Immunotherapy for Metastatic Uveal Melanoma Udai S. Kammula, M.D., F.A.C.S. Surgery Branch National Cancer Institute National Institutes of Health
Immunotherapy for Metastatic Uveal Melanoma
Udai S. Kammula, M.D., F.A.C.S.Surgery Branch
National Cancer InstituteNational Institutes of Health
20142013
Cancer Immunotherapy
• A type of cancer treatment designed to boost the body's natural defenses to fight the cancer.
• It uses substances either made by the body or in a laboratory to improve or restore immune system function.
What is Cancer Immunotherapy?
Nature reviews 2004
Innate Immunity(Rapid Response)
Adaptive Immunity(Slow Response)
Components of the Immune System
Tumor Specific T Cells
Proliferation: Cytokines
Activate (release inhibition): Checkpoint Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
Proliferation: Cytokines
Activate (release inhibition): Checkpoint Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
Proliferation: Cytokines
Activate (release inhibition): Checkpoint Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
Year Author Trial Type Therapy Criteria n PR CR ORR(%)
2011 Tarhini Phase II Tremelimumab 15mg/kg RECIST 8 0 1 132012 Danielli EAP Ipilimumab 10mg/kg mod WHO 9 0 0 0
2013 Luke EAP Ipilimumab 3 or 10mg/kgirRC and
mod WHO 35 1 1 6
2013 Kelderman EAP Ipilimumab 3mg/kgRECIST and irRC 14 1 0 7
2013 Khattak EAP Ipilimumab 3mg/kg RECIST 5 0 0 0
2013 Maio EAP Ipilimumab 3mg/kg irRC 82 4 0 5
2015 Joshua Phase II Tremelimumab 15mg/kg RECIST 11 0 0 02015 Zimmer Phase II Ipilimumab 3mg/kg RECIST 34 0 0 02014 Herbst NA MPDL-3280A (Anti-PD-L1) RECIST 4 0 0 0
2016 Kottschade EAP Pembrolizumab 2mg/kg irRC 8 2 1 38
2016 Karydis EAP Pembrolizumab 2mg/kgRECIST and irRC 25 2 0 8
2016 Algazi NAAnti-PD-1 or Anti-PD-L1
(various doses) RECIST 56 2 0 4 TOTAL 291 12 3 5%
Checkpoint Blockade in Uveal Melanoma
Agents Phase Mechanism of action Trial ID
Selumetinib + MEDI4736 I MEKi + anti-PD-L1 NCT02586987
Nivolumab + ipilimumab II Anti-PD-1 + anti-CTLA-4NCT01585194, NCT02626962
Indoximod+ pembrolizumab/
nivolumab/ipilimumab I/II IDO inhib + checkpoint NCT02073123
Pembrolizumab + Entinostat II HDAC inhib + checkpoint NCT02697630
Nivolumab + anti-CD137 +TIL I
TIL + checkpoint + agonistic CD137 ab NCT02652455
IMCgp100 I/II Immune mobilizing TCRsNCT02570308NCT02889861
Checkpoint Combinations and Others
Proliferation: Cytokines
Activate (release inhibition): Checkpoint Blockade
Adoptive transfer: Autologous TIL
Effective Immunotherapies Exploit Endogenous Tumor Specific T Cells
Adoptive Cell Transfer (ACT) with TIL
Non-myeloablative (NMA) lymphocyte depleting preparative regimen:
Cyclophosphamide (60 mg/kg/day X 2 days IV) Fludarabine (25 mg/m2/day IV X 5 days)
Intravenous infusion of TIL
High-dose intravenous (IV) IL-2
DAY -7 -5
Cy Fludarabine IL-2
TIL infusion
0
PBLTIL Infusion
Surgery Branch/NCI Adoptive TIL Transfer Therapy
n PR (%) CR (%) ORR (%)
194 62 (32%) 44 (23%) 106 (55%)
Adoptive TIL Transfer Therapy for Metastatic Cutaneous Melanoma: Surgery Branch/NIH
Liver Tumor Resection
Adoptive Transfer ofAutoreactive OM specific TIL
Expansion of Autoreactive OM specific TIL
1
2
3Tumor Exome Sequencingto Identify Driver Mutations
Establish and Screen TIL cultures for Tumor Reactivity
NCT01814046: Adoptive Immunotherapy for Metastatic Uveal Melanoma--Trial Design
Expansion of Tumor ReactiveUM Specific TIL
Adoptive Transfer of Tumor Reactive UM Specific TIL
Eligible and Consented for Metastasectomy
(n=28)
Successful TIL expansionfor potential therapy
(n=27; 96%)
Insufficient TIL expansion (n=1)
No TIL identified in tumor after prior Yttrium bead therapy
NCT01814046: Generation of TIL from Uveal Melanoma Metastases
Underwent Successful Metastasectomy(n=28)
Liver procurement (61%)
NCT01814046: Demographics of UM Patients Receiving Adoptive TIL Therapy
Number of patients 21Age (mean; range) 52; 32-63
Gender F:M 8:13
Primary Tumor TreatmentRT 15 (71%)
Enucleation 6 (29%)
Metastatic SitesLiver 20 (95%)
Extrahepatic 17 (81%)
AJCC M stage (Uveal criteria)M1a 3 (14%)M1b 10 (48%)M1c 8 (38%)
NCT01814046: Demographics of UM Patients Receiving Adoptive TIL Therapy
Prior Response
0/12
Number of patients 21
Prior systemic therapy 12 (57%)
Prior immunotherapy 9 (43%)Anti-CTLA-4 only 1 (5%)
Anti-PD-1 only 1 (5%)Anti-CTLA-4 + Anti-PD-1 7 (33%)
Number of patients 21
Cyclophosphamide (60 mg/kg/day X 2 days IV)Fludarabine (25 mg/m2/day IV X 5 days) All
Total cells (x109), median (range) 85 (17-138)% CD4+, median (range) 60% (2-95%)% CD8+, median (range) 39% (2-98%)
IL-2 doses, median (range) 5 (0-8)
NCT01814046: Treatment of UM Patients with Adoptive TIL Therapy
Event n %Lymphopenia 21 100Neutropenia 21 100
Thrombocytopenia 21 100Anemia 14 67Infection 6 29
Treatment related death 1 5
Adverse Events (Grade >3)
Chemotherapy RelatedNo significant immune related adverse events
9 19 5 13 1 8 4 12 6 18 3 17 2 15 10 14 20 21 11 16-100
-50
0
50
100
Max
imum
cha
nge
in tu
mor
size
from
bas
elin
e (%
)
Patient
n=19
919513184126183172201510141116 -100
-50
0
50
1005
16
Checkpoint refractoryNo prior checkpoint
Prior Immunotherapy
++
+
Best Overall Response to TIL Therapy in Metastatic Uveal Melanoma
20 evaluable patientsORR 7/20 (35%)
6 PR / 1 CR
52 F with metastatic uveal melanoma to liver, bone, peritoneum
Presented with rapidly deteriorating performanceAbdominal painEarly satietyAscitesWeight lossBone painNarcotic use
UM Patient #10
Baseline
UM Patient #10
Baseline Post ACT +1 month
UM Patient #10
Patient 12 Pre TIL 2 months1 month 3 months
PerOm
Liv
Bo Bo
Bo
Bo
PerOm
Bo
*
*
*
*
Pre
Tumor Regression in UM Patient #10 After TIL Therapy
Normalcardiacuptake
*
Tumor Regression in UM Patient #21 After TIL Therapy (checkpoint refractory)
Pre 1 month 2 months
Tumor Regression in UM Patient #21 After TIL Therapy (checkpoint refractory)
Pre 1 month 2 months
Pre Post 5 months Pre Post 5 months Pre Post 5 months
Pre Post 5 months Pre Post 5 months Pre Post 5 months
Patient 1Pre TIL
5 months
Tumor Regression in UM Patient #1 After TIL Therapy (checkpoint refractory)
Pre TIL
Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)
Pre TIL 21 months
Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)
Complete Regression in UM Patient #16 After TIL Therapy (checkpoint refractory)
0
5
10
15
20
-10 -5 0 5 10 15 20
Series1
Series20
5
10
15
20
-9-6-30369
Series1
Series2
Tum
or s
ize
(cm
2 )
Time relative to TIL therapy (months)
Post anti-CTLA-4/PD-1
TILInfusion
Liver met #1
Liver met #2
Data 1
0 5 10 15 20-100-80-60-40-20
020406080
100
Caruso 1TourignyParkerWinningScott
ChoateGuarinoProto, Michael
Warner, Ingemar
Dillon, John
Deschryver, Michelle
Begnaud, Lynn
Reichlin, Richard
Sandner, Kirsten
Dschuhan, Patricia
Chamberlain
white
McNeight
Bussman1
harrer
Cha
nge
in tu
mor
size
from
bas
elin
e (%
)
Time since TIL therapy (months)
PD (20% increase)
PD (New lesion)
Ongoing
Checkpoint refractoryNo prior checkpoint
Prior Immunotherapy Current response status
Kinetics of Tumor Response in Uveal Melanoma Patients After TIL Therapy
Selected metastatic uveal melanoma patients are responsive to TIL immunotherapy.
Durable complete regression can be achieved in metastatic uveal melanoma.
Clinical response correlates with the autologous tumor reactivity of the infused TIL
Summary
Limitations of Current Study and Unanswered Questions
Small pilot trial
Highly selected patients enrolled
Need more data to determine: Which patients will benefit? Durability of responses? How to improve the T cell product?
How can we help patients who don’t have reactive T cells in their TIL?
Genetic Engineering of T Cells to Target Uveal Melanoma
NIH PathologyMark RaffeldLiqiang XiTrinh Pham
CCR BioinformaticsEric StahlbergParthav JailwalaYvonne Edwards
AcknowledgmentsKammula LabSmita ChandranArvind SabesanBiman PariaAbhishek SrivastavaLuke RothermelDan StephensSyed ShahAnran Wang
Surgery Branch (SB)Anna PasettoTodd PrickettJared Gartner
SB Cell Production FacilityRob SomervilleJohn Wunderlich
Immunotherapy TeamMarie StatlerImmuno FellowsImmuno Senior StaffSteven Rosenberg
Restifo LabNick RestifoMadhu Sukumar
SB Retroviral CoreSteve Feldman
University of Miami J. William HarbourNicolas Acquavella
UM Patients and Families
Association Between Clinical Response and Pre-treatment TIL Reactivity
Pre-treatment In Vitro Tumor Reactivity Criteria
> 3% frequency> 2x109 cells> 100 pg/ml IFN-
< 3% frequency< 2x109 cells< 100 pg/ml IFN-
P = 0.003
0.1
1
10
100
<0.1
1
10
100
< 10
100
1000
10000
<
>
Tum
or in
duce
d IF
N-
(pg/
ml)
R NR
>100
<100% T
umor
rea
ctiv
e T
cells
>3
<3
Num
ber
of tu
mor
reac
tive
T ce
lls (x
109
)
R NR
>2x109
<2x109
Response vs. Frequency of Tumor Reactive TILs
Response vs. Number of Tumor Reactive TILs
A. B.
R NR
Response vs. IFN- release from Tumor Reactive TILs
C.
P = .01 P = .008 P = .006