Immune Checkpoint discovery yielded remarkable therapeutics (anti-CTLA4, anti-PD-1) but has more recently stalled out. Here I explore some of the issues the field has uncovered. Presented at the ICI-IO conference in March 2019. F

1. 1
Establishing a New Set of Biological Goals
for Checkpoint Inhibitors
and IO Combinations
Paul Rennert, President & CSO
Aleta Biotherapeutics

2. Outline
• Restate the goal
• IO combo reality check
• Generating new hypotheses
• TME disruption
• IO lessons and CAR T

3. Restate
the goal
• Establishing a New Set of Biological
Goals for Checkpoint Inhibitors and
IO Combinations .....
• New goal:
✧ Propose several hypotheses to
explain why we have sometimes
misread pathways of anti-tumor
immunity
✧ Use these hypotheses to think
about how we can best move
forward

4. Why pursue novel immune checkpoint
pathways and IO combinations?
• Most patients do not respond to immune checkpoint
therapy
4

5. ...reading anti-tumor
immunity
• We and many
others took a
reductionist view
which yielded a
rich list of
potential targets
5Mahoney et al. 2015. NRDD

6. Where we've been...
• The guiding therapeutic principal has been "remove the
brakes and step on the gas" (ie. on T cells)
✧ a T cell centric view
• We've been protein superfamily centric (IgSF, TNFRSF), a
hangover from the human genome sequencing era
• We proposed that the right combinations of checkpoint
inhibition and/or T cell activation for each indication
would boost response rates – more patients would respond
6

7. What we got right
• We focused on standard of care combinations: chemotherapy,
irradiation, targeted therapeutics (eg. BRAF & VEGF targeting)
• We focused on NK cells, the myeloid lineage and the tumor
microenvironment
7
• and on tumor
cell/stromal
interactions
Mahoney et al. 2015. NRDD

8. regardless, clinical progress has been slow
• novel checkpoints have less clinical tumor than anticipated– 1st
generation IDO inhibitors, CSF1R antagonists, antibodies to
TIM-3, Lag3, VISTA etc
• agonist antibodies to stimulate T cells have underperformed to
date: 41BB, OX40 etc.
• utility may be uncovered for these targets, but...
• the preclinical data sets were compelling for many of
these pathways– why has clinical translation been
difficult?
8

9. IO combo
clinical
translation
• Q: why has clinical translation been
difficult despite compelling
preclinical data?
• A: compelling preclinical and
translational stories can be built on
problematic evidence

10. Sources of problematic evidence – one
• the mouse (Mus musculus)
• as we use them: inbred, genetically and immunologically
customized
• are these animals actually useful for modeling anti-tumor
immunity?
10

11. Mouse immunity
• Evolved to mature quickly &
reproduce: 2 months lifespan
in the wild. Cause of death:
predation, infection,
parasitism
• The mouse immune system
has evolved to fight off
pathogens and parasites
• We are fortunate that PD-1
produced a clear signal in
chronic viral infection
models, otherwise we might
have missed it
11

12. Sources of problematic evidence – two
• Retrospective analysis of target association with disease
outcome (prognosis) data
12
survivor's analyte x
not survivor's analyte x

13. Observation vs hypothesis testing
13
• Observation: expression of X correlates with
patient outcome in this indication
• Typical hypothesis: X is an important
component of disease pathogenesis
• However, the formal hypothesis is the null
hypothesis
• The null hypothesis is that X has nothing to
do with patient outcome and disease
pathogenesis, ie. that the observed
correlation is spurious

14. How do we normally go about testing our
hypotheses?
14
• Hypothesis: X is an important component of
disease pathogenesis

15. How do we usually go about testing our
hypotheses?
15
• we buy more mice

16. Sources of problematic evidence – three
16
• lack of randomized control trials in Phase 2
• difficult to address given the state of the IO clinical space:
✧ massive numbers of trials
✧ many patients are refractory to SOC and refractory to
PDx therapy
✧ designing an appropriate control arm
• this means that for many targets we are moving into late
clinical development without having formally tested the
null hypothesis

17. analysis of
PDx
treatment
response
data
• Building new hypotheses
• Analyses of response, resistance &
relapse characteristics (pre vs post-
therapy) have been very informative

18. Analyses of response, resistance & relapse
in tumors
• An immune signature is a good sign (CD3, CD8)
• Resistance and relapse mechanisms are becoming clearer:
• T cell intrinsic: phosphatases that shut down signaling
• tumor cell intrinsic: mutations that block response to IFNg
• signatures that reflect TME status: fibroblasts, myeloid cells,
TGF-b, b-catenin, VEGF and others
• TME status reflects, in part, immune exclusion and immune
deserts, ie. cold tumor microenvironments
18

19. TME disruption
• IO/chemotherapy combos
• IO/targeted therapy combos
• Emerging novel IO combos (eg. PDx
with TLR9, PD-L1 x TGbR-trap)
• Several novel IO pathways (eg.
targeting CD47)

20. A few examples of IO combo success
20
indication PDx combination type control cohort
RCC pembrolizumab axitinib VEGFRi sunitinib
TNBC atezolizumab abraxane nab-paclitaxel
nab-paclitaxel
alone
CRPC durvalumab olaparib PARPi -
NSCLC pembrolizumab dual chemo
carboplatin and
nab-paclitaxel
carboplatin and
nab-paclitaxel
• chemo, targeted therapy, synthetic lethality – there are
many other examples

21. what do these strategies have in common?
• The combo therapy induces tumor cell death, with the
potential for de novo immune responses
• The combo therapy perturbs the TME, providing a window
in which T cells can proliferate and mount a cytotoxic attack
• The combo therapy disrupts immunosuppressive pathways
(eg. VEGFRi)
21

22. Example: VEGF
targeting
22
© Beacon Intelligence/Hanson Wade 2018

23. "New biological goals" for novel IO agents
and proposed IO combos
• Articulate a molecular hypothesis - what is the immune
mechanism of action
• Pursue a therapeutic hypothesis - how is the immuno-therapy
relevant in a specific indication or indications in the context of
current standard of care (including anti-PDx)
23