphocytes Hegde et al, Clin Cancer Res 2016 26

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? - New targets - Combination strategies 27

New targets 28

Marcq E, et al. Targeting immune checkpoints: new treatment option in mesothelioma? Cancer Treat Rev 2015, 41(10): 914-924. Marcq E, et al. Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma. Oncoimmunology 2017, 6(1): e1261241. Marcq E, et al. Abundant expression of TIM- 3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients. Oncotarget 2017, Epub. Elly Marcq Marcq E et al, Cancer Treatment Reviews 2015 29

Jacobs J, et al. CD70: an emerging target in cancer immunotherapy. Pharmacol Ther, 2015; 155: 1-10. Jacobs J, et al. Immune checkpoint modulation in colorectal cancer: What s new and what to expect. J Immunol Res 2015; 2015: 158038. Jacobs J, et al. Unlocking the potential of CD70 as an interesting immunotherapeutic target for non-small cell lung cancer. Oncotarget 2015; 6(15): 13462-13475. Jacobs J, et al. Preclinical data on the combination of cisplatin and anti- CD70 therapy in non-small cell lung cancer as an excellent match in the era of combination therapy. Oncotarget 2017, Epub. Julie Jacobs 30

Julie Jacobs Jacobs et al, J Immunol Res 2015 31

Combination strategies Anti-CTLA-4 + anti-pd-1/pd-l1 - 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 32

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 34

Challenges 1. Immune-mediated toxicity 2. Financial toxicity We might not need to treat for long. 3. Overcoming resistance: new targets and combinations 4. Search for predictive biomarkers and markers to monitor treatment response 36

2. Cell therapy 37

Antitumor immune response Degli-Esposti and Smyth, Nat Rev Immunol 2005 38

Dendritic cell vaccine against cancer Cancer cell Non-active killer cell Active killer cell Cancer cell license to kill vaccine ATTACK Cell death Transfer of cancer marker through gene transfer Dead cancer cell Dendritic cell 39

Vaccine preparation Apheresis WHITE BLOOD CELLS CliniMACS CD14+ cells Intradermal injection WT1 mrna Electroporation MONOCYTES In vitro culture 6 days GM-CSF + IL-4 + 2 days TNF- /PGE2/KLH MATURE DENDRITIC CELLS Smits et al, Methods Mol Biol 2016 40

Clinical experience 2 decades of worldwide clinical experience with dendritic cell vaccines Safety profile: - Common: local reactions at injection site - Extremely uncommon: systemic grade 3-4 toxicity and immunerelated adverse events 41

Anguille et al., Lancet Oncology 2014 Clinical efficacy of DC cancer therapies Clinical benefit in terms of objective clinical responses is real, but limited Where overall survival has been monitored, there is clear evidence that DC immunotherapy can have clinical benefit 42

Center for Cell Therapy and Regenerative Medicine Antwerp University Hospital 43

Immune profiling, immune checkpoints and novel combination therapies at the Center for Oncological Research, University of Antwerp 44

Sponsoring 45