Advances in Immunotherapy

8/20/2019 Advances in Immunotherapy

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pdate on

Immunotherapy

Charles G. Drake MD / PhD

Professor: Medical Oncology, Immunology and Urology

Co-Direcor: Di!ision of Immunology

Co-Direcor: Muli-Disci"linary Prosae Cancer Clinic

#ohns $o"kins %immel Cancer Cener


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Disclosure

• Consulting: Agenus, Dendreon, NexImmune, ImmunExcite, Janssen, Lilly,Merck, Pierre Fare, !oc"e # $enentec"

• Patents

A% Medimmune, &M', Janssen

• 'tock"older Com(ugen, NexImmune, Poten)a, *i)ona

• '(onsored !esearc" Agreement

&M', Janssen, Aduro &iotec"


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• Enrolled on /irst P"ase I o/ MD56778+ 1no

Ni-oluma2• !ecei-ed 9 on study treatments

• 'ide E//ects "y(ot"yroidism, $I disturance

• Discontinued due to stale (artial res(onse

• Last seen 78#&'(), C* 'can Com(lete !es(onse

Continued ;<

'(/()/'* +"re- '/&)/'* '0/&&/'*

U1-guided 2io"sy:

3o !ia2le umor

'4/&&/'*


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•

0o does current immunot"era(y =ork>?• 0o o/ten does immunot"era(y ork?

• Can e select (atients /or immunot"era(y?

• Can immunot"era(y e im(ro-ed?

– Comining @ c"eck(oint locking agents

– Comining a cancer -accine it" immunot"era(y

utline


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&iology o/ Immune

C"eck(oint &lockade


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CDB * Cells Are

=&orn to 4ill>


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'ome Cancers are

0ea-ily In/iltrated it" 4iller CDB * Cells

&ron 'taining CDB


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PD6L7 Engages PD67 to 'end t"e =N $> 'ignal:

PD6L7 1or L@2 is t"e Foot on t"e &rake

CD* 5 cell5umor cell

M0C

PD6L7

PD6L@PD67

5umor 6nigen

*C!

PD67

- - -

- - -

7 7 7

PD6L7 Ex(ression on *umor Cells !

Myeloid Cells 'END' t"at Negati-e 'ignal


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89haused5umor

Infilraing

5 Cell

6ni-PD-( or

6ni-PD-;(

&locking PD67 or PD6L7

Allos CDB * Cells to !egain t"e Ca(acity to 4ill


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O2


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PD67 &lockade Dri-esCDB * Cell Proli/eration

6ni-PD-( or

6ni-PD-;(

89haused

5umorInfilraing

5 Cell


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CD* 5 Cell Proliferaion

May ;ead o 8Pseudo-Progression

Drake CG et al Journal o/ Clinical ncology, @879 A'C Annual Meeting Astracts<ol 97, No 7GHsu((l 1May @8 'u((lement2, @879: .G7. A'C @879

6 months


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Dura2le es"onse Off 5reamen

Is his Immune Memory=

Drake CG et al Journal o/ Clinical ncology, @879 A'C Annual Meeting Astracts<ol 97, No 7GHsu((l 1May @8 'u((lement2, @879: .G7. A'C @879

Generally tolerable: fatigue, rash, pruritus, diarrhea- 3 deaths: pneumonitis (non-RCC)

Preliminary eay in hea!ily pre-treated patients:- 29% objective responses- "edian P#$ %&3 months

6 months

Durability

ofResponseEven O

Drug

'll stopped therapy


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Clinical As(ects o/Immune C"eck(oint

&lockade


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Pi-otal *rial o/ PD67 &lockade in !CC:

Ni-oluma -s 'C

Presented y '"arma et al at t"e Euro(ean Cancer Congress, ienna, @+ 'e(temer


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19

5reamen-relaed 69s in ('? of "aiens

Ni-olumaN .8+

E-erolimusN 9

6ny grade Grade Grade 0a 6ny grade Grade Grade 02

*reatment6related AEs, K 7B 7 BB 99 .

Fatigue 99 @ 8 9. 9 8

Nausea 7. 7 8 7 7 8

Prurius 7. 8 8 78 8 8

Diarrhea 7@ 7 8 @7 7 8

Decreased a""eie 7@ 7 8 @7 7 8

ash 78 7 8 @8 7 8

Cough 8 8 7 8 8

6nemia B @ 8 @. B 7

Dys"nea 7 8 79 7 8

9dema "eri"heral . 8 8 7. 7 8

Pneumoniis . 7 7 7G 9 8

Mucosal inflammaion 9 8 8 7 9 8Dysgeusia 9 8 8 79 8 8

$y"erglycemia @ 7 7 7@ 9 7

1omaiis @ 8 8 @ . 8

$y"erriglyceridemia 7 8 8 7+ . 7

9"isais 7 8 8 78 8 8

a $rade . AEs not listed in tale: increased lood creatinine 172, acute kidney inury 172, ana("ylactic reaction 172<

$rade . AEs not listed in tale: increased lood triglycerides 1@2, acute kidney inury 172, se(sis 172, c"ronicostructi-e (ulmonary disorder 172, increased lood c"olesterol 172, neutro(enia 172, (neumonia 172<


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• Pemroli)uma in melanoma

• Ni-oluma in melanoma

• Ni-oluma in N'CLC 1suamous2

• Ni-oluma in N'CLC 1non6suamous2

• Ni-oluma in 4idney Cancer

• ? Next O Ate)oli)uma in &ladder Cancer

PD67 # PD6L7 &locking Antiodies:

Partial list o/ FDA A((ro-als


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0o//man6Centis, A'C $ @87+

6ni-PD-;( In ladder Cancer

Im!igor &(' +Phase II


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6ni-PD-;( In ladder Cancer

esuls


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Can PD6L7 Ex(ression in t"e *umor # *umor

Microen-ironment Predict !es(onse?

CD* 5 cell

5umor Cell OOher Cells

Eihin 5umor

M0C

PD6L7

- - -

PD6L@PD67

- - -

5umor 6nigen

*C!

PD67

7 7 7

CDB * Cells are &eing 0eld in C"eck

30EN PD6L7 is Ex(ressed


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PD-;( 9"ression on Myeloid Cells

Is +Eeakly 6ssociaed Fih es"onse


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Immunot"era(y

Comination !egimens


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C*LA6. is Ex(ressed on CD. * Cells

1*reg2 t"at *urn o// CDB 4iller * Cells

CD* 5 cell 5umor cell

M0C*C!

777

egulaory CD0

5 Cell

+oP7

C5;6-0

777

C5;6-0

777

1u"ressi!e

acors

-- - --


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Anti6C*LA6. May De(lete t"e 'u((ressi-e

!egulatory * Cells

CD* 5 cell 5umor cell

M0C*C!

777

1u"ressi!e

acors

egulaory CD0

5 Cell

+oP7

C5;6-0

777

C5;6-0

777

-- - --

6ni-C5;6-0

$igh ae of Immune elaed 6d!erse 9!ens Fhen


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$igh ae of Immune-elaed 6d!erse 9!ens Fhen6ni-C5;6-0 is Com2ined Fih 6ni-PD-(

Eolchok #D e al. 3 9n l # Med &'(HB>:(&&-(

$e"aiis

Coliis

3e"hriis

Dermaiis


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&locking &*0 PD67 and C*LA6.1i(ilimuma and ni-oluma in ad-anced melanoma2

Eolchok #D e al. 3 9ngl # Med&'(HB>:(&&-(


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Mot)er et al al A'C @87G

Com2ined Check"oin lockade in

%idney Cancer


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Increased es"onse ae Fih Com2inaion

5reamen

Increased 5oiciy Fih Com2inaion 5reamen


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C i i 'i l l *


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Comining 'i(uleucel6*

3it" C*LA6. &lockade

$ipuleuel- (*+)

pilimumab (+)

mmediate

.elayed

R

;arry ong UC1 and Pam 1harma MD6CC


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'ummary

7< Immune C"eck(oint &lockade Ex(anding !ole in Cancer *reatment

7< 3ell6tolerated

@< $ood res(onse rate9< 'ome res(onses maintained long6term o//6treatment

.< utstanding uestions

7< (timal regimen

@< Predicti-e iomarkers /or res(onse

@< 3"y are t"e Non6!es(onsi-e *umors Non6!es(onsi-e?

9< Comination A((roac"es Next 'te( Forard

7< C"emot"era(y

@< !adiation *"era(y9< Cancer accines

.< Comining multi(le c"eck(oint locking agents


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Extra 'lides


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utstanding Clinical Questions

7< 3"at are mec"anisms o/ (rogression a/ter initial res(onse ?

(. ;oss of umor anigen

@< Loss o/ Class I M0C on *arget Cells

9< Emerging su((ressi-e cells

@< 3"at are mec"anisms o/ resistance to immunot"era(y?

(. ;ack of 5 cell infilrae

@< t"er immune c"eck(oint molecules

9< 'u((ressi-e cells 1* cells and ot"ers2

.< 'u((ressi-e cytokines 1*$F6eta, IL6782

9< 3"at are o(timal comination regimens?

7< Anti6PD67 # PD6L7 (lus anti6C*LA6.

@< Anti6PD67 # PD6L7 (lus a E$F6targeted t"era(y

9< Comining c"eck(oint lockade it" an agonist 15.8, CD.8, .7&&2

.< 3"at is o(timal treatment regimen?7< Fixed time (eriod t"en sto(

@< Continuous i


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3"at is an Antigen ?

* Cell:

Antigen Pe(tide in M0C $roo-e

& Cell:

Antigen 9D 'tructure !ecogni)ed

y Antiody


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3"at is an AN*I6ody ?

0ansel et< al, Nature Rev Drug Discovery , @878: :9@G<


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CDB * Cells1&orn to 4ill2

!ecogni)e a 1P9CIIC target (rotein

1antigen2 in t"e groo-e o/ AN*0E!

molecule called M0C

'(eci/ically and (oer/ully kill t"eir

targets

'erial killers

3it" memory


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CD. * Cells1"el(ers2

AL' recogni)e t"eir target (rotein

1antigen2 in t"e groo-e o/ AN*0E!molecule called M0C

CD. * cells 0ELP t"eir /ello CDB *

cells to kill

CD. * cells 0ELP & cells to make

antiodies


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Dendritic Cells

3"ere t"e magic egins ;


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CD.

CDB

DC

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Advances in Immunotherapy