1. Immune Oncology Drugs: A Wolf in Sheep’s Clothing?

2. Immune Therapy in 2016 Glass half-full:
- A subset of patients clinically respond (increasing range of histologies)
- Variety of effective approaches (CTLA-4, PD-1, PD-L1, CAR T cells)
- For patients in whom a response occurs, response can be quite durable
- Notable toxicities are immune-related, but these are usually manageable and
reversible
- Encouraging early reports with combinations
Glass half-empty:
- Vast majority of patients do not response to single checkpoint mABs
- Is the survival “tail” really as high and as flat as we thought?
- Lack of clear predictive biomarker of response (including tumour PD-L1)
- Move to dual checkpoint therapy met with increased toxicity

3. SCCHN patient: Durvalumab
Ninety-six year-old female, progressed on previous cetuximab, PD-L1+, and no treatment-related toxicities reported to date. Treatment ongoing at 16 weeks; confirmed PR ongoing.

4. Dempke et al. 2015

5. Dempke et al. 2015

7. NK Cell Receptors
Handgretinger et al. 2016

8. Approval of Checkpoint mABs
Ipi adj.
Nivo 1st
Nivo
2nd
Pem-bro 1st
Pembro 2nd
Ipi mono
Nivo +Ipi
Melanoma
2011
2012
2013
2014
2015
2016
Nivo 2nd RCC
Nivo 2nd NSCLC (sq)
Pembro 2nd NSCLC
Nivo 2nd NSCLC (n-sq)
Non-Melanoma
Atezo 2nd Bladder
Nivo 4th Hodgkin

9. Activity of PD-1/PD-L1 mAB
Melanoma (17-50% of patients responding)
Lung Cancer (10-30%)
Renal Cancer (12-29%)
Bladder Cancer (15-30%)
Ovarian Cancer (6-23%)
Head-and-Neck Cancer (20-25%)
Hodgkin’s Lymphoma (65-87%)
GI Tumours, TNBC, Mesothelioma, HCC, ….
Some patients DO respond to IO drug treatment – biomarkers to identify them?

10. NSCLC: KEYNOTE-001
Many patients do NOT respond to IO drug treatment – resistance mechanisms?
Cure!

11. “Cold” and “Hot” Tumours

12. T cell immune surveillance of cancer
T cell response, Elimination, Immunoediting,
Escape
Resistance to Immune Therapy
T cell response, Host/Tumour Immune Suppression, Peripheral Tolerance
Overcome with CTLA-4 or PD-1 mAB, or both
Escape
HOT
Host/Tumour Immune Suppression, no T cell response, Immune Privilege
Overcome by vaccination AND block immune suppression
No Escape
COLD

13. “Cold” and “Hot” Tumours
Spranger et al., 2015
Responsive to immune therapy!
Resistant to immune therapy!

14. Role of β-Catenin for IO Resistance

15. β-Catenin and IO Resistance
Approximately one third of solid tumours (TCGA data) are non- T cell-inflamed.
Activation of WNT/β-catenin signalling likely contributes to the non-T cell-inflamed phenotype that occurs in many cancers.
β-Catenin as a mediator of immune-exhaustion may represent a rationale therapeutic target to overcome IO resistance (“cold“ versus “hot“ tumour).

16. Therapeutic Intervention: Opportunities
Non-Immunogenic tumours (epigenetically silenced)
- epigenetic immunotherapy (e.g., in combination with HADCs, HMAs)
Tumours with immune checkpoint related immune evasion
- co-inhibitory checkpoint inhibitors (e.g., TIM-3, LAG-3)
Non-Immunogenetic tumours
- common cytokine-receptor γ family (IL-2, IL-7, IL-15, IL-21)
- co-stimulatory checkpoint pathways (OX-40, CD137, GITR, CD40)
- cancer vaccines
- chemotherapy/radiation
- T cell therapies (e.g., CARTs)

17. TKIs plus IOs: ongoing studies

18. IO plus IO Combinations: Rationale
Makouk & Weiner 2015

19. TKIs and IOs: Toxicities
Study
Phase
Main Toxicity
Reference
Vemurafenib plus Ipilimumab I
ALAT & ASAT Grade 3 in 6/16 patients: study stopped!
Ribas et al. 2013
Dabrafenib plus Ipilimumab
(ongoing)
No grade 3/4 liver toxicity reported so far. 1 patient with severe colitis
Puzanov et al. 2014
Dabrafenib plus Trametinib plus Ipilimumab
No grade 3/4 liver toxicity reported, two cases with severe colitis/GI perforation): study stopped!
Minar et al. 2015
Nivolumab plus Erlotinib
Grade 3/4 ALAT & ASAT
in 4/21 patients
Rizvi et al. 2014
Durvalumab plus Gefitinib or Osimertinib
Grade 3/4 ALAT & ASAT and > 50% ILD reported: study stopped!
Creelan et al. 2015

20. IOs and IOs: Toxicities
Study
Phase
Main Toxicity
Reference
Ipilimumab plus IDO inhibitor
I/II
Grade 3/4 liver toxicity: study stopped
AACR Abstract 2016
Atezolizumab plus MOXR0916 I
MTD not reached, no significant AEs reported
ASCO Abstract 2016
Ipilimumab plus Nivolumab versus Ipilimumab
III
55% grade 3/4 AEs for the combination;
27.3% grade 3/4 AEs for Ipi mono
Larkin et al. 2015
Nivolumab plus LAG-3 inhibitor
Ongoing (no results yet)
BMS, personal communication
Pembrolizumab plus Utomilumab (4-1BB agonist)

21. Executive Summary Many “breakthrough” immune therapies
Field is incredibly competitive
New targets – new modalities
Resistance mechanisms far from being clear
Combinations may improve efficacy
Most critical issue: Toxicity!
Are combinations financially toxic as well?

22. IOs: A Wolf in Sheep’s Clothing….
Some beautiful successes, even with cure in 10-20% of patients!
Significant and increased toxicities for combinations (-> some studies stopped!)

23. The “Glass-is-Full“ perspective“!