Immunotherapy in Cancer: How It All Began · 2018-06-01 · immunotherapy by 2025 • >$80B market...
Transcript of Immunotherapy in Cancer: How It All Began · 2018-06-01 · immunotherapy by 2025 • >$80B market...
Immunotherapy in Cancer: How It All Began
Drew Pardoll MD, PhD Director, Bloomberg-Kimmel Institute
Johns Hopkins School of Medicine
Immunotherapy: History, Present Status & Future
“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
Coley’s toxins
Approval of IL-2 for melanoma
TIL formelanoma
αCTLA-4 approvedfor melanoma
αPD-1 formelanoma,renal, lung
αPD-1 in10 morecancers,TVEC formelanomaCD19 bitesfor B-ALL
CAR Ts
Advances in Cancer Immunology & Immunotherapy
ClinicalImmunotherapy
Milestones
Basic Immunology/Cancer
Immunology TIL, tumor-infiltrating lymphocytes
Phan GQ, et al. Proc Natl Acad Sci U S A. 2003;100(14):8372-8377. Attia P, et al. J Clin Oncol. 2005;23(25):6043-6053. Yang JC, et al. J Immunother. 2007;30(8):825-830.
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
Tumor
PD-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-Years of Tumor Remission for Solid Cancers in 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 yrs,50% willhave died
Duration of Response and Overall SurvivalLung Cancer
NSCLC Respondersa,b by Histology
Time, Week0 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
onsq
uam
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 Treatment129 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
Brahmer JR, et al. J Clin Oncol. 2014;32(5_Suppl): Abstract 8112. Brahmer JR, et al. J Thorac Oncol. 2014;9(4 Suppl1): Abstract 96PD.
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 Cell T Cell
IFN-g
T cell–induced PD-L1 upregulationAdaptive Resistance
STATsTumor-infiltrating leukocyte
PD-1
PD-L1
Topalian SL, et al. Cancer Cell. 2015;27(4):450-461.
Implication: The immune surveillance hypothesis was half right – patients DO have an extant repertoire of antitumor 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?
*Triplenegative
Lawrence MS, et al. Nature. 2013;499(7457)214-218.
Colorectal Cancers Are Generally Unresponsive to PD-1 Blockade, but the MSI-High Subset Has a High
Mutational Load
Microsatellite instability (MSI): genetic hypermutabilityresulting from impaired DNA mismatch repair, present in ~15% colon cancers, 5%-20% of multiple other tumor types
Lawrence MS, et al. Nature. 2013;499(7457)214-218.
-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
Objective ResponsesMMR-Deficient CRC
(MSI) MMR-Proficient CRC
(MSS)
MMR-Deficient Non-CRC
(MSI) N 13 25 10Objective Response Rate 62% 0% 60%
Disease Control Rate 92% 16% 70%
Le DT, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA100.
*
*
*
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 upregulated in tumors (cancer-testes Ag), but their role in antitumor 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
Feng H, et al. Science. 2008;319(5866):1096-1100.
> 40% of MCC patients develop distant disease...
Goh G, et al. Oncotarget. 2015;7(3):3403-3415.
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 PT, et al. N Engl J Med. 2016;374(26):2542-2552.
Why Don’t More Patients Respond to Anti-PD-1?
How do we capture the remaining 80%-90%?
1) Multiple checkpoints on antitumor T cellsSolution – multicheckpoint blockade (>500 trials)
EGFR, Stat3Raf/MEK
Tumor
DendriticCell
Treg
Tumor-specific
CTL
MΦ/MDSC
PD-L1
PD-L1
Tumor Antigens
Antitumor Cytotoxic T Cell Responses Against Tumors Are Suppressed by Multiple Mechanisms
IL10,TGFβ
IL-35Neuritin
IDOArginase
PD-1LAG-3
Tim3TIGIT
T helperCell
Foxp3
Tbet
HLANeuropilinCTLA4
TIGITGITR
“Help” topromote CTL
1) Multiple checkpoints on antitumor T cellsSolution – multicheckpoint blockade (>500 combotrials, αPD-1 + αCTLA-4 promising, but high toxicity)
2) Suppressive cells in the tumor microenvironment:a) Treg, b) myeloid-derived suppresor cells/MΦSolution – block receptors that promote these cells or
block suppressive molecules they produce3) Endogenous antitumor T-cell response too weak
Solution – Activate the T cells the patient has: a) vaccinesb) intra-tumor injection (endogenous vaccine)c) targeted therapy (BRAF, EGFR, MEK in clinic)
4) Chimeric antigen receptor and TCR-engineered ACT
Why Don’t More Patients Respond to Anti-PD-1?
How do we capture the remaining 80%-90%?
Considerations for Predictive Biomarker Use in Clinical Development of Immunotherapies• No obvious clean selection biomarker such as
oncogene mutation. MSI best current biomarker, PD-L1 second best – 4 PD-L1 tests approved. CD8 infiltrate a possibly simpler biomarker.
• In the absence of a “clean” biomarker, imperfect biomarkers useful in prioritizing (ie, 1st vs 2nd line)
• If biology suggests the target is acting in the tumor microenvironment, the likely biomarker will be in the tumor biopsy
• Retrospective analysis of biomarker expression and its correlation with response are the first step in defining useful biomarkers
Pretreatment Tumor PD-L1 Expression Correlates With Response to Anti-PD-1 Pembrolizumab) in
NSCLC: Individualizing Treatment Strategy
≥ 50% tumor cells PD-L1+- Response rate 45%- Median survival not reached
< 50% tumor cells PD-L1+- Response rate 11%-17%- Median survival 8.8 months
Garon EB, et al. N Engl J Med. 2016;372(21):2018-2028.
Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Thanks to patients and collaborating clinical trial centers.