1. Immuno-Oncology Drugs: A Land of Opportunity?
Wolfram C. M . Dempke, MD, PhD, MBA
Professor of Haematology & Oncology
SaWo Oncology Ltd
Cambridge, April 2017

2. Immune Therapy in 2017
Only 10-15% of patients achieve durable clinical responses.
However, responses are seen across various histologies.
Cell evading immune surveillance is far from being clear, but several IO resistance mechanisms have been identified so far.
Many encouraging results with combinations (e.g., > 800 clinical trials for PD-1/PD-L1 combinations ongoing), however, toxicity is critical.
Current research focus: conversion of “cold” tumours to “hot” tumours.

3. Resistance
Dempke et al. 2015

4. IOs: Resistance Mechanisms
At least one third of solid tumours (TCGA data) are non-T cell- inflamed (“cold tumours”)
Several mechanisms of resistance to IO drugs have been identified:
- β-catenin/Wnt overexpression/mutation
- downregulation of target (e.g., PD-1/PD-L1)
- JAK1,2 mutations
- PTEN loss (→ PI3K-γ mutations)
- impaired binding to MHCs
- bypassing by other checkpoint molecules

5. Overcoming IO Resistance
Based on the concept of “hot” (inflamed) and “cold” (non-inflamed) tumours, three general mechanisms to overcome IO resistance have been identified:
Targeting the tumour microenvironment with small molecules to induce CD8+ T cell infiltration (“crossing the PD-L1 wall“): IDOs, A-2A-R inhibitors, PI3K-γ inhibitors
Combination of different checkpoint inhibitors and co-stimulators (“bypassing PD-1/PD-L1 expression change“): anti-PD-1/PD-L1 + anti-CTLA-4, CD40, ICOS, OX40 etc. .
Tumour Vaccination Concepts

6. IO Treatment: Quo Vadis?
Targeted Therapies
(e.g., TKIs, SKIs etc.)
Targeted Therapies
(Second-Line)
Chemotherapy, Others, BSC
10%
No Cure (except CML)
Immuno-oncology Drug Combinations
(Second-Line)
Immuno-Oncology Drugs
(e.g., Checkpoint modulators)
Tumour Vaccination Approaches (?), CTx, BSC
90%
Immuno-Oncology Drugs plus Small Molecules
Cure (10-15%)

7. T Cell “Stay on the gas“ “Cutting the brakes“ IL-2R (CD122)
CTLA-4 (CD152)
PD-1 (CD279)
CD137 (4-1BB)
PD-L1 (CD274)
ICOS (CD278)
TIM-3
T Cell
CD27
VISTA (B7-H5)
LAG-3 (CD223)
“Stay on the gas“
“Cutting the brakes“
CD28
KIRi
OX40 (CD134)
CCR4 (CD194)
BTLA (CD272)
KIRs
IDO-1,2
GITR (CD357)
B7-H3 (CD276)
CD40
TIGIT
A2AR
Novel Immune Checkpoint!
T cell stimulation

8. Small Molecules & New Targets
IDO1,2 Inhibitors (e.g., Indoximod, Epacadostat, BMS etc.)
PI3K-γ Inhibitors (e.g., IPI-549)
Adenosine-A2A-Receptor Inhibitors (e.g., CPI-444)
Others: anti-CD73, TIGIT, oral compounds targeting VISTA and PD-L1 (e.g., CA-170, BMS-202 etc.)

9. PI3K-γ Inhibitor: IPI-549
PI3K-γ (phosphoinositide-3 kinase) is mainly expressed on myeloid cells.
Growing evidence suggests that high levels of PI3K-γ are associated with IO resistance and poor prognosis.
Targeting PI3K-γ with IPI-549 can enhance CD8+ T cell infiltration and thereby overcome resistance to checkpoint inhibitors (e.g., anti-PD-1/PD-L1).
De Henau et al. 2016

10. PI3K-γ Inhibitor: IPI-549
PI3K-γ (phosphoinositide-3 kinase) controls a critical switch between immune stimulation and suppression during inflammation and cancer.
In addition, selective inactivation of macrophage PI3K-γ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immuno-stimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity.
Kaneda et al. 2016

11. CD122/
155
TIGIT
CD122/155
TIGIT
MTIG7192G

12. PI3K-γ Inhibitor: IPI-549
The small molecule IPI-549 (Infinity) targets PI3K-γ, is active as a single molecule and increases CD8+ T cells in mice.
The molecule has demonstrated a large IC50 window (excellent safety profile in the ongoing phase I trial) and can reverse resistance to checkpoint inhibitors.
IPI-549 has shown synergistic effects with anti-PD-1 antibodies in animal models.

13. PI3K-γ Inhibitor: IPI-549
IPI-549 (20 mg twice daily) is currently evaluated in a phase I clinical trial alone and in combination with nivolumab (NCT ).

14. IDO-1 Inhibitor: BMS
Indoleamine pyrrole 2,3-dioxygenase (IDO) converts L-tryptophane to kynurenine.
This results in a decreased tryptophan level which then suppresses T cell proliferation, a mechanism being involved to terminate the immune reaction.
High IDO expression is associated with resistance to chemo-, radio- and immunotherapy and a marker of poor prognosis.
Dempke et al. 2017

15. CD122/
155
TIGIT
CD122/155
TIGIT
MTIG7192G

16. IDO-1 Inhibitor: BMS
Overexpression of IDOs (IDO-1 and IDO-2) (e.g., by IFN-γ, IL-6, TNF-α) leads to Treg activation and stimulates PD-1 and PD-L1 expression.
Moreover, treatment with anti-CTLA-4 antibodies stimulates also IDO overexpression.
Several IDO inhibitors are currently undergoing phase II/III clinical development: indoximod (NewLink Genetics, inhibits IDO-2); epacadostat (Incyte, inhibits IDO-1).
Dempke et al. 2017

17. IDO-1 Inhibitor: BMS
BMS is a new small molecule targeting IDO-1 and is currently undergoing phase I/II clinical evaluation (NCT ) either alone or in combination with nivolumab ( mg).
Clinical data demonstrated a >60% reduction of plasma kynurenine in this trial (epacadostat: < 50%).
In addition, reduction of intratumoural kynurenine was found to be up to 90%.
MTD is not reached so far; and no grade 4-5 toxicities were seen for the combination.
BMS is thought to be the best-in-class of all IDOs tested.

18. IDO-1 Inhibitor: BMS

19. IDO-1 Inhibitor: BMS
Treatment with nivolumab and BMS : Patient with a metastatic head-and-neck tumour (previously pre-treated with two lines of platinum-based chemotherapy).

20. IDO-1 Inhibitor: BMS
Treatment with nivolumab and BMS : Patient with a metastatic renal cell carcinoma (previously treated with pazopanib).

21. IDO-1 Inhibitor: Indoximod
Indoximod is a small molecule targeting IDO-2. The drug is currently undergoing phase II clinical evaluation.
Preclinical data demonstrated a synergistic effect of indoximod and nivolumab and pembrolizumab.
Thus, the combination of indoximod and pembrolizumab in a phase II trial for metastatic malignant melanoma is ongoing (NCT ) (N = 60).

22. IDO-1 Inhibitor: Indoximod

23. IDO-1 Inhibitor: Indoximod
Patients

24. IDO-1 Inhibitor: Indoximod

25. IDO-1 Inhibitor: Indoximod
Parameter
All Patients (N = 60)
Cutaneous/Non-ocular
(N = 51)
ORR
31(52)
30(59) CR
6(10)
6(12) PR
25(42)
24(47) SD
13(22)
11(22)
DCR
44(73)
41(80) PD
16(27)
10(20)

26. IDO-1 Inhibitor: Indoximod
The ORR for the entire study cohort was 52% (CR rate: 12%).
The combination of indoximod and pembrolizumab has shown an ORR of 59% and a DCR of 80% in patients with cutaneous and non-ocular advanced melanoma.
The combination was well tolerated.
Historic controls:
- Pembrolizumab alone: ORR 33%
- Ipilimumab + Nivolumab: ORR 57.6%

27. Adenosine-A2A-Receptor Inhibitor: CPI-444
The adenosine-A2A receptor is generally accepted to be a checkpoint inhibitor.
Several studies have demonstrated that blockage of this receptor can enhance the anti-tumour activity of other checkpoint inhibitors (e.g., anti-CTLA-4; anti-PD-1/PD-L1).
Receptor antagonists have been developed for cancer treatment, although some antagonists are been tested in phase III trials for Parkinson’s disease.
Leone et al. 2015

28. Leone et al. 2015

29. Adenosine-A2A-Receptor Inhibitor: CPI-444
Tumours secret nucleotides into the tumour environment; this creates an immunosuppressive niche that promotes tumour growth and metastasis.
Adenosine signaling via the adenosine-A2A-receptor on immune cells suppresses anti-tumour immunity and has been shown to limit the effıcacy of immunotherapies such as anti- PD-L1 or anti-PD-1 monoclonal antibodies.
Blockade of this receptor (e.g., with CPI-444) was found to restore tumour infiltration with CD8+ T cells in vivo.

30. Adenosine-A2A-Receptor Inhibitor: CPI-444
CPI-444 (Corvus) is a small molecule that targets the adenosine-A2A-receptor and is currently undergoing phase I clinical evaluation either alone or in combination with atezolizumab (N = 113; NCT ).
Heavily pre-treated patients (up to 5 prior treatment lines) were enrolled.
80% of the patients enrolled had prior chemotherapy; 50% were resistant or refractory to anti-PD-1/PD-L1 treatment.

31. Adenosine-A2A-Receptor Inhibitor: CPI-444
CPI-444 was found to be well tolerated as single agent and in combination with atezolizumab (common grade 1-2 toxicities: nausea, fatigue, pruritus).
In patients resistant or refractory to anti-PD-1 or anti-PD-L1 treatment 23/37 patients with PR or SD still remain on study.
Amongst all patients treated those with RCC, TNBC, and NSCLC appeared to be “good responders”.
CPI-444 treatment was found to significantly increase CD8+ T cells in a NSCLC patients (14% → 70%).

32. Adenosine-A2A-Receptor Inhibitor: CPI-444
Treatment of a NSCLC patient with CPI-444. Left: pre-treatement; right: tumour shrinkage after 2 months of treatment.

33. Adenosine-A2A-Receptor Inhibitor: CPI-444
Patient with metastatic renal cell carcinoma who received pre-treatment with TKIs, nivolumab, bevacizumab, and mTOR inhibitors before enrollment.
Left: IHC stain revealed only marginal tumour infiltration of CD8+ T cells (14%, before treatment with CPI-444).
Right: massive infiltration with CD8+ TILs (70%) following CPI-444 treatment (2 months).

34. Others: TIGIT
TIGIT (T cell immuno-receptor with Ig and ITIM domains) is a novel immune checkpoint molecule.
TIGIT binds CD122 and CD155 (dendritic cells, macrophages); intracellular signaling is then propagated via CD 226.
TIGIT stimulation inactivates NK cells and CD8+ TILs whereas Tregs (high expression!) are activated.

35. CD122/
155
TIGIT
CD122/155
TIGIT
MTIG7192G

36. Others: TIGIT
Blake et al. 2016

37. Others: TIGIT
TIGIT antagonistic monoclonal antibodies have shown excellent tumour regression in vivo in combination with other checkpoint inhibitors (e.g., PD-1 and PD-L1).
Several TIGIT monoclonal antibodies are currently in phase I/Ib development (alone or in combination):
- MTIG-7192G (Genentech; NCT )
- BMS (BMS; NCT

38. Others: anti-CD73
Ecto-5’-nucleotidase (CD73) is mainly expressed on the surface of many tumour cells (GPI-anchored) and catalyses the conversion of AMP to adenosine and phosphate.
CD73 expression is associated with a poor prognosis.
Activation of CD73 results in a “adenosine cloud” which suppresses immune response of T cells.
Blockade of CD73, however, can enhance the efficacy of anti- PD-1/PD-L1 and anti-CTLA-4 antibodies in animal models.

39. Others: anti-CD73
Allard et al. 2013

40. Others: anti-CD73
Anti-CD73 monoclonal antibodies are currently evaluated in early phase I trials (either alone or in combination with checkpoint inhibitors):
- MEDI9447 (AstraZeneca; NCT )
- CPX-006 (Corvus; phase I in preparation)

41. Executive Summary Field is incredibly competitive
Many “breakthrough” immune therapies
Field is incredibly competitive
New targets are already tested in phase I trials
Resistance is gradually emerging
Combinations may improve efficacy
Most critical issue: Toxicity!
Current focus: How to convert “cold” tumours to “hot” tumours (→ small molecules)?

42. AACR 2018: Chicago
April 14-18, 2018:
Chicago Convention Center