Recent Updates in Cancer Immunotherapy

H. Miles Prince

Epworth Healthcare

Peter MacCallum Cancer Centre

How do we choose?

What is the next ‘new’ flavour?

Where does immunotherapy fit in?

St Sebastian

Archilles

versus

Immune mechanisms to attack haematological cancers

• Monoclonal antibodies

ADCC: Antibody-dependent Cell Cytotoxicity

• Monoclonal antibodies

• Allogeneic transplantation

• Immune stimulants• Interferon

• hairy cell leukemia, follicular lymphoma,myeloma

• Immunomodulatory Drugs (thalidomide, lenalidomide, pomalidomide)

• Myeloma, follicular lymphoma, myelodysplasia

Immune mechanisms to attack haematological cancers

Cereblon

Non- cereblon targets

=new drugs

Immune mechanisms to attack cancer• Monoclonal antibodies

• Allogeneic transplantation

• Immune stimulants• Interferon

• Immunomodulatory Drugs• thalidomide, lenalidomide, pomalidomide

• Chimeric Antigen Receptor (CAR) – T cells

• Bi-specific antibodies• antibodies that bind target and T cells

• Checkpoint inhibitors• CTLA4, PD1 axis

The future beyond chemotherapy

• Monoclonal antibodies

• Immune stimulants• Interferon

• Immunomodulatory Drugs• thalidomide, lenalidomide, pomalidomide

• Allogeneic transplantation

• CAR–T cells

• Bi-specific antibodies• antibodies that bind target and T cells

• Checkpoint inhibitors• CTLA4, PD1 axis

• Small molecules• Tyrosine Kinase Inhibitors

• bcr-abl (CML)

• BTK (CLL, lymphomas)

• FLT3 (AML)

• JAK2i (myeloproliferative)

• Epigenetic targets• Demethylating agents

• Readers/Writers/Erasors

• HDACi, BETi

• Mutations

• EZH2, IDH

• Pro-apoptotic• BH3-mimetcs, MCLi

VS

The future beyond chemotherapy

A story of CD19/CD20 for lymphoma/leukaemia

B cell target

Rituximab in B cell NHL

• Induction• Diffuse large B cell Lymphoma

• Follicular Lymphoma

• Marginal zone lymphoma

• Burkitt’s lymphoma

• Chronic Lymphocytic Leukemia

• Maintenance• Low grade NHL

• Salvage/Re-treatment

Radio-immunotherapy B cell NHL

• Effective

• Cumbersome process

• Utilization is falling

• Competing therapies are taking the ‘market share’

• BH3 mimetics

Ease of use is critical to utilization

Second-generation CAR used in current clinical studies at Penn and CHOP

Shannon L. Maude et al. Blood 2015;125:4017-4023

©2015 by American Society of Hematology

Second-generation CAR used in current clinical studies at Penn and CHOP

Shannon L. Maude et al. Blood 2015;125:4017-4023

©2015 by American Society of Hematology

Antigen Antigen Antigen

Targeting CD19

CAR-T in ALL

UPen: CTL019 CAR-T cells

• Children (n = 25) and adults (n=5)

• CTL019• proliferated in vivo

• detected in blood, marrow and CSF

• CR in 27 (90%)

• All pts had cytokine release syndrome• severe = 27%

• Predicted 6m• EFS = 67%

• OS = 78%

• persistence of T cells = 68%

• B cell aplasia = 73%

Event-free survival in 30 children and adults treated

with CTL019 therapy.

Shannon L. Maude et al. Blood 2015;125:4017-4023

CLL

Summary of CAR T-cells in lymphoproliferative diseases

• 2nd generation CAR-T

• Against CD19 currently

• ALL – high + deep response rate – prolonged remissions

• CLL - effective in smaller proportion: will this have a place with new targeted therapies?

• NHL – under investigation

• MM – promising: why are CD19 effective?

• Cytokine Release Syndrome predicts response

• Responding patients had persistence of CAR T cells more than several months post-Rx

• Persistence of CAR-T required to maintain response

• Patients with persistence of CAR T cells had B cell aplasia

Where can the process be modified?

Patient

Selection

Where can the process be modified?

cytokine

cocktail

Where can the process be modified?

Vector construct

Where can the process be modified?

Number and phenotype: CRS

Where can the process be modified? Tumour bulk reduction

Immune suppression

Checkpoint inhibitors

Immunostimulants

Next steps

New Parkville facility 2016/17

A

B

C

D

U

Peter Mac’s (and CTPL’s) new home• 10 clean rooms fully PIC/S compliant• Most steps in grade A & B zones• Substantial amounts of in-process testing and PD in grade C• Scale-up and validation areas• Segregation of EM testing• Biosafety Levels 2 and 3

40

A

B

C

D

U

Bi-specific T cell engagers BiTe

Bi-specific T cell engagers BiTe

•Long infusions

•Toxicities

•Non-persistence: relapse and retreatment

•ALL, NHL

The ‘fate’ of peripheral T cells

Central memory - CMTerminal memory - TM

Effector memory - EM

10/30/13 Leukemia Patients Remain in Remission More Than Two Years After Receiving Genetically Engineered T Cell Therapy

www.uphs.upenn.edu/news/news_releases/2012/12/tcell/print.html 1/2

 

December  9,  2012

CONTACT:

Holly  Auer215-­349-­5659holly.auer@uphs.upenn.edu

This  release  is  available  online  athttp://www.uphs.upenn.edu/news/News_Releases/2012/12/tcell/

Leukemia  Patients  Remain  in  Remission  More  Than  Two  Years

After  Receiving  Genetically  Engineered  T  Cell  Therapy

University  of  Pennsylvania  Researchers  Report  on  Results  of  Trial  in  12  Patients,  Including  TwoChildren

ATLANTA  —  Nine  of  twelve  leukemia  patients  who  received  infusions  of  their  own  T  cells  after  the  cells  had  beengenetically  engineered  to  attack  the  patients’  tumors  responded  to  the  therapy,  which  was  pioneered  by  scientistsin  the  Perelman  School  of  Medicine  at  the  University  of  Pennsylvania.  Penn  Medicine  researchers  will  presentthe  latest  results  of  the  trial  today  at  the  American  Society  of  Hematology’s  Annual  Meeting  and  Exposition.

The  clinical  trial  participants,  all  of  whom  had  advanced  cancers,  included  10  adult  patients  with  chroniclymphocytic  leukemia  treated  at  the  Hospital  of  the  University  of  Pennsylvania  (HUP)  and  two  children  withacute  lymphoblastic  leukemia  treated  at  the  Children’s  Hospital  of  Philadelphia.  Two  of  the  first  three  patientstreated  with  the  protocol  at  HUP  –  whose  cases  were  detailed  in  the  New  England  Journal  of  Medicine  andScience  Translational  Medicine  in  August  2011  –  remain  healthy  and  in  full  remissions  more  than  two  years  aftertheir  treatment,  with  the  engineered  cells  still  circulating  in  their  bodies.  The  findings  reveal  the  first  successfuland  sustained  demonstration  of  the  use  of  gene  transfer  therapy  to  turn  the  body’s  own  immune  cells  intoweapons  aimed  at  cancerous  tumors.

“Our  results  show  that  chimeric  antigen  receptor  modified  T  cells  have  great  promise  to  improve  the  treatment  ofleukemia  and  lymphoma,”  says  the  trial’s  leader,  Carl  June,  MD,  the  Richard  W.  Vague  Professor  inImmunotherapy  in  the  department  of  Pathology  and  Laboratory  Medicine  and  director  of  Translational  Researchin  Penn’s  Abramson  Cancer  Center.  “It  is  possible  that  in  the  future,  this  approach  may  reduce  or  replace  theneed  for  bone  marrow  transplantation.”

The  results  pave  the  way  for  a  potential  paradigm  shift  in  the  treatment  of  these  types  of  blood  cancers,  which  inadvanced  stages  have  the  possibility  of  a  cure  only  with  bone  marrow  transplants.  That  procedure  requires  alengthy  hospitalization  and  carries  at  least  a  20  percent  mortality  risk  -­-­  and  even  then  offers  only  a  limitedchance  of  cure  for  patients  whose  disease  has  not  responded  to  other  treatments.

Three  abstracts  about  the  new  research  will  be  presented  during  the  ASH  meeting.  David  Porter,  MD,  director  ofBlood  and  Marrow  Transplantation  in  the  Abramson  Cancer  Center,  will  give  an  oral  presentation  of  Abstract#717  on  Monday,  Dec.  10,  at  5  PM  in  the  Thomas  Murphy  Ballroom  4,  Level  5,  Building  B  of  the  Georgia  WorldCongress  Center.  Michael  Kalos,  PhD,  director  of  the  Translational  and  Correlative  Studies  Laboratory  at  Penn,will  give  an  oral  presentation  on  Abstract  #756  on  Monday,  Dec.  10,  at  5:45  PM  in  C208-­C210,  Level  2,  BuildingC.  Stephan  Grupp,  MD,  PhD,  director  of  Translational  Research  in  the  Center  for  Childhood  Cancer  Research  atthe  Children's  Hospital  of  Philadelphia,  will  present  a  poster  of  Abstract  #2604  on  Sunday,  Dec.  9,  at  6  PM  in  HallB1-­B2,  Level  1,  Building  B.

The  protocol  for  the  new  treatment  involves  removing  patients'  cells  through  an  apheresis  process  similar  toblood  donation,  and  modifying  them  in  Penn's  cell  and  vaccine  production  facility.  Scientists  there  reprogram  thepatients’  T  cells  to  target  tumor  cells  through  a  gene  modification  technique  using  a  HIV-­derived  lentivirus  vector.The  vector  encodes  an  antibody-­like  protein,  called  a  chimeric  antigen  receptor  (CAR),  which  is  expressed  on  thesurface  of  the  T  cells  and  designed  to  bind  to  a  protein  called  CD19.

The  modified  cells  are  then  infused  back  into  the  patient's  body  following  lymphodepleting  chemotherapy.  Oncethe  T  cells  start  expressing  the  CAR,  they  focus  all  of  their  killing  activity  on  cells  that  express  CD19,  whichincludes  CLL  and  ALL  tumor  cells,  and  normal  B  cells.  All  of  the  other  cells  in  the  patient  that  do  not  expressCD19  are  ignored  by  the  modified  T  cells,  which  limits  systemic  side  effects  typically  experienced  during

“I’ve told the team that resources are notan issue. Speed is the issue.” Novartis Chief Executive Joseph Jimenez

Emma Whitehead refractory relapse of B-ALL “The elephant in the room”

Versus

The competition

Pro-apoptotic agents

BH3-mimetics

Targeting the B cell receptor pathway

Ibrutinib – CLL, NHL

Idelalisib – CLL, NHL

TKI

Archilles

Targeting the B cell receptor pathway

Ibrutinib – CLL, NHL

Idelalisib – CLL, NHL

TKI

Assessing

mutations can

predict

response to

BTK inhibitors

Next Gen

sequencing now

becoming

standard

investigation

Drug effectiveness is dependent on sutype of Diffuse Large Cell Lymphoma

Drug effectiveness is dependent on sutype of Diffuse Large Cell Lymphoma

Effectiveness is dependent on mutation status of Diffuse Large Cell Lymphoma

Immunomodulatory agents in lymphoma (lenalidomide)• Standard therapy in myeloma

• Effective in follicular lymphoma• Responses achieved

• Synergystic with rituximab

• Not effective in maintenence

• Ongoing trials

• Some effect in large cell lymphoma

• (Activated B cell only)

Drug effectiveness is dependent on sutype of Diffuse Large Cell Lymphoma

St Sebastian

The immune synapse

T cell

Target

-Virus

-Bacteria

-Cancer

Checkpoint = suppressed immune system

Checkpoint inhibitors

Pembrolizumab Monotherapy Has Shown Activity in 20 Tumors

64

Melanoma1

-100

0

100NSCLC2 Gastric6H&N3 TNBC5 cHL7

NHL PMBCL8

Urothelial4

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ize

, %

Mesothelioma9 Anal14SCLC11 NPC13

Biliary Tract15 Colorectal16

Esophageal12Ovarian10

ER+/HER2– BC17

1. Daud A et al. ASCO 2015; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. ASCO 2015; 4. Plimack E et al. ASCO 2015; 5. Nanda R et al. SABCS 2014; 6.

Bang YJ et al. ASCO 2015 ; 7. Moskowitz C et al. ASH 2014; 8. Zinzani PL et al. ASH 2015; 9. Alley EA et al. AACR 2015; 10. Varga A et al. ASCO 2015; 11. Ott PA

et al. 2015 ASCO; 12. Doi T et al. ASCO 2015; 13. Hsu C et al. ECC 2015; 14. Ott PA et al. ECC 2015; 15. Bang Y-J et al. ECC 2015; 16. O’Neil B et al. ECC 2015;

17. Rugo HS et al. SABCS 2015;

18. Frenel JS et al. ASCO 2016; 19. Mehnert JM et al. ASCO 2016; 20. Cohen R et al. ASCO 2016.

Cervical18 Thyroid19 Salivary20

-100

0

100

PD1 inhibitors in Hodgkin’s disease

PD-1 axis inhibitors

•Melanoma

•Non-small-cell lung cancer

•Renal-cell cancer

•Hodgkin lymphoma

•(NHL, T cell lymphoma, myeloma)

Summary of responses

Duration of response

Median PFS: 17.4 months (95% CI, 11.7–18.8)

Microenvironment in

Lymphoma

• Many lymphomas evolve from a

polyclonal response to infectious and

auto-antigens

• Tumor cells retain microenvironment

dependency

• Tumor cells use microenvironment for

immunosuppression

• Microenvironment mediates therapy

resistance

Lymphoma Microenvironment

Fowler et al. Haematologica 2016

Lymphoma Microenvironment Model Interactions

Follicular Lymphoma:

Immune Response Signatures

Dave et al. NEJM 2004

Follicular Lymphoma:

Role of Treg Infiltration

Farinha et al. Blood 2010

Lymphoma Microenvironment:

Targeted Approaches

Fowler et al, Haematologica 2016

Hitting the target (immunologically)

CD30

Hodgkin

Lymphoma

Anaplastic T cell

lymphoma

Cutaneous

T cell lymphoma

MediastinalB cell

lymphoma

Hitting the target (immunologically)

CD30

Hodgkin

Lymphoma

Anaplastic T cell

lymphoma

Cutaneous

T cell lymphoma

MediastinalB cell

lymphoma

Expression of CD30 +++++

+++++

+

+++++

Hitting the target (immunologically)

CD30

Hodgkin

Lymphoma

Anaplastic T cell

lymphoma

Cutaneous

T cell lymphoma

MediastinalB cell

lymphoma

Expression of CD30 +++++

+++++

+

+++++

Efficacy of Brentuximab vedotin

Hitting the target (immunologically)

CD30

Hodgkin

Lymphoma

Anaplastic T cell

lymphoma

Cutaneous

T cell lymphoma

MediastinalB cell

lymphoma

Expression of CD30 +++++

+++++

+

+++++

Efficacy of Brentuximab vedotin

Progression-free survival (ITT population)

Assessed by independent review

Bex, bexarotene; MTX, methotrexate Prince et al. Lancet 2017

1.0

0.9

0.8

0.7

0.6

0.5

0.4

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Number of patients at risk:

Brenuximab vedotin

Methotrexate or bexarotene

Time from randomization (months)

Log-rank test p-value: <0.001

Hazard ratio (95% CI): (0.169, 0.430)

Median (months): BV: 16.7 MTX or Bex: 3.5

Number of events: BV: 36 MTX or Bex: 50

Brentuximab vedotin

Methotrexate or bexarotene

Censored

Censored

Hitting the target (immunologically)

CD30

Hodgkin

Lymphoma

Anaplastic T cell

lymphoma

Cutaneous

T cell lymphoma

MediastinalB cell

lymphoma

Expression of CD30 +++++

+++++

+

+++++

Efficacy

What target?

Microenvironment?

Immunotherapy in the future

Biology

toxicity

delivery

•Target expression

•Pathways (NFkB)

•Smart combinations

•Mutation targets

•Ease of delivery

•Length of treatment

•Cost

•Cytokine release

•Immunosupression

•Neurotoxicity

•Combination capacity

Immunotherapy in the future

Biology

toxicity

delivery

•Target expression

•Pathways (NFkB)

•Smart combinations

•Mutation targets

•Ease of delivery

•Length of treatment

•Cost

•Cytokine release

•Immunosupression

•Neurotoxicity

•Combination capacity