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Immunotherapy: History, Present Status & FutureDrew Pardoll MD, PhD

Director, Bloomberg-Kimmel Institute Johns Hopkins School of Medicine

Ten years fromtoday, >50% of patients with inoperable cancer will be receiving some form of immunotherapy- Drew Pardoll January,

WSJ, 2014

1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2015

Discovery of antibodies/Magic bullet theory

Monoclonalantibodies

Elucidation oftumor associated

antigens

Elucidation ofImmune checkpoints

Elucidation of howT cells recognize antigen

Coleys toxins

Approval of IL-2 for melanoma

TIL formelanoma

CTLA-4 approvedfor melanoma

PD-1 formelanoma,renal, lung

PD-1 in10 morecancers,TVEC formelanomaCD19 bitesfor B-ALL

CARTs

Advances in Cancer Immunology & Immunotherapy

Phan et al., PNAS 2003; Attia et al., JCO 2005; Yang et al., J Immunother 2007

IMMUNE CHECKPOINT BLOCKADE: ANTI-CTLA-4 10 % objective response rate (mel and RCC) 23-33% grade 3/4 autoimmune toxicities 1st approved checkpoint inhibitor but ONLY melanoma as single agent

PRE-RX POST-RX

Colitis

Hepatitis

Dermatitis

Activation(cytokines, lysis, prolif.,

migration)

Role of CTLA-4 vs PD-1 in suppressing antitumor immunity

TumorPD-L1PD-1

(-)(-) (-)

Inhibition

PD-1 expressedTraffic to tumor

APC T cellB7.1/2 CD28

TCR Signal 1MHC-Ag

Tumoror Vaccine

B7.1/2 CTLA-4

+

-

Lung(NSC, SC) 155,000 20% 1.5 = 46,500Mesothelioma 5000 30% 1.5* = 2250Breast (TN) 12,000 20% 1.5* = 3600Bladder 16,000 30% 1.5* = 7200Melanoma 9000 40% 2.5 = 9000Kidney 14,000 25% 1.5 = 5250Liver 25,000 20% 1.5* = 7500Gastric 11,000 25% 1.5* = 4125Esophageal 15,000 25% 1.5* = 5625Head & Neck 9000 25% 1.5* = 3375Ovarian 14,000 15% 1.5* = 3150Merkel Cell 1000 70% 1.5* = 1050MSI (multiple) 15,000 65% 3.0* = 29,250

127,875 pt yrs

Mutation-targeted drugs #Annual cases %mutated Resp. rate Durability (yrs)NSCLC (EGFR+ALK+ROS1+BRAF): 128,000 15% 60% .6 = 6396 Melanoma (BRAF+cKIT): 9000 60% 60% .6 = 1620Pap. thyroid ca/CRC (BRAF): 3500 60% 50% .6 = 630GIST (cKIT): 1500 60% 70% 1 = 525Basal cell ca (Hh) 2000 60% 45% 1.6 = 1440

10,611 pt yrs

Anti-PD-1/L1 #Annual cases Resp. Rate Durability (yrs)

Patient-yrs of tumor remission for solid cancers is US: PD-1 blockade vs mutant oncogene-targeted drugs

* Estimated as DOR not available yet

>50% of cancer patients will receive immunotherapy by 2025

>$80B market by 2025 Chemotherapy market will decrease >50%

by 2025 Oncogene-targeted therapy will become a

primer for immunotherapy

Conservative Predictions for thefuture of cancer immunotherapy

Long-term survival of patients with melanoma receiving immune checkpoint

blocking drugs

0 1 2 3 4 5 6 7 8 9 10

100

90

80

70

60

0

50

40

30

20

10Ove

rall

Surv

ival

(%)

Years

IPI (Pooled analysis mixture of 1st & 2nd line)NIVO Monotherapy (Second-Fourth line)NIVO Monotherapy (First line)

At 5 yr,50% willhave died

Duration of Response and Overall SurvivalLung Cancer

NSCLC Respondersa,b by Histology

Time (Week)0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160

Vertical line at 96 weeks = maximum duration of continuous nivolumab therapy

a Responses were assessed by modified RECIST v1.0bAll efficacy analyses based on data collected as of September 2013

Squa

mou

sN

on-s

quam

ous

Duration of response up to discontinuation of therapyOngoing responseTime to responseResponse duration following discontinuation of therapy

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months Since Initiation of Treatment

129 111 82 66 48 35 31 28 20 9 4 3 3 3 2 1 1 1 0 0

Subjects at RiskTotal

All Treated Subjects with NSCLC

Died/Treated Median (95% CI)94/129 9.90 (7.80,12.40)

Prop

ortio

n Su

rviv

al

Median OS: 9.9 Months (7.8, 12.4)

1 year OS Rate 42% (48 pts at risk)

2 year OS Rate 24% (20 pts at risk)

At 4 yr,85% willhave died

TUMOROncogenicpathway (AKT)or geneamplification

T CellTCR

PD-1

MHC-peptide

PD-L1

Constitutive tumor signalinginduces PD-L1 on tumor cells

Innate (tumor cell intrinsic) Resistance

TUMOR

STATs

TUMOR T CellT Cell

IFN-g

T cell-induced PD-L1 up-regulationAdaptive Resistance

STATsTumor infiltrating leukocyte

PD-1

PD-L1Topalian, Drake, Pardoll, Cancer Cell 2015

Implication: The Immune Surveillance hypothesis was half right Patients DO have an extant repertoire of anti-tumor T cells

**

**

**

*

**

*

Tumor Tumor-specific T cell

Tumor-specific T cell

Genetic mutations in cancer encode altered proteins- Some can be tumor specific antigens the biochemical signature

that the immune system uses to recognize the tumor as foreign

*

*

****

**

Many mutations Many antigens Stronger immune response

Mutational heterogeneity in cancer: Altered proteins contain neoepitopes for immune recognition

Does mutational load correlate with responsiveness to immune checkpoint blockade?

Lawrence et al., Nature 2013

*Triplenegative

Colorectal cancers are generally unresponsive to PD-1 blockade, but the MSI-high subset has a high mutational load

Microsatellite instability (MSI): genetic hypermutability resulting from impaired DNA mismatch repair, present in ~15% colon cancers, 5-20% of multiple other tumor types

Lawrence et al., Nature 2013

Objective Responses

MMR-deficient CRC MMR-proficient CRC MMR-deficient non-CRC N 13 25 10

Objective Response Rate 62% 0% 60%

Disease Control Rate 92% 16% 70%

-1 0 0

-5 0

0

5 0

1 0 0M M R -p ro fic ie n t C R C

M M R -d e fic ie n t C R C

M M R -d e fic ie n t n o n -C R C

% C

ha

ng

e f

rom

Ba

se

lin

e S

LD

(MSI) (MSS) (MSI)

*

*

*

Tumor

Tumor-specific T cell

Even in tumors with a lower # of mutations, one or two will likely produce a tumor antigen more than 90% of patients

possess tumor specific T cells

Much evidence for T cell responses against shared tumor-associated antigens ie self-antigens up-regulated in tumors (cancer-testes Ag), but their role in anti-tumor immunity remains to be determined

Viral antigens in virus-induced cancers are the other type of neoantigen

EBV (Hodgkin,Burkitt,NPC)HPV (Cervical, vulvar, anal, H&N)

MCPyV (Merkel Cell Cancer)HBV,HCV (Liver Cancer)

Overview: Merkel cell carcinoma ~ 2,000 cases/year in the US

UV exposure, age >50, immune suppression

Merkel cell polyomavirus present in 80% of cases

17

Adapted from Feng, Science 2008

> 40% of MCC patients develop distant disease...

Goh et al., Oncotarget 2015

Virus-positive vs.

negative MCC: at the extremes of mutational frequency

compared to TCGA data for other cancers

Virus Positive Virus Negative

UV mutations

MCC antigens: Virus-positive tumors have a low mutational burden but express viral

oncoproteins that are strong immune stimulants (ORR = 62%) Virus-negative tumors have a very high carcinogen-induced

mutational burden (UV light) (ORR = 44%)

Nghiem,

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