The immune checkpoint landscape in 2015: combination therapy

03-24-2015

Paul D. Rennert

www.sugarconebiotech.com

Immune Checkpoint Inhibitors and the

Evolution of Combinatorial

Immuno-Oncology

sugarconebiotech.com

• The biology and utility of immune checkpoint modulation

drivers and critical issues in the evolution of cancer care

dissociating efficacy from toxicity

• Case study: immune checkpoint inhibitors in melanoma

• Combination immunotherapy

efficacy and toxicity profiles – can we improve both?

combinations with other therapeutic modalities

tumor cells, lymphocytes, the tumor microenvironment

• Future directions and new targets

What we'll cover

2


Combinatorial – combination therapy is critical, and not just immune

checkpoint combinations

Pro: agnostic and opportunistic as to type of therapy used in combination

Con: there is currently little data to inform combo treatment choices

Immuno-oncology – the therapeutic approach targets the immune

system

Pro: novel immuno-modulatory targets will broaden the therapy toolkit

Con: we don't know how to sort patients yet, and the choices made may

have unique toxicities

diverse indications with a wide variety of SOC

complex indication subtypes with unique genetics, few other biomarkers

in all cases, unique patients

3

Immune checkpoint therapeutics are a component of

combinatorial immuno-oncology

What does that mean?


primers

• cytotoxic

• cytokines

• vaccines

checkpoints

• CTLA4

• PD-1/PD-L1

• TIM3, many others

• other suppressors

expanders

• TNFRs

• cytokines

• CAR-T

• BiTEs

- Tumor cells

- Stromal cells/ECM

- Lymphocytes

- Therapeutics

Big Picture: Immune Checkpoint Modulation

4


primers

• cytotoxics

• cytokines

• vaccines

checkpoints

• CTLA4

• PD-1

expanders

• TNFRs

• CAR T

• BiTEs

Idealized picture of combination immunotherapy

5

patient combo


Idealized picture of combination immunotherapy

6

combo synergy

• this is what preclinical models show – we cannot

overinterpret those models and acknowledge that

these data only generate clinical hypotheses

• patient by patient analyses show dramatic variability in

genetics, mutation burden, immune profile

• nonetheless, some combinations have already

produced impressive results


Complex indications, complex patients

7

driver mutations in metastatic melanoma and in lung cancers



8

expression of lymphocyte markers and PD-L1 in NSCLC

but this picture is highly variable degree of infiltration (starting at none)

geography of infiltration (marginal, interstitial, stromal, excluded)

functionality of infiltrates (PD-1, TIM-3, LAG3)

T cells NK cells

CD3+/CD8+ T cells



9Galon et al 2013. Immunity 39: 11-26

CD3+

CD8+


Such compexity offers significant challenge, but also

opportunity, for new drugs to have a positive impact

back to our combinatorial landscape....

10


primers

• cytokines

• vaccines

• cytotoxics

expanders

• TNFRs

• CAR T

• BiTEs

Checkpoints Dominate....

11

checkpoints

• CTLA4

• PD-1

• Inhibition appears to be

dominant over activation

Preclinical models support

this view

Early clinical data support this

view, e.g. monotherapeutic

activity of TNFR agonists is

low

Even CAR T cells can be shut

down by immune checkpoint

expression

• We don't yet understand the

impact of removing constraints on

NK cell activity and on immuno-

suppression imposed by stromal

cells


primers

• cytokines

• vaccines

• cytotoxics

checkpoints

• CTLA4

• PD-1

• TIM3 etc

expanders

• TNFRs

• CAR-T

• BiTEs

Chemotherapy

Radiation Therapy

Targeted Therapy

other (e.g SCT)

immune modulation does not exist in a vaccuum

12


Surgery

Debulking

Chemotherapy

Irradiation

Targeted Tx

Transplant

Indication

Genetics

Line

Age

13

Patient

So here's a patient...

sugarconebiotech.com 14

high

low

low high

Efficacy/Tolerability

Newly diagnosed:

potential for

greatest benefit

Ideal Profile for New Therapeutics

indication

unmet need


high

indication

unmet

need

low

low Efficacy/Tolerability high

15

newly

diagnosed

Clinically/Commerically unacceptable


high

Unmet

Need

low

low high

Tolerability

naive


high

Unmet

Need

low

low high

Tolerability

Ist line


high

Unmet

Need

low

low high

Tolerability

2nd-3rd line


high

Unmet

Need

low

low high

Tolerability

last - salvage


high

Unmet

Need

low

low high

Tolerability

This is a typical early stage

clinical trial population


Efficacy v Tolerability: an old issue with rapidly evolving

expectations

Chemo/irradiation • poor tolerability, potential for a high intial overall response rate (ORR)

• rarely induces complete responses (CR); poor durability (DOR)

• measurable impact on progression-free survival (PFS)

• limited impact on median overall survival (med OS)

• drives resistance

Targeted therapies (NCEs, mAbs)• variable tolerability

• can induce a high ORR

• some CRs; good PR rate

• limited DOR

• better PFS than chemo alone

• can improve OS

• drives resistance

• some notable successes


Efficacy v Tolerability: an old issue with rapidly evolving

expectations

Immunotherapy –

• low ORR, but...

• CRs, PRs and SD with good DOR

• Clear PFS and OS benefit, but let's look more closely...

with immune checkpoint

monotherapy this

number can be low

the long tail

drags OS with it


Efficacy/Tolerability: where we are headed depends on

the indication

Hematologists have been excited about the "post-chemo" era.

Why? Ibrutinib, rituxumab, idelalisib, revlimid etc ...

Solid tumor oncologists already know from targeted therapies that

some of their patients can be cured (e.g. targeted therapies &

antibodies in breast cancer) – anticipating better cure rates with IO

Oncologists in general are seeing success where for decades there has

been only abject failure (NSCLC, H&N, bladder, etc)

All oncologists recognize the importance of being able to treat their

elderly (or just beaten down) patients

In this landscape, the efficacy/tolerability profile can be

differentiating


Next Gen Immuno-Oncology: Central Themes

• what we want in specific indications:

better response rates

more durable responses

better tolerability

• because we are addressing new benchmarks clinical

practice is evolving quickly

• for preclinical and early clinical programs a critical

exercise is to look ahead in an effort to anticipate unmet

need in a rapidly changing environment

24


The Big Three

25


Immunotherapeutics: CTLA-4 and PD-1

Lymph Node "inflammatory site (tumor)


Immunotherapeutics: CTLA4

Lymph Node

• ipilimumab, IgG1 (BMS)

approved for refractory or

advanced metastatic

melanoma (Vervoytm)

Blocks CTLA4 from shutting

down T cell activation

Likely blocks or depletes

Tregs in the lymph node and

the tumor

• tremelimumab (Pfizer), in many

trials, including with anti-PD-L1

(Medi4736; AZN)

Phase 3 monotherapy trial in

advanced melanoma stopped in

2008 on futility

27


Immunotherapeutics: PD-1

"inflammatory site (tumor)

• anti-PD-1 mAbs

nivolumab, IgG4 (Opdivotm,

BMS)

pembrolizumab, IgG4

(Keytrudatm,Merck)

• anti-PD-L1

MDPL3280A, IgG1 (Roche)

MEDI-4736, IgG1 (AZN)

• These agents block the interaction

of PD-L1 (expressed on tumor

cells and Tregs) with PD-1

expressed on T effector cells

28

anti-PD-1 approvals

Pembrolizumab (Keytruda)

1) Unresectable or metastatic melanoma who no longer respond to other

treatments (September 2014)

Pembrolizumab was granted accelerated approval

Nivolumab (Opdivo)

1) Unresectable or metastatic melanoma who no longer respond to other

treatments (December 2014).

- breakthrough designation, priority review and orphan product designation

- where treatments include Vervoy (ipilimumab) or, if BRAF V600 mutation

positive, a BRAF inhibitor.

2) Advanced/metastatic squamous non-small cell lung cancer (NSCLC) with

progression on or after platinum-based chemotherapy (March 2015)

29sugarconebiotech.com

Melanoma case study



Immunotherapy case study: melanoma

31

Historical treatment of stage III/IV non-resectable and/or metastatic

disease (not segmented by mutation status)

ORR med OS 1 yr survival

dacarbazine, other chemo 10-15% 7-9 mo 26-36%

high-dose IL-2 16%* 12 mo n/r

• *A small number patients experience long-term survival. High-dose IL-2

regimen is not more widely used due to toxicity profile.

These IL-2 data supported the hypothesis that melanoma is an immune

responsive cancer.


Ipilimumab in resistant/advanced melanoma patients

Phase 3, n= 676*

ORR %med OS

(months)

1 yr %

survival

%

progressed

ipilimumab 38** 10 45.6 59

ipi+gp100 20 10.1 43.6 51

gp100 15 6.4 25.3 65

* Hodi et al. 2010. NEJM 363: 711-723; **atypically high


Ipilimumab in treatment-naive melanoma

33

ORR %med OS

(months)

1 yr %

survival

comparator data

(prior slide)

20 10 45

ipilimumab 38 13.5 54

* Dummer et al. 2014. J. Transl. Med. 12(Suppl 1):P8.

post-hoc analysis of 4 trials*

• moving to first line modestly improves outcome

• stresses need for combination therapy

• toxicity is a complicating issue, approved dose is 3mpg


Ipilimumab plus SOC

34

• ipilimumab plus dacarbazine in adv melanoma*

not better than ipilimumab alone at 1 year

higher dropout rate than monotherapy due to adverse events

med OS 1 yr OS Gr 3/4 AEs

combo 11.2 mo 47.3% 56.3%

dacarbazine 9.1 mo 36.3% 27.5%

* Robert et al. 2011 NEJM 364: 2517-2526


Ipilimumab and dacarbazine

35

prior

treatmenttreatment

3 yr %

survival

4 yr %

survival

5 yr %

survival*

Phase 3 (trial '024)

none ipi 10mpg plus

dacarbazine

21.2 19 18.2

" none dacarbazine 12.1 9.6 8.8

Phase 2 ('007, '008, '022)

none ipi 0.3, 3, 10

mpk

- 38 - 49 38 - 49

" yes " - 14 - 28 12 - 28

longer term followup

*JCO published online on February 23, 2015 (Wolchok)ESMO abstracts 2012


Toxicity is a complicating issue – why?

36

• biggest issue assocated with these toxicities is treatment discontinuation

(drop-out), leaving patients with an unclear path forward. This has the

effect of lowering therapy penetrance into the patient population.

• anti-PD-1 pathway therapeutics already show better tolerability


Check-in: central themes

• better response rates response rate improved

we don't know which patients will respond, and this

remains an issue for the front line setting

• more durable responses some durable responses are obtained

some responders can do remarkably well

• better tolerability better than chemo but toxicity may lead to discontinuation

tolerability is an evolving issue – still trumped by efficacy

37


Melanoma and PD-1 pathway inhibitors: nivolumab

38

ORR % med OS1 yr

survival %

pts

progressing

%

nivolumab in pre-

treated patients,

ipi-naive*

41 20.3 63 >55%

nivolumab in

untreated, BRAF

wt patients**

40

not reached

(follow-up up to

16.7 mo)

73 47

dacabazine

control** 14 10.8 42 85

* Hodi, ASCO 2014; ** Robert et al NEJM Nov 2014


PD-1 pathway inhibitors: pembrolizumab

39Mahoney and Atkins, 2014 Oncology 28 Suppl 3:39-48

adv/met melanoma

adv/met melanoma

adv/met melanoma


PD-1 pathway inhibition

resistant, ipi-refractory metastatic melanoma


ORR (2 diff

doses)PFS

1 yr

survival

pembro 26-34% 34-38 58-72%

chemo 4 16 26-35%


Nivolumab + ipilimumab combination


• 80% 1 year survival


Melanoma summary

42

ORR % med OS 1 yr survival %

where we

started12 8 months 30

ipi/nivo combo 42 40 months 85

best

comparator* 64

not

reached**72

* dabrafenib (BRAFi) + trametinib (MEKi) in BRAF V600E/K

mutated melanoma; Robert et al. NEJM Nov 2014.

** median followup ~10 months

Comparative tox profiles - monotherapy

43Kim and Eder 2014 Oncology


Tox profiles – combotherapy ipi/nivo

• 21% of patients terminated

treatment due to toxicity

• toxicity is associated with

positive clinical response

• oncologists: the GI tox is very

difficult and limits use

Kim and Eder 2014 Oncology

45

Tox profiles –

BRAF/MEK combo

• grade 3/4 AEs in 48% of pts

• 3 pts died: 2 w/ cerebral

hemorrhage and 1 w/

brainstem hemorrhage

• new tumors (non-

melanoma) developed

in 3 pts

• cardiac abnormalities in 8%

• we'll have to wait for

resistance data


Immunotherapy for melanoma: food for thought

46

• Resistance to ipilimumab therapy following radiotherapy includes

upregulation of PD-L1 (Victor et al 2015. Nature, doi:10.1038/nature14292; also

AACR15 abstract #2858)

• Preclinically, anti-CTLA4 and anti-PD-1 therapeutics have been

shown to augment neoantigen responses within TIL populations;

this has important implications for adjacent fields (e.g vaccines)

• BRAF inhibitors transiently release neoantigens that can expand T

cell responses in the presence of immune checkpoint inhibition;

conversely MEK inhibition may blunt T cell activation by direct

effects on T cells (AACR15 Abstract #SY26-03)

• The sequence in which combination therapies are applied has yet to

be optimized – update here?


Immunotherapy in other indications

47

BMS declared IO pipeline (March 2015)



Ipililumab Phase 3 examples

49

indication combination comparator trial

newly diagnosed

adv melanoma

nivolumab placebo CheckMate 067NCT01844505

adv melanoma nivolumab; dabrafenib*

(BRAFV600); trametinib(MEK)

none, cross-over

design by

sequence

NCT02224781

adv prostate - placebo NCT01057810

sq NSCLC + chemo chemo NCT02279732

adv/met RCC nivolumab sunitinib CheckMate 213NCT02231749

ED-SCLC + chemo chemo NCT01450761

* Rx of melanoma w/1 mo run-in w/vemurafenib (BRAF V600E i) followed by ipilimumab caused grade 3

elevations in aminotransferase levels and concomitant grade 2/3 change in the total bilirubin level: liver

toxicity sufficiently severe to cause study termination (Ribas et al. 2013. NEJM 368: 1365-1366)


Ipililumab: interesting combos

50

Radiation

lung, liver

anti-VEGF

melanoma

Radiosurgery

melanoma

lenalidomide

adv cancers

Chemo

melanoma


Ipililumab combos continued

51

imatinib (TKI)

adv cancers

IL-21

melanoma

an RTKi*

renal

radiation

melanoma

* Sunitinib blocks VEGF signaling and it's use is linked to elevated immune responses to solid tumors,

notably RCC. But we have to be careful....a clinical trial of ipilimumab and sunitinib was halted abrupty

due to acute renal failure


Nivolumab in the clinic: recent and ongoing trials

52

indication comparator trial Phase

recurrent

melanoma

ipilimumab CheckMate 238NCT02388906

3

Sq NSCLC - (multiple line

failures)

CheckMate 063NCT01721759

2 stopped on

efficacy

Sq NSCLC docetaxel CheckMate 017NCT01642004

3 stopped on

efficacy

adv/res NSCLC chemo (investigator's

choice)


3

recurrent GBM bevacizumab (anti-

VEGF)


3

adv/res Sq H&N cetuximab (anti-

EGFR) +/- chemo


3

adv/res gastric

cancer

placebo NCT02267343 3

Nivolumab in the clinic: interesting combos

53

RTK* or ipilimumab

met RCC

Abraxane/Chemo

adv solid tumors

CELG

anti-KIR

heme malignancies

kitchen sink

NSCLC

anti-VEGF

mRCC


Nivolumab combos...

54

dasatinib (Bcr-Abl TKI)

CML

ibrutinib (BTKi)

heme malignancies

JNJ

IDO

adv cancers

INCY, BMS

ipilimumab

adv solid tumors


Nivolumab combos...last page

55

anti-CD27

select adv cancers

Celldex, BMS

ipilimumab

CNS melanoma

dabrafenib +/- trametinib

melanoma


Pembrolizumab in the clinic:

Phase 3 and other select examples

56

indicationcombination

or othercomparator trial note

met Sq H&N (1st

line)

chemo cetuximab

(anti-EGFR) +

chemo

Keynote-048NCT0235803 P3

PD-L1+ adv

NSCLC

- chemo Keynote-042NCT02220894 P3

adv melanoma - ipilimumab Keynote-006NCT01866319

P3

adv urothelial

cancer

- chemo Keynote-045NCT02256436 P3

adv/res gastric

adenoCa

- paclitaxel Keynote-061NCT02370498 P3

adv cancers response relative

to tumor PD-L1+- Keynote-001

NCT01295827

P1, NSCLC data at

AACR15 #CT104

mesothelioma - - Keynote-028NCT02054806

P1, data at

AACR15 #CT103


Pembrolizumab: example combos

57

VEGFR1/2-Fc

adv solid cancers

post-chemoradiation

NSCLC

Abraxane

NSCLC

Merck, CELG

chemoradiation

pancreatic cancer

RTKi (EGFR/Her2)

NSCLC


Pembrolizumab – other indications

58

chemo

CRC

Merkel Cell

HL and DLBCL

bevacizumab(anti-VEGF)

GBM


Pembrolizumab... a few others

59

pazopanib

RCC

BTKi (?)

bladder Ca

thymic Ca

anti-4-1BB

adv solid tumors


What does this landscape tell us?

• the volume of clinical data will be enormous, difficult to absorb

• immune checkpoint inhibitors to CTLA4, PD-1 and PD-L1 (see

backup slides) are likely to become dominant background

therapeutics in many indications

• the penetrance of these therapeutics into diverse indications will

depend on at least three distinct factors:

immune response profile of the specific indication and further, of

that indication (tumor) in each specific patient (e.g, immunoscore)

mutational profile (oncogenic, antigenic) of the tumor(s) in each

specific patient

efficacy/safety profile of the therapeutic in combination with SOC

or novel therapeutics

the evolving competitive landscape

- as an example, hematologic malignancies may be better served

by other therapeutic modalities

Novel therapeutics will need to fit into this landscape

60


A note on PD-L1 inhibition

61

• Anti-PD-L1 inhibitors have the gentlest tox profile of the class, albeit

with less efficacy data behind them, so we'll see...

• updates here?

MEDI4736 (PD-L1)

dabrafenib (BRAFi)

trametinib (MEKi)


WHAT NEXT?

62


Novel Immunotherapies: Organizing Principals

63

Tumor cells Lymphocyte subsets

Microenvironment

www.sugarconebiotech.com 64

which is what is wrong with this

picture:

• Diverse targets

• Inhibitory and activating pathways

• Known and unknown biologies

• Static

• Rationale required for targeting as

mono- or combo-therapy absent

How do you approach this

complexity?

Mahoney et al, NRDD in press

This target list just

keeps growing


Organizing Principals – Deconstructing the landscape

sugarconebiotech.com 66Mahoney et al. NRDD, in press

Activating pathways of the TNFRSF

• Multiple antibodies in clinical development, none very far advanced

• All appear relatively tolerable, once dose is established

• Although diverse MOA are postulated within this group of receptors, it is

unclear how much the biology will overlap or be affected by FcR-engagement


4-1BB/CD137

• Co-stimulatory molecule on T cells and NK cells: ligation induces cell activation

and enhances effector function

• Abundant preclinical data support of combination studies with many other

agents

• Clearly capable of driving T cell expansion and memory as demonstrated

(artificially) by the UPenn CAR T program

• Early clinical PD data show expansion of T cell and NK cell subsets and clinical

activity in melanoma, RCC, ovarian Ca (PR and sustained SD)

• 4-1BB expression appears to accurately identify tumor reactive TIL in some

tumor types, such as ovarian cancer*

• On NK cells, FcR-engagement by therapeutic antibodies (rituximab, cetuximab,

etc) strongly upregulates 4-1BB expression, opening the door for rational

combinations**

* Ye et al. 2014. Clin. Can. Res. 20: 44-55

** Khort et al. 2014. JCI 124: 2668-2682


Therapeutics targeting 4-1BB

• Broad campaign by BMS to profile anti-4-1BB agonist activity of urelumab, an

IgG4 agonist

monotherapy: solid tumors and Non-Hodgkin lymphoma (NHL)

rituximab combination for NHL

combination with elotuzumab (anti-CS-1 mAb) or lirilumab (anti-KIR mAb) for

multiple myeloma

nivolumab combination in solid tumors and NHL

cetuximab (anti-EGFR mAb) in colorectal, Head and Neck carcinomas

• Pfizer campaign with PF-05082566, an IgG2 agonist

monotherapy cohorts in melanoma and Merkel cell carcinoma and combination

trials with rituximab in NHL

combination with pembrolizumab in solid tumors

The PFE/MRK deal will bring additional combos


OX-40/CD134

• OX40L/OX40 pathway sustains the immune response during inflammation,

i.e. during T cell activation, allowing T cell memory to develop

• OX40 engagement can activate memory T cells as well and has diverse

(mainly negative) effects on Tregs

• Early clinical data showed a PD response that included increased numbers of

circulating CD4+ T cells, CD8+ T cells and NK cells

• OX40 plus 4-1BB agonist combination may drive an anti-tumor immune

response by generating CD8+ T cell activity characterized by very high levels

of IFN-g and granzyme B – the super CD8s

We'll come back to look at CD27 in a bit...

sugarconebiotech.com 70Mahoney et al, NRDD, in press

TCR, B7/CD28 and PD-L1/PD-1 clusters

Novel targets:

HHLA2 – TMIGD2

ICOS – agonist

LAG3 – antagonist

VISTA - ?


HHLA2

• HHLA2 (aka B7H7/B7-H5/B7y): most closely related to butyrophilins

• Putative ligand identified and an inhibitory role postulated

• HHLA2 protein is widely expressed in human cancer*

breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon,

prostate, kidney, esophagus

In 50 patients with stage I-III TNBC, 56% of patients had high HHLA2 expression

that was significantly associated with regional lymph node metastasis

low level normal expression on epithelial cells (gut, kidney, breast)

• TCGA analysis showed that HHLA2 copy number gains were present in 29%

of basal breast cancers

• No clinical assets developed

* Janakiram et al. Clin Can Res Dec 2014


LAG3• A CD4 homologue, LAG3 was shown to confer Treg function on transfected

naive CD4+ T cells

• LAG3 binds to the MHCII protein and is required (with CD4) for optimal T cell

activation

• LAG3 overexpression (e.g on anergic T cells and tumor cells) functions as a

negative regulator of T cell response to MHCII-restricted antigen

• Antagonism of both LAG3 and PD-1 can synergistically reactivated

exhausted CD8+ T cells in mouse models

• LAG3/PD-1 gene-deficient mice are highly competent to reject even poorly

immunogenic tumors.

• Several clinical agents in development, no data yet.


VISTA

• Normally expressed on hematopoietic cells including myeloid

cells and T cells

• In multiple cancer models VISTA is found at particularly high

levels on tumor-infiltrating myeloid cells

• Appears to be a negative regulator of T cell responses, may

suppress myeloid cell responses in the tumor microenvironment

• Anti-VISTA antibody treatment blunts tumor development even in

the presence of high PD-1 expression

• Antibodies to VISTA are being developed by a private company,

ImmuNext, in collaboration with Johnson&Johnson (JNJ)

73


Complicated targets

74


Complicated targets

75

Ceacam-1*

Huang et al. 2015. Nature 517: 386-390

Ceacam-1*

• Excellent preclinical data support targeting TIM-3, Ceacam1 and select

components of the LIGHT/HVEM system

• It seems likely that the clinic will teach us more about the activity of the HVEM

and TIM-3 systems than we can learn from mouse modeling – the actual

kinetics and function of pathway components in situ is likely to be critical to

successful targeting


• lets break away, and look

more closely at specific

cell types within the tumor

microenvironment


B7-H3/B7-H4: Poorly understood

biology, B7-H3 is an ADC target

Butyrophilins are widely expressed,

ligands usually unknown, likely that

new targets will be found here

Aberrant and highly variable

expression of TNFRs – ADC targets,

CD30 also a CAR T target

Mahoney et al, NRDD, in press

Immune-modulatory proteins on tumor cells

78Mahoney et al, NRDD, in press

Immune-modulatory proteins on Tregs

• Primary targets: inhibition overrules

activation

• Additional TNFRSF proteins: all of

these are under preclinical and clinical

investigation

• VEGF receptors critical for cross-talk

with stromal cells


CD27, our third costimulatory TNFR

• CD27 is constitutively expressed on most T effectors and a subset of NK cells

• As postulated for 4-1BB and OX-40, CD27 is important for sustained T cell

activity and the generation of T cell memory; indeed, CD27 is a marker of

memory T cells; CD27 also drives the cytolytic activity of some NK cells

• Celldex has developed varililumab, an anti-CD27 agonist antibody and arly

clinical data from a Phase 1 dose trial in NHL and solid tumors demonstrated

tolerability and some measureable clinical responses

• Listed clinical trials include a combination with nivolumab in solid tumors

Other critical pathways under active investigation:

CD40

GITR

TNFRSF25

DR5/TrailR2


NK cells: the next wave of immune-modulators


NK cells: the next wave of immune-modulators

Watch list:

KIRs (Innate Pharma)

LIRs (ILTs)

Siglecs

The PVR/nectin family (TIGIT; Genentech)

C-Type lectins (Innate Pharma)


KIR-modulators

• Killer inhibitory receptors fall into two subclasses,

the killer cell immunoglobulin-like receptors (KIRs)

C-type lectin transmembrane receptors (eg. NKG families)

• KIR function is regulated through interaction with cell surface HLA

proteins that transduce an inhibitory signal to NK cells.

• lirilumab is an antagonist antibody that binds to the KIR2DL1,2,3

receptors to prevent their inhibitory signaling and increasing NK cell–

mediated killing of HLA-C–expressing tumor cells.

• In a Phase I monotherapy trial in acute myeloid leukemia (AML)

IPH2101/lirilumab had only modest toxicity (grades 1-2) and showed

signs of clinical activity

• A Phase II study of lirilumab in AML is in progress


BMS doubles-down with Innate's mAb

• Innate Pharma and BMS are collaborating to develop lirilumab.

• Combination Phase 1 trials of lirilumab in combination with nivolumab and

ipilimumab for solid tumors have begun and a combination trial with

elotuzumab (depleting anti-CS1 antibody from BMS and AbbVie) is underway

for multiple myeloma.

• A recent update to clinical trial filings indicates that BMS is adding lirilumab

combinations with nivolumab to clinical trials of ipilimumab/nivolumab combos

for hematological malignancies (next slide)

• These updates are suggestive of broad utility of engaging NK cell activity

• Innate is also developing an anti-MICA antibody to block inhibition mediated

by MICA/NKG2D interaction, and they have an NKG2A program. Both are

quite early.

sugarconebiotech.com84

Lirilumab clinical trials: focus on heme malignancies


TIGIT• TIGIT is a relatively new IgSF protein, with clear cell inhibitory function.

• Defined binding to PVR and Nectin-2, potentially leading the way to

influencing both T cells and NK cells through inhibition of this pathway

• However, proteins in the nectin family may have diverse binding partners,

complicating development, e.g. the TIGIT ligands may also bind DNAM and

other PVRs

• Genentech has developed TIGIT-specific therapeutics and recently showed

that co-blockade of TIGIT and PD-L1 resulted in tumor rejection by restoring

the function of exhausted tumor-infiltrating CD8+ T cells; however high

concentration of ADCC-competent antibody was used, complicating

interpretation*

• Regardless, targeting TIGIT may be especially beneficial in tumor settings

where both T cells and NK cells have therapeutic potential

johnston et al. 2014. Cancer Cell


Tumor microenvironmentthe new frontier, a wealth of targets


IDO1

Indoleamine 2,3-dioxygenase (IDO1) is the rate-limiting enzyme for the catabolism

cellular tryptophan. High levels of IDO1 reduce tryptophan levels and create

bioactive tryptophan metabolites, a highly immunosuppressive combination

In the tumor microenvironment IDO is produced by tumor cells and by tumor

associated MDSC and tumor-associated macrophages (TAM) in response to

inflammatory signals (IL-10, IFNy)

Incyte's IDO1 inhibitor INCB024360 is in Phase 1 & 2 clinical trials for metastatic

melanoma in combination with ipilimumab and as monotherapy for ovarian cancer.

In the ipilimumab combination study, many patients demonstrated an objective

response and maintained stable disease

Other studies include a Phase 1/2 study in advanced/metastatic cancers including

melanoma and NSCLC in combination with pembrolizumab, nivolumab, MPDL3280A

and MEDI4736 – the benefit of multiple collaborations

Newlink and Flexus deals highlight the intense interest in this target


TGFb• Diverse methods have been employed in attempts to safely block TGFb activity,

one of the most potent immunosuppressive growth factors

• Among many other activities, TGFb stimulates expression and phosphorylation

of IDO. This triggers additional signaling to allow paracrine (and chronic)

expression of both TGFβ and IDO1

• Current therapeutics target activating integrins, e.g. avb6 or the GPCRs that are

responsible for activating the integrins (e.g. LPA, other GPCRs)

• LY2157299/galunisertib is a small-molecule kinase inhibitor from Eli Lilly

designed to selectively block TGFb receptor signaling

• Galunisertib has a well-defined therapeutic window based on reducing receptor

signaling and has shown clinical activity in a variety of solid tumor models

• Successful (safe) targeting of TGFb will be a stunning advance


Adenosine

A2aR is expressed on CD8+ TIL, NK cells and MDSC and is an important

component of immune regulation, helping to stop immune responses in the

context of inflammation

Adenosine is produced by the nucleotidases CD39, an ATP/ADPase, and CD73,

an AMPase. Both nucleotidases can be upregulated on tumor cells and also on

tumor-associated Treg

A proof of concept study using a substrate analog inhibitor of CD73 demonstrated

additive anti-tumor activity with anti-CTLA4 antibody treatment in a melanoma

model

An anti-CD73 antibody had additive activity when combined with anti-CTLA4 or

anti-PD-1 antibodies in multiple tumor models


adenosine ...

This study demonstrated particularly strong additive activity in the setting of

anti-PD-1 therapy, possibly because adenosine upregulated PD-1 expression

on the target tumor cells.

These two studies focused on the effect of adenosine production and

signaling through A2aR on CD8+ T cells.

Emerging data suggest that A2aR signaling also triggers MDSC to promote

immunosuppression, and that NK cells are negatively regulated via this

pathway


• Checkpoints

CTLA4 and PD-1/L-1: crowded, little room for differentiation

although top tier assets are still being sought – not every antibody

is a success (see pidilizumab)

TIM-3, LAG-3: multiple programs underway at large pharma

(NVS) and many small biotechs

Enough deals have been done that some sub-par assets are

sitting on the shelf

• Novel Pathways

What are these? everyone wants one...

Drives steep valuations (e.g. NLNK, Flexus)

How can drug discovery navigate this landscape

91


• Vaccines

High value accrues to some programs, but the rules for

success are unknown

Biggest issue: high risk – vaccines fails in Phase 3!

• Immuno-stimulatory Pathways

4-1BB, GITR, OX40 illustrate the tortuous development

pathways these assets can take

Some legacy anti-TNFRs signal non-physiologically

There is room for novel constructs like bispecifics

There are many novel pathways that are under-

represented

How can drug discovery navigate this landscape

92


• The optimal efficacy/tolerability paradigm will impact more

and more indications as therapeutics are successful

• Niche indications with high unmet need allow access to

this remarkably competitive landscape

• Novel interrogation points to drive diffferentiation:

T cells: effectors and Tregs

NK cells

The tumor microenvironment

The tumor itself

Moving ahead

93


Novel Therapeutics: Organizing Principals

94

Tumor cells Lymphocyte subsets

Microenvironment

• TNFRSF proteins

• KIRs

• C-type lectins

• TGFb

• IDO-1

• Chemokine receptors

• LAG3

• HHLA2

• TIM-3


On Twitter @PDRennert

LinkedIn/paulrennert

[email protected]


BACKUPs on PD-L1 antagonists


Medi4736 in the clinic

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MPDL3280a in the clinic

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Science

The immune checkpoint landscape in 2015: combination therapy