Thomas Davis, MD Celldex Therapeutics, Inc. 2 weeks CDX‐1401 (i.c.) Poly ICLC (s.c.) R848 (topical...
Transcript of Thomas Davis, MD Celldex Therapeutics, Inc. 2 weeks CDX‐1401 (i.c.) Poly ICLC (s.c.) R848 (topical...
Robust science is always the highest goal Our intent is to help people Within our system, effective agents require
commercial marketing to make them available to patients
The path through the regulatory and commercial gauntlet is therefore unavoidable
Commercialization ultimately defines success, encouraging further development
Broad view and final endpoint is critical◦ Keep next steps and final ambition in mind
Build value with minimal risk◦ Biphasic interest curve Exciting early data or proven technology more viable
Single agent or simple development preferable
Fail early and learn IP and competition are critical Limited ability to talk publicly
Antibodies are no longer “immunotherapy” “Checkpoint inhibitors” have validated generic
immune activation approaches◦ Had a tenuous start
Vaccines are still not accepted readily◦ RR versus OS◦ Manufacturing and Marketing complexity of DC
vaccine has compromised the field Individual vaccine platforms are even harder
to validate◦ Proof of principle important
Smaller companies more prepared to accept risks◦ Partnering or Commercialization important◦ While small companies are loath to halt development,
the standards are still similar to larger companies More potent effects are important◦ Fail early is still important◦ Modest OS benefits are very difficult to prove efficiently◦ Immune response alone may be inadequate◦ It is hard to justify expensive advanced development
based upon the subtler aspects of the Immune Response Criteria
Reasonable path to approval◦ Feasibility is critical
CANDIDATE PHASE 3
Rindopepimut
CDX-011
Rindopepimut
CDX-1135
CDX-1127
CDX-301
CDX-1401
INDICATION
Front-line Glioblastoma
Breast Cancer
Recurrent GBM
Dense Deposit Disease
Lymphoma, Cancer
HSC Transplantation
Multiple Solid Tumors
PHASE 2PHASE 1
EMERGE TrialEMERGE Trial
ReACT TrialReACT Trial
ACT IV Registration TrialACT IV Registration Trial
PilotPilot
Rindopepimut: both PFS and OS improvement against non-study comparators
Surv
ival
Pro
babi
lity
Median (months)
OS at 24
Months
OS at 36 Months
Comparison to Historical
Control
ACT III (n=65) 24.6 52% 31% p = <0.0001ACT II (n=22) 24.4 50% 23% p = 0.0034ACTIVATE (n=18) 24.6 50% 33% p = 0.0003Matched historical control (n=17)
15.2 6% 6%
Vaccinations begin approximately 3 months after diagnosisOS from Diagnosis (Months)
Median duration of follow-up: ACT III: 48.7 monthsACT II: 71.8 monthsACTIVATE: 99.3 months
Enhanced immunity to protein vaccines by antigen delivery to DCs in situ◦ Targeting antigens with mAbs to MR and DEC-205
Enhancing T cell responses with co-stimulation◦ Development of an anti-human CD27 agonist mAb
Expansion of DC subsets◦ Flt3L-back in the clinic
DEC-205CD205MR
CD206
B11Hu IgG1
3G9Hu IgG1
Antibody Specificity APC Binding in human tissues AffinityKD (M)
B11 Mannose receptor
Dermal DCs, Interstitial DCs, macrophages in most tissues
~7 x 10‐10
3G9 DEC‐205 DCs in lymph nodes, tissue DCs ~2 x 10‐10
Genetically fused
antigen
Recombinant antibody product
Takemasa Tsuji et al J Immunol. 2011, 186: 1218
IFN-CD8+
DC
Recognition by NY-ESO-1-specific CD8+ T cell clone
0
100
200
300
400
500
600
M
R-C
on
t
M
R-E
SO
D
EC
-Co
nt
D
EC
-ES
O
ES
O p
rote
in
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tid
e (9
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pu
lsedN
umbe
r of
IFN
-sp
ots
/ 2,
000
cells
NY-ESO-1protein
-MR-NY-ESO-1or
-DEC-NY-ESO-1
Targeting improves crossTargeting improves cross--presentation presentation of NYof NY--ESOESO--11
-1401
1-20
11-3
0
21-4
0
31-5
0
41-6
0
51-7
0
61-8
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101-
120
111-
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119-
143
131-
150
139-
160
151-
170
161-
180
#1-1
7
Unp
ulse
d
Num
ber o
f IFN
-sp
ots
0
100
200
300
400
500
600
700
peptide pool3G9-NYESO-1
Presensitized with
Peptide 101-109/ HLA-B*4002
Peptide 124-133/ HLA-B*4002
Peptide 157-165/ HLA-A*0201
NY-ESO-1 peptide
Stimulation of NY-ESO-1 CD8+ T cell responses from patient SB
Takemasa Tsuji et al J Immunol. 2011, 186: 1218
2 weeks
CDX‐1401 (i.c.)
Poly ICLC (s.c.)R848 (topical or s.c.)
Repeat ifStable Disease
Treatment schedule
Cohort 10.1 mg CDX-1401 i.c.
500 g topical resiN = 9 / NY-ESO-1+ = 3
Cohort 21 mg CDX-1401 i.c.500 g topical resi
N = 8 / NY-ESO-1+ = 3
Cohort 33 mg CDX-1401 i.c.500 g topical resi
N = 6 / NY-ESO-1+ = 3
Cohort 61 mg CDX-1401 i.c.
500 g s.c. resi2 mg Poly ICLC s.c.
N = 6 / NY-ESO-1+ = 6
Cohort 51 mg CDX-1401 i.c.20-500 g s.c. resi
N = 7 / NY-ESO-1+ = 7
Cohort 41 mg CDX-1401 i.c.2 mg Poly ICLC s.c.
N = 5 / NY-ESO-1+ = 3
Advanced melanoma and other cancers 45 patients enrolled, no SAEs Of 38 pts analyzed, 12 pts with SD (up 13 Mo) 3 with documented tumor shrinkage
IFN- ELISPOT7 day IVS with
NY-ESO-1 peptide pool(control peptides subtracted)
Specimen_001_Tube_003 ESO pep.fcs
APC-A
Paci
fic B
lue-
A
101 102 103 104 105101
102
103
104
10529.14% 0.49%
69.81% 0.56%
Specimen_001_Tube_002 ctr pep.fcs
PE-Cy7-A
Paci
fic B
lue-
A
101 102 103 104 105101
102
103
104
10530.74% 0.05%
69.09% 0.13%
Specimen_001_Tube_003 ESO pep.fcs
PE-Cy7-A
Paci
fic B
lue-
A
101 102 103 104 105101
102
103
104
10529.46% 0.17%
70.11% 0.26%
IFN-
CD
8
Specimen_001_Tube_002 ctr pep.fcs
APC-A
Paci
fic B
lue-
A
101 102 103 104 105101
102
103
104
10530.60% 0.18%
69.01% 0.21%
TNF-
CD
8
NY-ESO-1 peptidesControl peptides
# CDX‐1401
Adjuvant Pre Post
1
0.1 mg
Topical Resi
2 3 4 5 6 7 8 1
1.0 mg
Topical Resi
2 3 4 5 6 7 1
3.0 mg
Topical Resi
2 3 4 1
1.0 mg
Poly ICLC2 3 4 5 1
1.0 mg
S.C. Resi
2 3 4 5 6 1
1.0 mg
S.C. Resi +
Poly ICLC
2 3 4 5 6
On-going
Member of the TNF-receptor superfamily (CD40, 4-1BB,OX-40)◦ Single ligand is CD70 (tightly regulated)◦ Constitutively expressed on most T cells and a subset of B and NK cells
Co-stimulatory molecule◦ Role in generation and long-term maintenance of T cell immunity◦ Role in NK cell differentiation/activation
CD27 activation:◦ Signaling through Traf2, Traf5◦ Activation of the NF-κB pathway◦ Cell survival, activation, proliferation
104 syngeneic CT26 cells inoculated s.c. in huCD27Tg mice on day 0Antibody treatment ‐ 600 g i.p. on days 3, 5, 7, 9, 11
1 11 21 31 41 51 61 71
mouse 11mouse 12mouse 13mouse 14mouse 15mouse 16mouse 17mouse 18mouse 19mouse 20
1 11 21 31
mouse 1mouse 2mouse 3mouse 4mouse 5mouse 6mouse 7mouse 8mouse 9mouse 10
Tum
or V
olum
e (c
m3)
Saline CDX‐1127
Days Days
3
2
1
0
3
2
1
00 11 22 33 44 55 66 77
mouse 21mouse 22mouse 23mouse 24mouse 25mouse 26mouse 27mouse 28mouse 29mouse 30
104 CT26 cells s.c. on day 0(day 99 relative to 1st inoculation)
1 11 21 31 41 51 61 71 81
mouse 11mouse 12mouse 13mouse 14mouse 15mouse 16mouse 17mouse 18
Re‐challenge
Days
3
2
1
0
3
2
1
0
Re‐challenge Controls
104 CT26 cells s.c. on day 0
Days
2000
3000
4000
1000Tum
or V
olum
e (m
m3 )
Days post tumor inoculation
No treatment
Control mAb, 0.1 mg/dose
CDX-1127 0.1 mg/doseCDX-1127 0.03 mg/dose
No treatment
Control mAb, 0.1 mg/dose
CDX-1127 0.1 mg/doseCDX-1127 0.03 mg/dose
5000
Treatment
CDX-1127 has direct efficacy on CD27-expressing human lymphoma cells in immuno-compromised (SCID) mice
Similar efficacy with other human B and T cell tumor lines- Daudi, Namalwa, CCRF-CEM
Xenograft model of human B lymphoblastic tumor cell line (Raji) in SCID mice
Flt3L: potent stem cell mobilizer and dendritic cell growth factor
Previous clinical studies (Immunex/Amgen) demonstrated safety and biological activity (>500 subjects dosed)
Program acquired from Amgen in 2009 Multiple clinical opportunities